Paternal Age and De Novo Single Gene Disorders ETC.

2010-03-19T15:26:00.000-07:00

Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta

2010-01-15T07:58:00.000-08:00

Journal of Medical Genetics 1986;23:227-230; doi:10.1136/jmg.23.3.227
Copyright © 1986 by the BMJ Publishing Group Ltd.
Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.
A D Carothers, S J McAllion, C R Paterson

The mean paternal age at birth of 80 presumed mutant cases of dominant osteogenesis imperfecta (OI) was significantly higher than that of population controls and remained so after adjusting for maternal age. There was also an increase in mean maternal age (not significant) which disappeared after adjusting for paternal age. No significant increase in maternal or paternal age was found in cases having OI either of a dominant type with an affected parent or of a type (Sillence type III) usually regarded as recessive. We conclude that, as in certain other dominant conditions, the risk of mutant OI increases with paternal age. However, the rate of increase of risk with paternal age appears to be considerably lower than, for example, in achondroplasia. The overall risk of fresh dominant mutation in older fathers may therefore be lower than has previously been suggested.

OVERVIEW ON PROGERIA: A RARE DISEASE OF CHILD Older Fathers and Mutation In Lamin A Gene

2009-12-31T08:35:00.000-08:00

OVERVIEW ON PROGERIA: A RARE DISEASE OF CHILD

Kamal Singh Rathore, Sunita P., Khushboo Sharma, R.K.Nema

Progeria is a rare disease, fatal genetic condition that produces rapid aging, beginning in childhood also known as “Hutchinson–Gilford progeria syndrome” or “HGPS” and “Hutchinson–Gilford syndrome” wherein symptoms resembling aspects of aging are manifested at an early age. Progeria was first described in an academic journal by Dr. Jonathan Hutchinson in 1886, and Dr. Hastings Gilford in 1897 – both in England.

Its name is derived from the Greek and means “prematurely old.” Approximately 1 in 4000000 people are diagnosed with this condition. Those born with progeria typically live about 13-20 years, It is a genetic condition that occurs as a new mutation and is not usually inherited, although there is a uniquely inheritable form. This is in contrast to another rare but similar premature aging syndrome, dyskeratosis congenita (DKC), which is inheritable and will often be expressed multiple times in a family line.

Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Progeria signs include growth failure, loss of body fat and hair, aged-looking skin, stiffness of joints, hip dislocation, generalized atherosclerosis, cardiovascular (heart) disease and stroke. The children have a remarkably similar appearance, despite differing ethnic background. Children with Progeria die of atherosclerosis (heart disease) at an average age of thirteen years (with a range of about 8 – 21 years). According to Hayley’s Page “At present there are 53 known cases of Progeria around the world and only 2 in the UK”. There is a reported incidence of Progeria of approximately 1 in every 4 to 8 million newborns. Both boys and girls run an equal risk of having Progeria.

Symptoms

Progeria is a progressive genetic disorder that causes children to age rapidly, beginning in their first two years of life. The condition is rare; since 1886, only about 130 cases of progeria have been documented in the scientific literature. Usually within the first year of life, growth of a child with progeria slows markedly so that height and weight fall below average for his or her age, and weight falls low for height. Motor development and mental development remain normal.

Signs and symptoms of this progressive disorder include:

Limited growth or Growth failure during the first year of life Narrow, shrunken or wrinkled face failure to thrive Baldness (alopecia) Insulin-resistant diabetes (diabetes that does not respond readily to insulin injections) Skin changes similar to that seen in scleroderma (the connective tissue becomes tough and hardened) Loss of eyebrows and eyelashes a distinctive appearance (small face and jaw, pinched nose) Short stature and small, fragile bodies, like those of elderly people Large head for size of face (macrocephaly) Open soft spot (fontanelle) Small jaw (micrognathia) Dry, scaly, thin skin Limited range of motion Teeth – delayed or absent formation Later, the condition causes wrinkled skin, atherosclerosis, and cardiovascular problems. Slowed growth, with below-average height and weight A narrowed face and beaked nose, which makes the child look old Head too large for face Prominent scalp veins Prominent eyes Small lower jaw (micrognathia) High-pitched voice Delayed and abnormal tooth formation Loss of body fat and muscle Stiff joints Hip dislocation

Causes

Progeria usually occurs without cause – it is not seen in siblings of affected children. In extremely rare cases more than one child in the same family may have the condition.

It is only very rarely seen in more than one child in a family. Progeria is a childhood disorder caused by a point mutation in position 1824 of the LMNA gene (Lamin A), replacing cytosine with thymine, creating an unusable form of the protein Lamin A. Lamin A is part of the building blocks of the nuclear envelope. 90% of children with progeria have a mutation on the gene that encodes the protein lamin A. a protein that holds the nucleus of the cell together. It is believed that the defective Lamin A protein makes the nucleus unstable. This instability seems to lead to the process of premature aging among Progeria patients.

Diagnosis

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test. The health care professional will possibly suspect Progeria if the signs and symptoms are there – aging skin, loss of hair, stiffness of joints, etc. This can then be confirmed through a genetic test. The Progeria Research Foundation has created a Diagnostic Testing Program.

No diagnostic test confirms progeria. Doctors typically make a diagnosis based on signs and symptoms, such as failure to grow and hair loss, which typically aren’t fully evident until your child is nearly 2. However, with the discovery of the genetic mutation that causes progeria, it’s possible to use genetic testing for LMNA mutations at the first suspicion of progeria. The sooner you know your child has progeria, the sooner your doctor can recommend treatments that may help ease the signs and symptoms of the disorder.

A blood test may reveal that your child has a low level of high-density lipoprotein (HDL) cholesterol, the so-called good cholesterol that helps keep arteries open. This laboratory finding isn’t diagnostic by itself, but may lend support to a diagnosis of progeria.

Treatment

No treatments have been proven effective.

Most treatment focuses on reducing complications (such as cardiovascular disease) with heart bypass surgery or low-dose aspirin. A daily dose may help prevent heart attacks and stroke. Growth hormone treatment has been attempted. Drugs known as farnesyltransferase inhibitors (FTIs), which were developed for treating cancer, have shown promise in laboratory studies in correcting the cell defects that cause progeria. FTIs are currently being studied in human clinical trials for treatment of progeria. it has been proposed, but their use has been mostly limited to animal models. A Phase II clinical trial using the FTI Lonafarnib began in May 2007. Physical and occupational therapy. These may help with joint stiffness and hip problems, and may allow your child to remain active. High-calorie dietary supplements. Including extra calories in your child’s daily diet may help prevent weight loss and ensure adequate nutrition. Feeding tube. Infants who feed poorly may benefit from a feeding tube and a syringe. You can use the syringe to push pumped breast milk or formula through the tube to make it easier for your child to feed. Extraction of primary teeth. Your child’s permanent teeth may start coming in before his or her baby teeth fall out. Extraction may help prevent problems associated with the delayed loss of baby teeth, including overcrowding and developing a second row of teeth when permanent teeth come in.

Prognosis

There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attack or stroke.

Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They do not develop physically mediated “wear and tear” conditions commonly associated with aging, like cataracts (caused by UV exposure) and osteoarthritis (caused by mechanical wear).

Epidemiology

Classical Hutchinson-Gilford Progeria Syndrome is almost never passed on from parent to child. It is usually caused by a new (sporadic) mutation during the early division of the cells in the child. It is usually genetically dominant; therefore, parents who are healthy will normally not pass it on to their children. Affected children rarely live long enough to have children themselves.

Research indicates that a chemical (hyaluronic acid) may be found in greatly elevated levels in the urine of Hutchinson-Gilford Progeria Syndrome patients. The same abnormality has been found in Werner Syndrome, which is sometimes called ‘progeria of the adult’.

Lamin A

Nuclear lamin A is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.

Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated and allows prelamin A to bind membranes, specifically the nuclear membrane. After prelamin A has been localized to the cell nuclear membrane, the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now lamin A, is no longer membrane-bound, and carries out functions inside the nucleus.

In 2003, NHGRI researchers, together with colleagues at the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities, and the University of Michigan, discovered that Hutchinson-Gilford progeria is caused by a tiny, point mutation in a single gene, known as lamin A (LMNA). Parents and siblings of children with progeria are virtually never affected by the disease. In accordance with this clinical observation, the genetic mutation appears in nearly all instances to occur in the sperm prior to conception. It is remarkable that nearly all cases are found to arise from the substitution of just one base pair among the approximately 25,000 DNA base pairs that make up the LMNA gene. The LMNA gene codes for two proteins, lamin A and lamin C, that are known to play a key role in stabilizing the inner membrane of the cell’s nucleus. In laboratory tests involving cells taken from progeria patients, researchers have found that the mutation responsible for Hutchinson-Gilford progeria causes the LMNA gene to produce an abnormal form of the lamin A protein. That abnormal protein appears to destabilize the cell’s nuclear membrane in a way that may be particularly harmful to tissues routinely subjected to intense physical force, such as the cardiovascular and musculoskeletal systems. Interestingly, different mutations in the same LMNA gene have been shown to be responsible for at least a half-dozen other genetic disorders, including two rare forms of muscular dystrophy. In addition to its implications for diagnosis and possible treatment of progeria, the discovery of the underlying genetics of this model of premature aging may help to shed new light on humans’ normal aging process.

Possible Complications

Heart attack (myocardial infarction)

Stroke

How we can help children with Progeria?

Make a financial contribution. Donations are needed to continue the vital work. No donation is too little or too big – every penny counts in our fight for a cure! Donate your time. Volunteers are also important to success. Hold a special event like a bake sale or letter writing campaign; translate documents for the families; help with a mailing – we’ll find something for you to do that fits your schedule, location and talents! Donate in-kind services or items. Do you own a printing or office supply business? Do you have a background in non-profit development? These are just some of the many types of talents and connections. The more tasks we can get accomplished on a pro bono basis, the more we can spend on research! Spread the word and tap into your connections. Do you know anyone who can do any of the above.

Care, Coping and support

Learning your child has progeria can be emotionally devastating. Suddenly you know that your child is facing numerous, difficult challenges and a shortened life span. For you and your family, coping with the disorder involves a major commitment of physical, emotional and financial effort. In dealing with a disorder such as progeria, support groups can be a valuable part of a wider network of social support that includes health care professionals, family and friends. In a support group, you’ll be with people who are facing challenges similar to the one that you are. Talking to group members can help you cope with your own feelings about your child’s condition. If a group isn’t for you, talking to a therapist or clergy member may be beneficial. Ask your doctor about self-help groups or therapists in your community. Your local health department, public library, telephone book and the Internet also may be good sources for finding a support group in your area.

Helping the child to cope

If your child has progeria, he or she is also likely to experience fear and grief as awareness grows that progeria shortens life span. Your child eventually will need your help coping with the concept of death, and may have a number of difficult but important questions about God and religion. Your child also may ask questions about what will happen in your family after he or she dies. It’s critical that you are able to talk openly and honestly with your child, and offer reassurance that’s compatible with your belief system. Ask your doctor, therapist or clergy member to help you prepare for such conversations with your child. Friends who you meet through support groups also may be able to offer valuable guidance.

Conclusion and General Discussion

Progeria, or Hutchinson-Gilford progeria syndrome, is a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Children with progeria usually have a normal appearance in early infancy. At approximately nine to 24 months of age, affected children begin to experience profound growth delays, resulting in short stature and low weight. They also develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small, nose; prominent eyes and a subtle blueness around the mouth. In addition, by the second year of life, the scalp hair, eyebrows, and eyelashes are lost (alopecia), and the scalp hair may be replaced by small, downy, white or blond hairs. Additional characteristic features include generalized atherosclerosis, cardiovascular disease and stroke, hip dislocations, unusually prominent veins of the scalp, loss of the layer of fat beneath the skin (subcutaneous adipose tissue), defects of the nails, joint stiffness, skeletal defects, and/or other abnormalities. According to reports in the medical literature, individuals with Hutchinson-Gilford progeria syndrome develop premature, widespread thickening and loss of elasticity of artery walls (arteriosclerosis), which result in life-threatening complications during childhood, adolescence, or early adulthood. Children with progeria die of heart disease (atherosclerosis) at an average age of 13 years, with a range of about eight to 21 years.

Progeria is caused by a mutation of the gene LMNA, or lamin A. The lamin A protein is the scaffolding that holds the nucleus of a cell together. Researchers now believe that the defective lamin A protein makes the nucleus unstable. That cellular instability appears to lead to the process of premature aging in progeria. Because neither parent carries or expresses the mutation, each case is believed to represent a sporadic, new mutation that happens most notably in a single sperm or egg immediately prior to conception.

REFERENCES

Ayres, S. C.; Mihan, R. : Progeria: a possible therapeutic approach. (Letter) JAMA 227: 1381-1382, 1974. Brown, W. T. : Human mutations affecting aging–a review. Mech. Aging Dev. 9: 325-336, 1979. Brown, W. T.; Abdenur, J.; Goonewardena, P.; Alemzadeh, R.; Smith, M.; Friedman, S.; Cervantes, C.; Bandyopadhyay, S.; Zaslav, A.; Kunaporn, S.; Serotkin, A.; Lifshitz, F. : Hutchinson-Gilford progeria syndrome: clinical, chromosomal and metabolic abnormalities. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A50 only, 1990. Brown, W. T.; Darlington, G. J. : Thermolabile enzymes in progeria and Werner syndrome: evidence contrary to the protein error hypothesis. Am. J. Hum. Genet. 32: 614-619, 1980. Brown, W. T.; Darlington, G. J.; Arnold, A.; Fotino, M. : Detection of HLA antigens on progeria syndrome fibroblasts. Clin. Genet. 17: 213-219, 1980. Cao, H.; Hegele, R. A. : LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J. Hum. Genet. 48: 271-274, 2003. Dahl, K. N.; Scaffidi, P.; Islam, M. F.; Yodh, A. G.; Wilson, K. L.; Misteli, T. istinct structural and mechanical properties of the nuclear lamina in Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 103: 10271-10276, 2006. DeBusk, F. L. : The Hutchinson-Gilford progeria syndrome. J. Pediat. 80: 697-724, 1972. De Martinville, B.; Sorin, M.; Briard, M. L.; Frezal, J. : Progeria de Gilford-Hutchinson a debut neonatal chez des jumeaux monozygotes. Arch. Fr. Pediat. 37: 679-681, 1980. de Paula Rodrigues, G. H.; das Eiras Tamega, I.; Duque, G.; Spinola Dias Neto, V. : Severe bone changes in a case of Hutchinson-Gilford syndrome. Ann. Genet. 45: 151-155, 2002. De Sandre-Giovannoli, A.; Bernard, R.; Cau, P.; Navarro, C.; Amiel, J.; Boccaccio, I.; Lyonnet, S.; Stewart, C. L.; Munnich, A.; Le Merrer, M.; Levy, N. : Lamin A truncation in Hutchinson-Gilford progeria. Science 300: 2055 only, 2003. Dyck, J. D.; David, T. E.; Burke, B.; Webb, G. D.; Henderson, M. A.; Fowler, R. S. : Management of coronary artery disease in Hutchinson-Gilford syndrome. J. Pediat. 111: 407-410, 1987. Erecinski, K.; Bittel-Dobrzynska, N.; Mostowiec, S. : Zespol progerii u dwoch braci. Pol. Tyg. Lek. 16: 806-809, 1961. Eriksson, M.; Brown, W. T.; Gordon, L. B.; Glynn, M. W.; Singer, J.; Scott, L.; Erdos, M. R.; Robbins, C. M.; Moses, T. Y.; Berglund, P.; Dutra, A.; Pak, E.; Durkin, S.; Csoka, A. B.; Boehnke, M.; Glover, T. W.; Collins, F. S. : Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature 423: 293-298, 2003. Faivre, L.; Van Kien, P. K.; Madinier-Chappat, N.; Nivelon-Chevallier, A.; Beer, F.; LeMerrer, M. : Can Hutchinson-Gilford progeria syndrome be a neonatal condition? (Letter) Am. J. Med. Genet. 87: 450-452, 1999. Fatunde, O. J.; Benka-Coker, L. B. O.; Scott-Emuakpor, A. B. : Familial occurrence of progeria (Hutchinson-Gilford progeria syndrome). (Abstract) Am. J. Hum. Genet. 47 (suppl.): A55 only, 1990. Fong, L. G.; Frost, D.; Meta, M.; Qiao, X.; Yang, S. H.; Coffinier, C.; Young, S. G. :A protein farnesyltransferase inhibitor ameliorates disease in a mouse model of progeria. Science 311: 1621-1623, 2006. Gabr, M.; Hashem, N.; Hashem, M.; Fahmi, A.; Safouh, M. : Progeria, a pathologic study. J. Pediat. 57: 70-77, 1960. Gilford, H. : Ateleiosis and progeria: continuous youth and premature old age. Brit. Med. J. 2: 914-918, 1904. Glynn, M. W.; Glover, T. W. : Incomplete processing of mutant lamin A in Hutchinson-Gilford progeria leads to nuclear abnormalities, which are reversed by farnesyltransferase inhibition. Hum. Molec. Genet. 14: 2959-2969, 2005. Goldman, R. D.; Shumaker, D. K.; Erdos, M. R.; Eriksson, M.; Goldman, A. E.; Gordon, L. B.; Gruenbaum, Y.; Khuon, S.; Mendez, M.; Varga, R.; Collins, F. S. : Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 101: 8963-8968, 2004. Goldstein, S.; Moerman, E. J. : Heat-labile enzymes in skin fibroblasts from subjects with progeria. New Eng. J. Med. 292: 1305-1309, 1975. Goldstein, S.; Moerman, E. J. : Heat-labile enzymes in circulating erythrocytes of a progeria family. Am. J. Hum. Genet. 30: 167-173, 1978. Harley, C. B.; Goldstein, S.; Posner, B. I.; Guyda, H. : Decreased sensitivity of old and progeric human fibroblasts to a preparation of factors with insulinlike activity. J. Clin. Invest. 68: 988-994, 1981. Hennekam, R. C. M. : Hutchinson-Gilford progeria syndrome: review of the phenotype. Am. J. Med. Genet. 140A: 2603-2624, 2006. Hutchinson, J. : Case of congenital absence of hair, with atrophic condition of the skin and its appendages, in a boy whose mother had been almost wholly bald from alopecia areata from the age of six. Lancet I: 923 only, 1886. Jones, K. L.; Smith, D. W.; Harvey, M. A. S.; Hall, B. D.; Quan, L. : Older paternal age and fresh gene mutation: data on additional disorders. J. Pediat. 86: 84-88, 1975. Khalifa, M. M. : Hutchinson-Gilford progeria syndrome: report of a Libyan family and evidence of autosomal recessive inheritance. Clin. Genet. 35: 125-132, 1989. Kirschner, J.; Brune, T.; Wehnert, M.; Denecke, J.; Wasner, C.; Feuer, A.; Marquardt, T.; Ketelsen, U.-P.; Wieacker, P.; Bonnemann, C. G.; Korinthenberg, R. : p.S143F mutation in lamin A/C: a new phenotype combining myopathy and progeria. Ann. Neurol. 57: 148-151, 2005. Labeille, B.; Dupuy, P.; Frey-Follezou, I.; Larregue, M.; Maquart, F. X.; Borel, J. P.; Gallet, M.; Risbourg, B.; Denceux, J. P. : Progeria de Hutchinson-Gilford neonatale avec atteinte cutanee sclerodermiforme. Ann. Derm. Venerol. 114: 233-242, 1987. Lewis, M. : PRELP, collagen, and a theory of Hutchinson-Gilford progeria. Ageing Res. Rev. 2: 95-105, 2003. Luengo, W. D.; Martinez, A. R.; Lopez, R. O.; Basalo, C. M.; Rojas-Atencio, A.; Quintero, M.; Borjas, L.; Morales-Machin, A.; Ferrer, S. G.; Bernal, L. P.; Canizalez-Tarazona, J.; Pena, J.; Luengo, J. D.; Hernandez, J. C.; Chang, J. C. : Del(1)(q23) in a patient with Hutchinson-Gilford progeria. Am. J. Med. Genet. 113: 298-301, 2002. Maciel, A. T. : Evidence for autosomal recessive inheritance of progeria (Hutchinson Gilford). Am. J. Med. Genet. 31: 483-487, 1988. Mallampalli, M. P.; Huyer, G.; Bendale, P.; Gelb, M. H.; Michaelis, S. : Inhibiting farnesylation reverses the nuclear morphology defect in a HeLa cell model for Hutchinson-Gilford progeria syndrome. Proc. Nat. Acad. Sci. 102: 14416-14421, 2005. McKusick, V. A. : The clinical observations of Jonathan Hutchinson. Am. J. Syph. 36: 101-126, 1952. Merideth, M. A.; Gordon, L. B.; Clauss, S.; Sachdev, V.; Smith, A. C. M.; Perry, M. B.; Brewer, C. C.; Zalewski, C.; Kim, H. J.; and 13 others : Phenotype and course of Hutchinson-Gilford progeria syndrome. New Eng. J. Med. 358: 592-604, 2008. Moulson, C. L.; Fong, L. G.; Gardner, J. M.; Farber, E. A.; Go, G.; Passariello, A.; Grange, D. K.; Young, S. G.; Miner, J. H. : Increased progerin expression associated with unusual LMNA mutations causes severe progeroid syndromes. Hum. Mutat. 28: 882-889, 2007. Ogihara, T.; Hata, T.; Tanaka, K.; Fukuchi, K.; Tabuchi, Y.; Kumahara, Y. : Hutchinson-Gilford progeria syndrome in a 45-year-old man. Am. J. Med. 81: 135-138, 1986. Parkash, H.; Sidhu, S. S.; Raghavan, R.; Deshmukh, R. N. : Hutchinson-Gilford progeria: familial occurrence. Am. J. Med. Genet. 36: 431-433, 1990. Plasilova, M.; Chattopadhyay, C.; Pal, P.; Schaub, N. A.; Buechner, S. A.; Mueller, H.; Miny, P.; Ghosh, A.; Heinimann, K. : Homozygous missense mutation in the lamin A/C gene causes autosomal recessive Hutchinson-Gilford progeria syndrome. J. Med. Genet. 41: 609-614, 2004. Rautenstrauch, T.; Snigula, F.; Krieg, T.;

Advancing paternal age is associated with deficits in social and exploratory behaviors in the offspring: a mouse model.

2009-12-31T08:27:00.000-08:00

PLoS One. 2009 Dec 30;4(12):e8456.

Advancing paternal age is associated with deficits in social and exploratory behaviors in the offspring: a mouse model.
Smith RG, Kember RL, Mill J, Fernandes C, Schalkwyk LC, Buxbaum JD, Reichenberg A.

Medical Research Council Social Genetic and Developmental Psychiatry Centre, King's College London, London, United Kingdom.

BACKGROUND: Accumulating evidence from epidemiological research has demonstrated an association between advanced paternal age and risk for several psychiatric disorders including autism, schizophrenia and early-onset bipolar disorder. In order to establish causality, this study used an animal model to investigate the effects of advanced paternal age on behavioural deficits in the offspring. METHODS: C57BL/6J offspring (n = 12 per group) were bred from fathers of two different ages, 2 months (young) and 10 months (old), and mothers aged 2 months (n = 6 breeding pairs per group). Social and exploratory behaviors were examined in the offspring. PRINCIPAL FINDINGS: The offspring of older fathers were found to engage in significantly less social (p = 0.02) and exploratory (p = 0.02) behaviors than the offspring of younger fathers. There were no significant differences in measures of motor activity. CONCLUSIONS: Given the well-controlled nature of this study, this provides the strongest evidence for deleterious effects of advancing paternal age on social and exploratory behavior. De-novo chromosomal changes and/or inherited epigenetic changes are the most plausible explanatory factors.

PMID: 20041141 [PubMed - in process]

Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1

2009-11-27T06:23:00.000-08:00

Clin Dysmorphol. 2009 Nov 24. [Epub ahead of print]

Limb malformations with associated congenital constriction rings in two unrelated Egyptian males, one with a disorganization-like spectrum and the other with a probable distinct type of septo-optic dysplasia.
Temtamy SA, Aglan MS, Ashour AM, El-Badry TH.

Departments of aClinical Genetics bOrodental Genetics, Division of Human Genetics and Genome Research, National Research Centre, Cairo, Egypt.

In this report, we describe two unrelated Egyptian male infants with limb malformations and constriction rings. The first case is developing normally but has severe limb anomalies, congenital constriction rings, scoliosis because of vertebral anomalies, a left accessory nipple, a small tumor-like swelling on his lower back with tiny skin tubular appendages, a hypoplastic scrotum, and an anchored penis. The second case is developmentally delayed with limb malformations, congenital constriction rings, a lumbar myelomeningeocele, hemangioma, and tiny tubular skin appendages on the back. The patient also had bilateral optic atrophy. The constellation of features in our patients cannot be fully explained by the amniotic disruption complex. The first patient may represent an additional case of the human homolog of the mouse disorganization mutant. The presence of bilateral optic atrophy in the second case, although without an absent septum pellucidum nor other brain anomalies resembles the infrequently reported disorder of septo-optic dysplasia with limb anomalies. Both cases were sporadic and could be caused by a new dominant mutation because of the high paternal age of case 1 and the history of paternal occupational exposure to heat for both fathers. We draw attention to the phenotypic overlap between the disorganization-like syndrome and septo-optic dysplasia with limb anomalies.

PMID: 19940763 [PubMed - as supplied by publisher]

2009-02-21T18:34:00.001-08:00

1: Paediatr Perinat Epidemiol. 2009 Jan;23(1):29-40.
Parental age as a risk factor for isolated congenital malformations in a Polish population.
Materna-Kiryluk A, Wiśniewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Boroń A, Czerwionka-Szaflarska M, Gajewska E, Godula-Stuglik U, Krawczyński M, Limon J, Rusin J, Sawulicka-Oleszczuk H, Szwalkiewicz-Warowicka E, Walczak M, Latos-Bieleńska A.
Department of Medical Genetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
Summary Materna-Kiryluk A, Wiśniewska K, Badura-Stronka M, Mejnartowicz J, Wieckowska B, Balcar-Boroń A, Czerwionka-Szaflarska M, Gajewska E, Godula-Stuglik U, Krawczyński M, Limon J, Rusin J, Sawulicka-Oleszczuk H, Szwalkiewicz-Warowicka E, Walczak M, Latos-Bieleńska A. Parental age as a risk factor for isolated congenital malformations in a Polish population. Paediatric and Perinatal Epidemiology 2009; 23: 29-40.Currently available data on the relationship between the prevalence of isolated congenital malformations and parental age are inconsistent and frequently divergent. We utilised the data from the Polish Registry of Congenital Malformations (PRCM) to accurately assess the interplay between maternal and paternal age in the risk of isolated non-syndromic congenital malformations. Out of 902 452 livebirths we studied 8683 children aged 0-2 years registered in the PRCM. Logistic regression was used to simultaneously adjust the risk estimates for maternal and paternal age. Our data indicated that paternal and maternal age were independently associated with several congenital malformations. Based on our data, young maternal and paternal ages were independently associated with gastroschisis. In addition, young maternal age, but not young paternal age, carried a higher risk of neural tube defects. Advanced maternal and paternal ages were both independently associated with congenital heart defects. Moreover, there was a positive association between advanced paternal age and hypospadias, cleft palate, and cleft lip (with or without cleft palate). No significant relationships between parental age and the following congenital malformations were detected: microcephaly, hydrocephaly, oesophageal atresia, atresia or stenosis of small and/or large intestine, ano-rectal atresia or stenosis, renal agenesis or hypoplasia, cystic kidney disease, congenital hydronephrosis, diaphragmatic hernia and omphalocele.
PMID: 19228312 [PubMed - in process]

Why are the wealthy corporate monied families in America funding the research at genome labs?

2009-02-20T08:15:00.000-08:00

Why are the wealthy corporate monied families in America funding the research at genome labs?

Alex asked: Are genetic disease and disorders caused by older paternal age and will there never be cures or for Alzheimer’s, diabetes, MS, hemophilia, autism, schizophrenia,cancers because in non-familial cases they are basic degradations of the human genome caused by genetic copy number variations?

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Men also have a biological clock

2009-01-21T14:40:00.000-08:00

Men also have a biological clock
Published: Jan. 21, 2009 at 4:04 PMOrder reprints | Feedback
VALENCIA, Spain, Jan. 21 (UPI) -- Mammalian males can reproduce until late in life, but their children may have more abnormalities, researchers in Spain said.

Although mammalian males can reproduce until late in life, evidence of hazards to offspring has emerged in human and animal models, the researchers said.

Silvia Garcia-Palomares of the University of Valencia in Spain and colleagues said that their study, published in the Biology of Reproduction, provides clear, well-controlled data of deleterious effects on the offspring of aged male mice mated to females of prime reproductive age.

The offspring from the elderly males exhibit abnormalities not only in several behavioral traits, but also in reproductive fitness and longevity -- the offspring fathered by old mice had a shorter life span.

Moreover, mating the offspring from aged males resulted in the production of pups exhibiting decreased weights at weaning when compared with pups from the offspring of younger males.

Garcia-Palomares said the defects causing these abnormalities in offspring are unknown and should be the objective of intriguing studies in the future.

Older men are having children, but the reality of a male biological clock makes this trend worrisome

2009-01-15T22:14:00.000-08:00

Older men are having children, but the reality of a male biological clock makes this trend worrisome
Feature Article
Publish date: Jan 15, 2009
By: Harry Fisch, MD
Source: Geriatrics

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Dr Fisch is Professor of Clinical Urology, Department of Urology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York City.
Disclosure: The author states that he has no financial relationship with any manufacturers in this area of medicine.
ABSTRACT

Couples are waiting longer to have children, and advances in reproductive technology are allowing older men and women to consider having children. The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. The age-related changes associated with the male biological clock affect sperm quality, fertility, hormone levels, libido, erectile function, and a host of non-reproductive physiological issues. This article focuses on the potentially adverse effects of the male biological clock on fertility in older men. Advanced paternal age increases the risk for spontaneous abortion as well as genetic abnormalities in offspring due to multiple factors, including DNA damage from abnormal apoptosis and reactive oxygen species. Increased paternal age is also associated with a decrease in semen volume, percentage of normal sperm, and sperm motility. Older men considering parenthood should have a thorough history and physical examination focused on their sexual and reproductive capacity. Such examination should entail disclosure of any sexual dysfunction and the use of medications, drugs, or lifestyle factors that might impair fertility or sexual response. Older men should also be counseled regarding the effects of paternal age on spermatogenesis and pregnancy.
Fisch H. The aging male and his biological clock. Geriatrics. 2009;64(1):14-17.
Keywords: apoptosis, hypogonadism, male biological clock, male infertility, paternal age, spermatogenesis, testosterone
The phrase "biological clock" commonly refers to the declining fertility, increasing risk for fetal birth defects, and altered hormone levels experienced by women as they age. Abundant scientific evidence suggests that men also have a biological clock.1,2 The hormonal and physiological effects of the male clock are linked with testosterone and fertility declines, as well as pregnancy loss and an increased risk of birth defects.3 In this article, we review the effects of the male biological clock, and the association between advanced paternal age and decreased spermatogenesis, pregnancy rates, and birth outcomes.
Male testosterone levels (both total and free) decline roughly 1% per year after age 30.4 The rate of decline in one study4 was not significantly different between healthy men and those with chronic illnesses or multiple comorbidities. This decline can shift men whose testosterone levels are in the low end of the normal spectrum to levels considered below-normal, or hypogonadal (testosterone <325 ng/mL) as they age. An estimated 2 to 4 million men in the United States fall in this category, either from age-related declines, illness, injury, or congenital conditions.5 The population of hypogonadal men is increasing due both to the aging of the general population and unknown factors that appear to be suppressing the average levels of testosterone in more recent birth cohorts.6 The increasing prevalence of abnormally low testosterone levels in elderly men was demonstrated in the Baltimore Longitudinal Study on Aging, which determined that hypogonadal testosterone levels were present in approximately 20% of men over 60, 30% over 70, and 50% over 80 years of age.7
Sub-normal testosterone levels are associated not only with decrements in fertility and sexual response, but also a wide range of other health problems such as declines in muscle mass/strength, energy levels, and cognitive function, as well as increased incidence of weight gain (particularly central adiposity), type 2 diabetes, the metabolic syndrome, and cardiovascular disease. Testosterone replacement therapy to address the wide range of health problems related to hypogonadism is becoming increasingly popular. Delivery via gels or transdermal patches can result in physiologically normal levels of testosterone, which is preferable to the spiky levels obtained via testosterone injections. Oral formulations are under development but none have progressed beyond the clinical trial phase. Fears that testosterone replacement therapy may promote the growth of prostate carcinomas has abated in light of findings from several studies that find no such link.8

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Declining fertility and increasing birth defects
It has long been recognized that female fertility declines with age and, obviously, ceases with menopause. Only relatively recently, however, has it been proven that male fertility also declines with age—often significantly so—and that semen quality and the related risk for birth defects is also sensitive to aging. Studies demonstrate that men older than age 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) as men younger than 25 years.9 Among couples undergoing fertility treatments with intra-uterine insemination, the amount of time necessary to achieve a pregnancy rises significantly with the age of the male. Further, after controlling for maternal age, couples in which the male is older than 35 have a 50% lower pregnancy rate compared with couples in which men are 30 or younger.10
The risk of birth defects is also now known to be related to paternal age. A significant association has been found between advancing paternal age and the risk of autism spectrum disorder (ASD) in children.11 Offspring of men 40 years or older were 5.75 times more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age.

Another study finds a link between paternal age and a higher risk of fathering a child with schizophrenia.12 Men older than 40 were more than twice as likely to have a child with schizophrenia as men in their 20s. A similar influence of paternal age on the risk of having a child with Down syndrome has been reported by several research teams,1 with paternal age a factor in half the cases of Down syndrome when maternal age exceeded 35 years. Other investigators have found that the rate of miscarriages increases with rising paternal age when maternal age was older than 35.13 Thus, there is convincing evidence for an effect of paternal age alone, as well as a combined effect of advancing paternal and maternal age, on increased risks of genetic abnormalities leading to miscarriage or disease in their children. A retrospective multi-center European study revealed that the effects of advanced paternal age and maternal age are cumulative. If both partners are advanced in age, the risk of spontaneous abortion is higher.
Mechanisms behind biological clock effects
The precise genetic and physiological malfunctions underlying the observed links between advanced paternal age and congenital abnormalities remain uncertain although clues have been discovered in recent years. Studies in the murine model, for example, have shown that changes in testicular architecture affect semen quality. At 18 months (defined as "older" in a mouse), several age-related changes occur, including increased number of vacuoles in germ cells and thinning of the seminiferous epithelium. At the age of 30 months, seminiferous epithelia with scant spermatocytes were identified. Overall, total sperm production was significantly reduced and mutation frequency was significantly increased in "older" mice.14
Such changes in testicular architecture, as well as changes in the germinal epithelium, prostatic epithelium, and a host of genetic alterations, undoubtedly underlie the well-documented declines in human semen parameters observed over the years. The literature (11 of 16 published studies) clearly shows, for example, a decrease in semen volume with advanced age. In 2 studies, which adjusted for the confounder of abstinence duration, a decrease in semen volume of 0.15-0.5% was reported for each increase in year of age.15 The semen volume of men aged 50 or older was decreased by 20-30% when compared with men younger than age 30. An association between advanced paternal age and decreased sperm motility is also apparent. In a review of 19 studies, 13 found a decrease in sperm motility with increasing age. Five studies adjusted for the duration of abstinence—a key potential confounder—and found statistically significant declines. A comparison of men age 50 or older to men younger than 30, revealed a 3% to 37% decline in motility.
Abnormal sperm morphology is also tied to advanced paternal age. In 14 studies reviewed, 9 studies found decreases in the percentage of normal sperm with advancing age with the rates of decline ranging from 0.2% per year to 0.9% per year of age when controlling for confounders of duration of abstinence and year of birth.16

Older men are having children, but the reality of a male biological clock makes this trend worrisomeFeature Article
Publish date: Jan 15, 2009
By: Harry Fisch, MD
Source: Geriatrics

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The male biological clock also "ticks" at the level of genes. The genetic integrity of sperm has been shown in several studies to decline with age. For example, age is associated with declines in the number of Leydig and Sertoli cells, as well as with an increase in arrested division of germ cells. There also seems to be an increasing failure of the body's ability to "weed out" genetically inferior sperm cells via the mechanism of apoptosis. Spermatozoa are continuously produced and undergo lifelong replication, meiosis, and spermatogenesis. An essential aspect of spermatogenesis that ensures selection of normal DNA is the process of apoptosis of sperm with damaged DNA. Since the rate of genetic abnormalities (such as double-strand breaks) during spermatogenesis increases as men age, the rate of apoptosis should rise as well. This, however, does not seem to be the case, for reasons that remain unknown, which results in higher levels of genetically damaged sperm in older men.
Oxidative stress may also play a role in the observed rise in the frequency of numerical and structural aberrations in sperm chromosomes with increasing paternal age. Spermatozoa have low concentrations of antioxidant scavenging enzymes, which makes them particularly susceptible to DNA damage from reactive oxygen species. A recent study found that seminal reactive oxygen species levels are significantly elevated in men older than 40 years of age.17
Aneuploidy errors in germ cell lines also occur at higher rates with advancing paternal age. The aneuploidy error of trisomy 21, for example, is responsible for Down syndrome. The rate of many autosomal dominant disorders such as Apert syndrome, achrondroplasia, osteogenesis imperfecta, progeria, Marfan syndrome, Waardenburg syndrome, and thanatophoric dysplasia increases with advanced paternal age. Apert syndrome, for example, is the result of an autosomal dominant mutation on chromosome 10, mutating fibroblast growth factor receptor 2 (FGFR2). With increasing paternal age, the incidence of sporadic Apert syndrome increases exponentially, resulting in part from an increased frequency of FGFR2 mutations in the sperm of older men.

The role of medications and comorbidities
The effects of the male biological clock can be exacerbated by both medications and comorbidities. Pharmacologically mediated fertility declines and/or sexual dysfunction has been demonstrated for antihypertensive drugs, antidepressants, and hormonal agents. Seminal emission can be blocked by alpha blocker medications, which are used to treat many symptoms of the lower urinary tract. Gonadotropin-releasing hormone agonists, which are used for prostate cancer treatment, can directly affect sperm production and testosterone levels. High doses of anabolic steroids, sometimes used for enhancement of performance and muscle enlargement, cause reduction of sperm production, which may be permanent. Erectile dysfunction, ejaculatory disorders, and decreased libido can be caused by the 5-alpha reductase inhibitors.
Sexual function and reproductive function can substantially decline in males treated for prostate cancer. Treatments such as radiotherapy, surgery or hormones, alone or in combination, can result in these dysfunctions in treated men of any age, though the severity of effects increases with age. A report found that ultrasound-guided needle biopsy of the prostate was associated with some abnormal semen parameters.18 Since prostate biopsy is more common in men 50 or older, this can be an issue for older would-be fathers.
Conclusions
The fact that men and women are waiting longer to have children, and that advances in reproductive technology are allowing older men and women to consider having children, carries a generally unrecognized public health risk in the form of increased infertility and risk for birth defects and other reproductive problems. CDC birth statistics show the average maternal age rose from 21.4 years of age in 1974 to 25.1 years of age in 2003. Paternal age is rising as well.
The lack of appreciation among both medical professionals and the lay public for the reality of a male biological clock makes these trends worrisome. This article has demonstrated a host of potential reproductive problems among older men. Semen parameters as well as semen genetic integrity decline with age, which leads to an increased risk for spontaneous abortion as well as genetic abnormalities in offspring. The decreasing apoptotic rate and increase in reactive oxygen species among the rapidly replicating spermatogonia are possible mechanisms behind an amplification of errors in germ cell lines of older men. Such errors may account for the observed increases in Down syndrome, schizophrenia, and autosomal dominant disorders in children born to older fathers.
Older men are having children, but the reality of a male biological clock makes this trend worrisomeFeature Article
Publish date: Jan 15, 2009
By: Harry Fisch, MD
Source: Geriatrics

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Future research may elucidate in greater detail the etiology and manifestation of the male biological clock in older men. Novel methods to reverse or slow the clock may be discovered by improved understanding of the cellular and biochemical mechanisms of gonadal aging. This research may diminish potential adverse genetic consequences in offspring and increase the chances that older couples will have a healthy child.
References
1. Fisch H, Hyun G, Golden R, et al. The influence of paternal age on Down syndrome. J Urol. 2003:169(6):2275-2278.

2. Eskenazi B, Wyrobek AJ, Sloter E, et al. The association of age and semen quality in healthy men. Hum Reprod. 2003;18(2):447-454.
3. Lewis BH, Legato M, Fisch H. Medical implications of the male biological clock. JAMA. 2006;296(19):2369-2371.
4. Feldman HA, Longcope C, Derby CA, et al. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002;87(2):589-598.
5. Rhoden EL, Morgentaler A. Risks of testosterone-replacement therapy and recommendations for monitoring. N Engl J Med. 2004;350(5):482-492.
6. Travison TG, Araujo AB, O'Donnell AB, et al. A population-level decline in serum testosterone levels in American men. J Clin Endocrinol Metab. 2007;92(1):196-202.
7. Harman SM, Metter EJ, Tobin JD, et al. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001;86(2):724-731.
8. Imamoto T, Suzuki H, Yano M, et al. The role of testosterone in the pathogenesis of prostate cancer. Int J Urol. 2008;15(6):472-480.
9. Ford WC, North K, Taylor H, et al. Increasing paternal age is associated with delayed conception in a large population of fertile couples: evidence for declining fecundity in older men. Hum Reprod. 2000;15(8):1703-1708.
10. Mathieu C, Ecochard R, Bied V. Cumulative conception rate following intrauterine artificial insemination with husband's spermatozoa: influence of husband's age. Hum Reprod. 1995;10(5):1090-1097.
11. Reichenberg A, Gross R, Weiser M, et al. Advancing Paternal Age and Autism. Arch Gen Psychiatry. 2006;63(9):1026-1032.
12. Malaspina D, Harlap S, Fennig S, et al. Advancing Paternal Age and the Risk of Schizophrenia. Arch Gen Psychiatry. 2001;58(4):361-367.
13. de la Rochebrochard E, Thonneau P. Paternal age and maternal age are risk factors for miscarriage: results of a multicentre European study. Hum Reprod. 2002;17(6):1649-1656.
14. Walter CA, Intano GW, McCarrey JR, et al. Mutation frequency declines during spermatogenesis in young mice but increases in old mice. Proc Natl Acad Sci. 1998;95(17):10015-10019.
15. Andolz P, Bielsa MA, Vila J. Evolution of semen quality in North-eastern Spain: a study in 22,759 infertile men over a 36 year period. Hum Reprod. 1999;14(3):731-735.
16. Auger J, Kunstmann JM, Czyglik F, et al. Decline in semen quality among fertile men in Paris during the past 20 years. N Engl J Med. 1995;332(5):281-285.
17. Cocuzza M, Athayde KS, Agarwal A, et al. Age-related increase of reactive oxygen species in neat semen in healthy fertile men. Urology. 2008;71(3):490-494.
18. Manoharan M, Ayyathurai R, Nieder AM, Soloway MS. Hemospermia following transrectal ultrasound-guided prostate biopsy: a prospective study. Prostate Cancer Prostatic Dis. 2007;10(3):283-287.
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Older paternal age and fresh gene mutation: data on additional disorders

2008-12-05T08:24:00.000-08:00

Pediatr. 1975 Jan;86(1):84-8.Related Articles, Links
Older paternal age and fresh gene mutation: data on additional disorders.

Jones KL, Smith DW, Harvey MA, Hall BD, Quan L.

Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown.

Publication Types:
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

PMID: 1110452 [PubMed - indexed for MEDLINE]

Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?

2008-12-01T10:37:00.001-08:00

Rev Epidemiol Sante Publique. 2005 Nov;53 Spec No 2:2S47-55.Related Articles, Links
Paternal age: are the risks of infecundity and miscarriage higher when the man is aged 40 years or over?

De La Rochebrochard E, Thonneau P.

Unité Inserm-Ined 569, Hôpital de Bicêtre, 82, rue du Général-Leclerc, 94276 Le Kremlin-Bicêtre. roche@ined.fr

BACKGROUND: Maternal age of 35 years or over is a well-known risk factor for human reproduction that has been extensively investigated by demographers and epidemiologists. However, the possibility of a paternal age effect has rarely been considered. We carried out review of the literature to investigate the effect of paternal age on the risks of infecundity and miscarriage. METHODS: We carried out a MEDLINE search and checked the exhaustiveness of our reference list. RESULTS: We identified 19 articles analysing the effect of paternal age. Epidemiological studies provided evidence that paternal age older than 35-40 years affects infecundity. However, the few studies based on data from assisted reproductive techniques (especially IVF with ovum donation) do not confirm this finding. All studies analysing the effect of paternal age on the risk of miscarriage showed an increased risk in men aged 35-40 years or over. Other studies have shown some evidence for a paternal age effect on late foetal deaths. CONCLUSION: The risks of infecundity and miscarriage increase with paternal age. Two main hypotheses can be considered. First, these risks increase after the age of 35-40 years. However, a later paternal age effect (after 45-50 years) cannot be excluded. Second, due to the interaction of the ages of the two partners, the risks of infecundity and miscarriage may be higher when both partners are older (woman aged 35 years or over and man aged 40 years or over).

Publication Types:
Review

PMID: 16471144 [PubMed - indexed for MEDLINE]

Sperm DNA Damage: Correlation To Severity Of Semen Abnormalities

2008-11-25T06:30:00.000-08:00

Sperm DNA Damage: Correlation To Severity Of Semen Abnormalities
Main Category: Fertility
Also Included In: Urology / Nephrology; Genetics
Article Date: 24 Nov 2008 - 1:00 PST

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SAN FRANCISCO, CA, USA (UroToday.com) - Evaluation of male fertility includes assessment of the standard semen parameters (SSP) and may include assessment of DNA damage. However, the relationship between DNA damage and SSP remains controversial. This study examined the the relationship of DNA damage to SSP in patients presenting for infertility evaluation.

The authors conducted an IRB approved retrospective review of semen samples from 2586 unselected non-azoospermic patients underwent computer-assisted semen analysis and flow cytometry based sperm DNA damage assessment expressed as the DNA Fragmentation Index (DFI). DFI was significantly negatively correlated to sperm concentration, motility, and normal morphology and positively correlated to age (P<0.001). DNA damage increased in relationship to the number of abnormalities in the SSP (P <0.001).

The authors concluded:

1. DNA damage is significantly related to standard parameters of semen analysis
2. DNA damage is significantly related to age
3. The degree of DNA damage increases with the number of abnormal parameters in a sample and is most severe in patients with oligo-astheno-teratospermia (OAT).

Editorial Comments:

The authors demonstrate the relationship between progressively more abnormal semen parameters and abnormal DFI. This is consistent with clinical observations and does not appear to demonstrate any incremental value to DFI assessment, in clinical practice, in the initial assessment of the infertile male.

Presented by S. I. Moskovtsev, J. Willis, and J. White, et al., at the 64th Annual Meeting of the American Society for Reproductive Medicine - November 8 - 12, 2008 - San Francisco, California

Reported by UroToday.com Contributing Editor Harris M. Nagler, MD

UroToday - the only urology website with original content written by global urology key opinion leaders actively engaged in clinical practice.

To access the latest urology news releases from UroToday, go to: www.urotoday.com

Copyright © 2008 - UroToday

His advice? "If my son or daughter was to ask, I'd tell them to have kids early -- and that's before 30."

2008-11-08T09:36:00.000-08:00

Yo, dude, check your bio clock -- now
New studies warn that it isn't just women who become less fertile as they age
Sarah Treleaven , The Ottawa Citizen
Recently, I've had a lot of conversations about baby-making with my male friends.

"I worry that I might be too selfish to ever have children," said my friend Joe, 29, somewhat pensively over gin and cucumber cocktails. Ditto for Colin, who just broke up with a woman he loves because she wants to have kids in the next few years and, at 35, he just doesn't feel ready yet. Kids or no, they both feel like they have all the time in the world to decide.

I, on the other hand, just turned 30 and have been making a lot of jokes about needing an apartment with a second bedroom for my soon-to-be-frozen eggs.

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Font:****Lots of women wring their hands about having a baby. Not only do we have to worry about our plummeting fertility (which begins to tank in our mid-20s), but we also have to worry about job retention and advancement once those kids (come biology, adoption or surrogacy) eventually appear. And it's the physical limitations of the female ability to procreate that have placed such a heavy emphasis on the reproductive biological clock, shaping the way many women live, work and even date.

But evidence is increasingly emerging that men, too, have a reproductive biological clock -- and that it ticks much more loudly than most of us have thought. Even as stories occasionally emerge about septuagenarian and octogenarian men becoming proud papas -- author Saul Bellow, for example, fathered a child at 84 -- several recent studies are challenging the conventional wisdom that men have an invincible ability to procreate.

A French study released in July found that women's pregnancy rates drop and miscarriages increase when the mother is over 35 and the father is over 40. Another study suggests that a man's fertility begins to decrease as early as his 20s. Researchers from the University of California at Berkeley and the Lawrence Livermore National Laboratory tested men between the ages of 22 and 80, and found that semen volume and sperm motility were both significantly compromised by aging.

Additionally, the increased odds for older fathers producing genetic abnormalities have been well documented, and studies have demonstrated that fathers over 40 are six times more likely to produce an autistic child than fathers under 30.

The numbers related to schizophrenia are similarly compelling. A study utilizing health databases in Jerusalem found that fathers over 40 were twice as likely to produce schizophrenic children as fathers who were under 25; for fathers over 50, the odds tripled when compared to fathers who were under 25.

Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center and the author of The Male Biological Clock, says that he's been ringing the alarm bell for years.

"There's a female biological clock; we all agree on the decline in fertility, more genetic problems and a decline in estrogen.

"The same thing happens in men -- a little bit differently, but essentially the same," Fisch says. "Why is it important? Well, demographically more men and women are waiting until they're over 30 to have a baby."

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Seasonal Affective Disorder May Be Linked to Genetic Mutation,

2008-10-31T13:23:00.000-07:00

Seasonal Affective Disorder May Be Linked to Genetic Mutation, Study Suggests
October 30, 2008 - With the days shortening toward winter, many people will begin to experience the winter blahs. For some, the effect can be devastating. About 6 percent of the U.S. population suffers from seasonal affective disorder, or SAD, a sometimes-debilitating depression that begins in the fall and continues through winter. Sufferers may even find it difficult to get out of bed in the morning.

(Media-Newswire.com) - October 30, 2008 — With the days shortening toward winter, many people will begin to experience the winter blahs. For some, the effect can be devastating.

About 6 percent of the U.S. population suffers from seasonal affective disorder, or SAD, a sometimes-debilitating depression that begins in the fall and continues through winter. Sufferers may even find it difficult to get out of bed in the morning.

• Ignacio Provencio discusses Seasonal Affective Disorder

The disorder, which is not well understood, is often treated with "light therapy," where a SAD patient spends time each morning before a bank of bright lights in an effort to trick the brain into believing that the days are not so short or dim.

A new study indicates that SAD may be linked to a genetic mutation in the eye that makes a SAD patient less sensitive to light.

"These individuals may require brighter light levels to maintain normal functioning during the winter months," said Ignacio Provencio, a University of Virginia biology professor who studies the genetics of the body's biological clock, or circadian rhythms.

Provencio and his colleagues have discovered that melanopsin, a photopigment gene in the eye, may play a role in causing SAD in people with a recently discovered mutation.

"We believe that the mutation could contribute to increasing the amount of light needed for normal functioning during winter for people with SAD," Provencio said. "Lack of adequate light may be a trigger for SAD, but not the only explanation for the disorder."

The findings are published in the online edition of the Journal of Affective Disorders, and will appear later in the print version.

The study was conducted with several other institutions, including the National Institute of Mental Health. It involved 220 participants, 130 of whom had been diagnosed with SAD and 90 participants with no history of mental illness.

Using a genetics test, the study authors found that seven of the 220 participants carried two copies of the mutation that may be a factor in causing SAD, and, strikingly, all seven belonged to the SAD group.

"While a person diagnosed with SAD does not necessarily carry the melanopsin mutation, what we found strongly indicates that people who carry the mutation could very well be diagnosed with SAD," Provencio said. "We think that if an individual has two copies of this gene, he or she has a reasonable chance of having the disorder."

The researchers found that a person with two copies of the gene is five times more likely to have symptoms of SAD than a person without the mutation.

"That is a very high effect for a mental illness, because most mental illnesses have many potential causes," Provencio noted. "A mental illness may arise from many mutations, and we have found one that has a clear link."

The melanopsin gene encodes a light-sensitive protein that is found in a class of photoreceptors in the retina that are not involved with vision, but are linked to many non-visual responses, such as the control of circadian rhythms, the control of hormones, the mediation of alertness and the regulation of sleep.

The mutation in this gene may result in aberrant regulation of these responses to light, leading to the depressive symptoms of SAD. About 29 percent of SAD patients come from families with a history of the disorder, suggesting a genetic or hereditary link.

"The finding suggest that melanopsin mutations may predispose some people to SAD, and that if you have two copies of this mutation, there is a very high probability that you will be afflicted," Provencio said. "An eventual understanding of the mechanisms underlying the pathological response to light in SAD may lead to improved treatments."

Provencio added that the finding, with further study, could also lead to improved testing for SAD.

Provencio's colleague and lead author in the study is Kathryn Roecklein, an assistant professor of psychology at the University of Pittsburgh.

The report said there was significant DNA damage to sperm in samples from men over the age of 35.

2008-10-23T08:26:00.000-07:00

Oct
23
2008
Men have their own biological clock
Published by Times of the Internet at 3:34 am under Top News

SYDNEY, Oct. 22 (UPI) —

An Australian study suggests men have a biological clock that signals a drop in fertility after the age of 35.

Researchers at Sydney IVF said sperm and DNA samples from more than 3,000 men shows DNA fragmentation of sperm increased with age, the Australian Broadcasting Corp. reported Wednesday.

The report said there was significant DNA damage to sperm in samples from men over the age of 35.

They cannot take fertility absolutely for granted, there is also an impact of male age on fertility, Mark Bowman of Sydney IVF said.

Copyright 2008 by United Press International
All Rights Reserved.

dHPLC and automated DNA sequencing were used to detect the paternally inherited fetal mutation in a maternal plasma sample collected at the 12th week

2008-09-26T20:47:00.000-07:00

Early noninvasive prenatal detection of a fetal CRB1 mutation causing Leber congenital amaurosis.Bustamante-Aragones A, Vallespin E, Rodriguez de Alba M, Trujillo-Tiebas MJ, Gonzalez-Gonzalez C, Diego-Alvarez D, Riveiro-Alvarez R, Lorda-Sanchez I, Ayuso C, Ramos C.
Department of Genetics, Fundacion Jimenez Diaz-Capio, CIBERER, Madrid, Spain. abustamante@fjd.es

PURPOSE: Leber congenital amaurosis (LCA) is one of the most severe inherited retinal dystrophies with the earliest age of onset. Mutations in the Crumbs homologue 1 (CRB1; OMIM 600105) gene explain 10%-24% of cases with LCA depending on the population. The aim of the present work was to study a fetal mutation associated to LCA in maternal plasma by a new methodology in the noninvasive prenatal diagnosis field: the denaturing High Performance Liquid Chromatography (dHPLC). METHODS: This study presents the case of a compound heterozygous fetus for two mutations in CRB1 (1q3.1-q32.2). dHPLC and automated DNA sequencing were used to detect the paternally inherited fetal mutation in a maternal plasma sample collected at the 12th week of gestation. To test the detection limit of dHPLC, we made serial dilutions of paternal DNA in control DNA. RESULTS: We were able to detect the presence of the paternally inherited fetal CRB1 mutation in maternal plasma by dHPLC. Moreover, by comparing chromatograms of serial dilutions to the plasma sample, we could ascertain that the percentage of fetal DNA in maternal plasma was at least 2%. However, the detection of the fetal mutation was not possible by automated DNA sequencing. CONCLUSIONS: dHPLC seems to be sensitive enough to detect small amounts of fetal DNA in maternal plasma samples. It could be a useful tool for the noninvasive prenatal detection of paternally inherited point mutations associated with retinopathies.

Achondroplasia a function of paternal ageing

2008-09-14T07:07:00.000-07:00

1: Am J Med Genet A. 2008 Sep 15;146A(18):2385-9. Links
The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, Pearson K, Romitti PA, Shaw GM, Hecht JT.
Houston Health Science Center, The University of Texas, Houston, Texas 77030, USA. kim.waller@uth.tmc.edu

There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and > or =40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records. Copyright 2008 Wiley-Liss, Inc.

PMID: 18698630 [PubMed - indexed for MEDLINE]

Change in Single Gene Causes Degenerative Brain Disease in Mice

2008-09-10T21:06:00.000-07:00

September 10, 2008
Change in Single Gene Causes Degenerative Brain Disease in Mice
Mice whose brains receive half the dose of a critical growth-regulating gene exhibit the altered behaviors and nerve cell tangles common in people with Alzheimer's disease or dementia, according to a new report by Howard Hughes Medical Institute (HHMI) scientists.

The study, led by HHMI international research scholar Freda Miller, shows that changing just one copy of the p73 gene threw off the balance between cellular life and death in the brain.

“The big shock was that half the level of just one gene had such a big impact.”
Freda D. Miller

“The big shock was that half the level of just one gene had such a big impact,” explains Miller, who is at the Hospital for Sick Children in Toronto. Finding a single protein with such a large impact on anatomy and behavior is an important step toward understanding and treating neurodegenerative diseases.

Miller and David Kaplan at the University of Toronto led the research team, which reports their finding in the September 11, 2008, issue of the journal Neuron.

As the brain develops, neural cells and connections that are no longer needed are pruned away. A number of different molecules determine when to kill off nerve cells that are damaged or no longer needed. To balance the molecules that bring about cell death, other molecules, like the p73 protein, play an “anti-death role” in the brain, Miller's team reported in a Science paper in 2000. “There are a number of checkpoints to keep cells from writing themselves off,” she says.

More recent investigations found that some patients with Alzheimer's disease naturally lack one copy of the p73 gene, and likely have lower p73 protein levels as a result. Those findings did not necessarily mean that lower levels of p73 contribute to Alzheimer's, but they strongly suggested that the protein may protect healthy individuals.

Looking for a more definitive answer, Miller's team studied genetically engineered mice that were born with only one copy of the p73 gene. The mice lacking one copy of p73 behaved differently than normal mice, and the differences increased as they grew older. For example, Miller's team found that mice with reduced p73 took longer to find their way out of a water maze than normal mice. They also displayed an unusual behavior clasping their legs together when held up by their tails. “Instead of splaying their legs out, they clasped them into their bodies,” Miller says. “My postdoc came and said, `Freda, these mice are acting very strangely.'”

Miller's team then searched for anatomical evidence that the reduction in p73 was affecting the brains of the mice. Using magnetic resonance imaging, the researchers found that the motor cortex and several other regions of the brain had 5-16 percent less volume than the same areas in healthy mice.

Later, when they dissected the brains, they found accumulations of Alzheimer's-related tangles inside and outside cells, composed mostly of a nervous system protein called tau that incorrectly attached to phosphate molecules. “Accumulation of the aberrant form of tau and tangles is bad for your brain,” Miller says.

It is still unclear how these accumulations harm the brain, but they are common in patients with neurodegenerative diseases. P73 may indirectly regulate the formation of tangles in its role as an anti-death cell monitor.

Miller's next step is to see if reductions in p73 have the same impact in humans. The team will look for changes in the number of copies of the p73 sequence in a larger population and see whether a reduced amount of p73 is more common in people with neurodegenerative disorders than in the healthy population, Miller says.

“The good news is this isn't a situation where people are completely missing this gene,” Miller says. The people already found to have variations in P73 genes tend to have some p73 production capacity, which might be exploited and improved with drugs. For instance, “we already know that growth factors really increase levels of the normal, pro-life version of p73.”

The mixture of molecules required to sustain our nerve cells for a human lifespan is so complicated, that “it's a miracle that as we get older we can think at all,” she jokes. People missing one copy of p73 will not necessarily suffer from degeneration of their brains, Miller says, but, “we think of it as a susceptibility factor for neurodegeneration or injury.”

What about sporadic retinoblastoma?

2008-09-09T08:40:00.000-07:00

Familial Retinoblastoma With Unilateral and Unifocal Involvement in 2 Families
Shaden Sarafzadeh, MD; Zélia M. Corrêa, MD, PhD; James J. Augsburger, MD

Arch Ophthalmol. 2008;126(9):1308-1309.

Since this article does not have an abstract, we have provided the first 150 words of the full text and any section headings.

Retinoblastoma is a malignant ocular tumor of childhood that occurs in approximately 1 in 18 000 children.1 Approximately 40% of patients with retinoblastoma have inherited a germ-line mutation of the RB1 gene (gene map locus 13q14.1-q14.2) (OMIN+180200), and approximately 85% of them develop bilateral tumors.2 We report on the cases of 2 children from 2 different families; all 4 of these children developed unilateral unifocal retinoblastoma despite no family history of retinoblastoma.

Methods

This is a retrospective report of 2 families without a history of retinoblastoma in which both children in each family developed unifocal unilateral retinoblastoma.

Results
Two sets of siblings (n = 4) developed unifocal unilateral retinoblastoma and neither family had a history of retinoblastoma. The first affected sibling in each family was male and received his diagnosis at age 11 months in family 1 and at age 10 . . . [Full Text of this Article]

Family 1

Family 2

Comment

AUTHOR INFORMATION

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© 2008 American Medical Association. All Rights Reserved.

Dad May Be Hazardous to Your Health

2008-08-30T17:13:00.001-07:00

The Fifty Foot Blogger: Caution: Dad may be hazardous to your health

A New Study on Paternal Age and Achondroplasia and Thanatophroic Dysplasia

2008-08-14T19:15:00.000-07:00

Am J Med Genet A. 2008 Aug 12. [Epub ahead of print]
The population-based prevalence of achondroplasia and thanatophoric dysplasia in selected regions of the US.Waller DK, Correa A, Vo TM, Wang Y, Hobbs C, Langlois PH, Pearson K, Romitti PA, Shaw GM, Hecht JT.
Houston Health Science Center, The University of Texas, Houston, Texas.

There have been no large population-based studies of the prevalence of achondroplasia and thanatophroic dysplasia in the United States. This study compared data from seven population-based birth defects monitoring programs in the United States. We also present data on the association between older paternal age and these birth defects, which has been described in earlier studies. The prevalence of achondroplasia ranged from 0.36 to 0.60 per 10,000 livebirths (1/27,780-1/16,670 livebirths). The prevalence of thanatophoric dysplasia ranged from 0.21 to 0.30 per 10,000 livebirths (1/33,330-1/47,620 livebirths). In Texas, fathers that were 25-29, 30-34, 35-39, and >/=40 years of age had significantly increased rates of de novo achondroplasia among their offspring compared with younger fathers. The adjusted prevalence odds ratios were 2.8 (95% CI; 1.2, 6.7), 2.8 (95% CI; 1.0, 7.6), 4.9 (95% CI; 1.7, 14.3), and 5.0 (95% CI; 1.5, 16.1), respectively. Using the same age categories, the crude prevalence odds ratios for de novo cases of thanatophoric dysplasia in Texas were 5.8 (95% CI; 1.7, 9.8), 3.9 (95% CI; 1.1, 6.7), 6.1 (95% CI; 1.6, 10.6), and 10.2 (95% CI; 2.6, 17.8), respectively. These data suggest that thanatophoric dysplasia is one-third to one-half as frequent as achondroplasia. The differences in the prevalence of these conditions across monitoring programs were consistent with random fluctuation. Birth defects monitoring programs may be a good source of ascertainment for population-based studies of achondroplasia and thanatophoric dysplasia, provided that diagnoses are confirmed by review of medical records. (c) 2008 Wiley-Liss, Inc.

PMID: 18698630 [PubMed - as supplied by publisher]

Early noninvasive prenatal detection of a fetal CRB1 mutation causing Leber congenital amaurosis - Paternally inherited point mutation

2008-08-07T16:32:00.000-07:00

1: Mol Vis. 2008 Aug 4;14:1388-94.
Early noninvasive prenatal detection of a fetal CRB1 mutation causing Leber congenital amaurosis.Bustamante-Aragones A, Vallespin E, Rodriguez de Alba M, Trujillo-Tiebas MJ, Gonzalez-Gonzalez C, Diego-Alvarez D, Riveiro-Alvarez R, Lorda-Sanchez I, Ayuso C, Ramos C.
Department of Genetics, Fundacion Jimenez Diaz-Capio, CIBERER, Madrid, Spain. abustamante@fjd.es

PURPOSE: Leber congenital amaurosis (LCA) is one of the most severe inherited retinal dystrophies with the earliest age of onset. Mutations in the Crumbs homologue 1 (CRB1; OMIM 600105) gene explain 10%-24% of cases with LCA depending on the population. The aim of the present work was to study a fetal mutation associated to LCA in maternal plasma by a new methodology in the noninvasive prenatal diagnosis field: the denaturing High Performance Liquid Chromatography (dHPLC). METHODS: This study presents the case of a compound heterozygous fetus for two mutations in CRB1 (1q3.1-q32.2). dHPLC and automated DNA sequencing were used to detect the paternally inherited fetal mutation in a maternal plasma sample collected at the 12th week of gestation. To test the detection limit of dHPLC, we made serial dilutions of paternal DNA in control DNA. RESULTS: We were able to detect the presence of the paternally inherited fetal CRB1 mutation in maternal plasma by dHPLC. Moreover, by comparing chromatograms of serial dilutions to the plasma sample, we could ascertain that the percentage of fetal DNA in maternal plasma was at least 2%. However, the detection of the fetal mutation was not possible by automated DNA sequencing. CONCLUSIONS: dHPLC seems to be sensitive enough to detect small amounts of fetal DNA in maternal plasma samples. It could be a useful tool for the noninvasive prenatal detection of paternally inherited point mutations associated with retinopathies.

Especially for point mutations, expanded simple tandem repeats and structural chromosome mutations, the contribution of the male germline is dominant.

2008-07-29T06:15:00.000-07:00

Hum Mol Genet. 2008 Jul 1;17(13):1922-37. Epub 2008 Mar 18.
Links
DNA double-strand break repair in parental chromatin of mouse zygotes, the first cell cycle as an origin of de novo mutation.
Derijck A, van der Heijden G, Giele M, Philippens M, de Boer P.
Department of Obstetrics and Gynaecology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
In the human, the contribution of the sexes to the genetic load is dissimilar. Especially for point mutations, expanded simple tandem repeats and structural chromosome mutations, the contribution of the male germline is dominant. Far less is known about the male germ cell stage(s) that are most vulnerable to mutation contraction. For the understanding of de novo mutation induction in the germline, mechanistic insight of DNA repair in the zygote is mandatory. At the onset of embryonic development, the parental chromatin sets occupy one pronucleus (PN) each and DNA repair can be regarded as a maternal trait, depending on proteins and mRNAs provided by the oocyte. Repair of DNA double-strand breaks (DSBs) is executed by non-homologous end joining (NHEJ) and homologous recombination (HR). Differentiated somatic cells often resolve DSBs by NHEJ, whereas embryonic stem cells preferably use HR. We show NHEJ and HR to be both functional during the zygotic cell cycle. NHEJ is already active during replacement of sperm protamines by nucleosomes. The kinetics of G1 repair is influenced by DNA-PK(cs) hypomorphic activity. Both HR and NHEJ are operative in S-phase, HR being more active in the male PN. DNA-PK(cs) deficiency upregulates the HR activity. Both after sperm remodeling and at first mitosis, spontaneous levels of gammaH2AX foci (marker for DSBs) are high. All immunoflurescent indices of DNA damage and DNA repair point at greater spontaneous damage and induced repair activity in paternal chromatin in the zygote.
PMID: 18353795 [PubMed - indexed for MEDLINE]
Related Articles
gammaH2AX signalling during sperm chromatin remodelling in the mouse zygote. [DNA Repair (Amst). 2006]
Mechanisms of DNA double strand break repair and chromosome aberration formation. [Cytogenet Genome Res. 2004]
An xrcc4 defect or Wortmannin stimulates homologous recombination specifically induced by double-strand breaks in mammalian cells. [Nucleic Acids Res. 2002]
Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos. [Development. 1997]
Ionizing radiation and genetic risks XIV. Potential research directions in the post-genome era based on knowledge of repair of radiation-induced DNA double-strand breaks in mammalian somatic cells and the origin of deletions associated with human genomic disorders. [Mutat Res. 2005]

A Must see Video

2008-07-15T21:52:00.000-07:00

Male Biological Clock How Single Gene Disorders that are De Novo/ non-familial/sporadic come into being

Man's Ability to Have Kids is Dependent on His Age Written by Theresa Maher

2008-07-07T18:16:00.000-07:00

Excellent Article by Theresa Maher!

Written by Theresa Maher

MONDAY, July 7, (News Locale) - Contrary to popular perception, a man is not able to have kids anytime he wishes. New research out of France indicates male fertility is also dependent on age and men who delay fatherhood may have a tough time conceiving later on.

It is believed that unlike women, men have no biological clock and can father children throughout their life. In fact it is not uncommon to see celebrities having babies well after they have crossed their 50s.

Now researchers at the Eylau Centre for Assisted Reproduction in Paris have revealed men who delay fatherhood have a less chance of impregnating their partners.

The study of more than 20,000 couples who sought fertility help at the center found men over the age of 35 are almost a third less likely to conceive as compared to their younger counterparts. Furthermore men over the age of 40 had poor quality of sperm, which could lead to frequent miscarriages in their partners. In fact the risk of miscarriage if the father was over the age of 40 was 75 percent.

Researchers believe the DNA in sperm starts to decay with age and this may be the cause of fertility issues in older men.

The details of the study were presented at the European Society of Human Reproduction and Embryology conference.

An earlier study by Danish researchers had revealed kids born to older fathers were more likely to die before they entered adulthood when compared to kids born to younger fathers. This incidence was attributed to the declining quality of sperm due to ageing.

The scientists found that congenital defects like heart and spine problems were the main cause of death in these children.

Additionally the risk of autism, epilepsy or schizophrenia also increased in these kids, which led to accidental deaths as well, the researchers had reported in the European Journal of Epidemiology.

Consumers must be aware that the mother's age has always been associated with pregnancy complications. The above study provides evidence that a father's age may also have a say in conception.

Men's fertility decreases after 35, study confirms

2008-07-06T11:01:00.000-07:00

Men's fertility decreases after 35, study confirms
Kate Benson Medical Reporter
July 7, 2008

IT HAS long been known that a woman's chance of reproducing declines once she hits 35, but now scientists have found that men who have some forms of fertility treatment in their 30s suffer the same fate.
A study by Laboratoire d'Eylau, a centre for assisted reproduction in Paris, followed more than 21,000 men who had intrauterine inseminations at fertility clinics. It found the process, where semen is washed to extract the sperm, resulted in a decrease in pregnancies and an increase in miscarriages.

All the men in the study, which will be presented today at the annual conference of the European Society for Human Reproduction and Embryology, were aged over 35.

"We already believed that couples where the man was older took longer to conceive," said the study's author, Stephanie Belloc.

"But how DNA damage in older men translates into clinical practice has not been shown up to now. Our research shows for the first time that there is a strong paternal age-related affect on [intrauterine insemination] outcomes and this information should be considered by both doctors and patients in assisted reproduction."

She said sperm with DNA damage, common in older men, could still enter the egg during intrauterine insemination, which could result in a failure to conceive or a miscarriage.

But during in vitro fertilisation, the zona pellucida, or outer membrane of the egg, was an efficient barrier in preventing the penetration of sperm with DNA damage.

"And in ICSI [intracytoplasmic sperm injection], the best sperm can be selected for use. These methods, although not in themselves a guarantee of success, may help couples where the man is older to achieve a pregnancy more quickly and reduce the risk of miscarriage," Dr Belloc said.

She followed 21,239 patients, and examined the sperm of each partner for count, motility and morphology. Pregnancy rates, miscarriage and delivery rates were also recorded.

"Some recent studies have established a relationship between the results of [intrauterine insemination] and DNA damage, which also correlated to a man's age, suggesting it might be an important factor, but until now there was no clinical proof. We have now found that the age of the father was important in pregnancy - men over 35 had a negative effect."

Down Syndrome one of the many disorders due to older paternal age and in this case older maternal age

2008-06-30T07:47:00.000-07:00

June 26, 2008

Fact or Fiction: Men Have a Biological Clock
Does male fertility have an expiration date?
By Anne Casselman

TICKING CLOCK: Male fertility declines just like female fertility.

The female biological clock—its tick-tock marking the decline of fertility that grows louder as a woman reaches middle age—is deeply ingrained in popular consciousness. Take this scene from the film Bridget Jones's Diary: Bridget's Uncle Geoffrey reminds her that as a career girl she "can't put it off forever," alluding to her declining fertility. His wife Una chimes in: "tick-tock, tick-tock," her finger wagging like a metronome.

The biological clock, although just a metaphor, refers to a real phenomenon: Women over 35 years of age are only half as likely to become pregnant in the most fertile part of their menstrual cycle than women younger than 26.

So do men suffer from the same thing?

"For women, a biological clock is a decline in fertility and an increased chance of having genetically abnormal babies as they age," says Harry Fisch, director of New York City's Male Reproductive Center and author of The Male Biological Clock: The Startling News About Aging, Sexuality, and Fertility in Men. "And that's exactly what's happening with men."

So how did Indian farmer Nanu Ram Jogi sire a healthy child at the age of 90 last year? Such a feat would be impossible for a woman, even in an age when Carmela Bousada, 67, gave birth to twins in January 2007 after lying about her age to the doctors who gave her in vitro fertilization. Whereas fertility declines along with testosterone levels as men age, it doesn't drop to zero.

Still, Jogi is definitely the exception rather than the rule. One study found that the odds of fatherhood for those under the age of 30 was 32.1 percent compared with 20 percent over the age of 50, signifying a 38 percent drop in male fertility across that age gap.

One study examined 97 men between the ages of 22 and 80 and found that as they aged their semen volume decreased by 0.001 ounce (0.03 milliliter) per year from an average total of 0.09 ounce (2.7 milliliters) and their "total progressively motile sperm count"—a rough index for the fertility potential of one's sperm based on its movement—decreased about five percent with each year they aged.

Fisch and his colleagues have also found that the children of women over 35 whose babies' fathers were also of that age were more likely to have Down's syndrome than offspring whose fathers were younger.

In other studies, older men were more likely to father children with mental illness or other deficits. Roughly 11 children out of a thousand conceived by men over age 50 developed schizophrenia compared with under three children out of a thousand for fathers under 20 in one study from the Archives of General Psychiatry. And the children of men 40 years or older were nearly six times more likely to have autism spectrum disorders than kids begot by men under 30.

So do men's sperm get staler over time? To maintain sperm levels, cells known as germ cells must continue dividing. After all, men find ways to dispose of sperm—ahem—and once ejaculated they only survive for several days. By the age of 50, these germ cells will have divided 840 times. Each one of those divisions is an opportunity for something to go wrong. "There's more of a chance to have genetic abnormalities the more the cells divide," Fisch says. In sperm these mutations dot the genes with changes in the basic structure of the DNA—and can lead to problems in the resulting offspring.

Bioengineer Narendra Singh of the University of Washington in Seattle and his colleagues compared the sperm of men of different ages. Sure enough, sperm in men older than 35 had more DNA damage than that from younger men. And although unhealthy sperm are supposed to commit cell suicide, some of the sperm they looked at had lost that ability to "take one for the team"—meaning they'd be around to fertilize an egg. "This may lead to offspring with defective DNA, which may translate to mental and physical defects," Singh says.

Can men prevent this damage? No, but they may be able to mitigate it. There are factors within men's control that can accelerate adverse effects: alcohol, smoking, drugs and environmental pollution—even coffee consumption. So avoid them, says Singh.

Still, even after correcting for various lifestyle factors, the DNA of sperm are increasingly damaged with advancing age.

"The question is, can we reverse the [male] biological clock?" asks Fisch, who is studying various ways to keep sperm healthy.

Perhaps Bridget Jones's Uncle Geoffrey and Aunt Una should have chastised her love interest, Mark Darcy, too, for procrastinating procreation. That "tick-tock, tick-tock," it would seem, applies to both sexes.

As men age they do not lose their capacity to generate spermatozoa; however, the quality of these gametes deteriorates. This change can be visualized

2008-06-14T17:55:00.000-07:00

Full Text
Expert Review of Obstetrics & Gynecology
May 2008, Vol. 3, No. 3, Pages 267-271
(doi:10.1586/17474108.3.3.267)

Just how safe is assisted reproductive technology for treating male factor infertility?
R John Aitken

Assisted reproductive technology (ART) has been responsible for the birth of over 3 million babies since the delivery of Louise Brown in the UK 28 years ago. Currently, one in 80–100 children born in the USA, one in 50 born in Sweden, one in 40 born in Australia and one in 24 born in Denmark are the product of this form of treatment. In 2003, more than 100,000 in vitro fertilization (IVF) cycles were reported from 399 clinics in the USA, resulting in the birth of more than 48,000 babies [1,101]. Worldwide, this figure has now exceeded 200,000 births per annum [2] and is continuing to rise. Indeed, it is a biological certainty that the more ART is used in one generation, the more it will be needed in the next. Given the cost of this form of treatment, and the fact that children born as a consequence of ART stand a 30–40% increased risk of birth defects [3], the current widespread use of assisted conception may constitute the beginnings of a serious public health problem.

There is general agreement that the two major reasons for patient referral to assisted conception programs are increased maternal age and male subfertility. The former can be easily reversed by public awareness and a change in social attitudes to family planning. However, the latter is a more intractable problem, as we have little or no understanding about the origins of this pathology. As a result, rational treatment or prevention of male infertility is all but impossible.

The importance of the male factor in human infertility has been highlighted by recent analyses of population trends in Denmark. This population has witnessed a steady decline in fertility rates in recent years, which is being addressed by increasing reliance on ART [4]. At the present time, 21% of young Danish men exhibit semen quality (in terms of sperm count and morphology) that falls below the internationally accepted thresholds of normality set by the WHO [5]. Moreover, it has been suggested that this situation is getting worse with the passage of time and, according to a recent publication [6]:

‘we may now have reached a level where semen quality of a significant segment of men in the population is so poor that it may contribute to the current widespread use of assisted reproduction’.

Although Denmark affords a particularly striking example of secular trends in male reproduction, semen quality in human males is notoriously poor. Indeed, it is a feature of the human condition, with at least one in 20 men in developed countries suffering from some level of infertility [7]. Most men produce sufficient numbers of spermatozoa to fertilize an egg in vivo; however, the gametes they generate have lost their biological potential for fertilization and the support of normal embryonic development. An important characteristic of these defective spermatozoa is a high level of DNA damage, which is, in turn, correlated with poor fertility, high rates of miscarriage and an increased incidence of disease in the offspring, including childhood cancer [8].

The use of such DNA-damaged spermatozoa in ART is thought to be a major contributor to the increased incidence of birth defects and other diseases seen in children conceived in vitro. Specifically, it has been proposed that the DNA damage brought into the fertilized egg by the spermatozoon may increase the mutational load carried by the embryo as a consequence of the aberrant or incomplete repair of this damage in the interval between fertilization and initiation of the first cleavage division [9,10]. Experimental verification of this relationship between DNA damage in the fertilizing sperm and embryo development has recently been secured in an animal model [11]. In these studies, intracytoplasmic sperm injection (ICSI) was performed in mice with fresh or DNA-damaged spermatozoa. Use of the latter was associated with poor preimplantation development and a reduction in the number of live births. Postnatal examination of the progeny revealed that the use of DNA-damaged spermatozoa in ICSI was associated with behavioral defects (increased anxiety, lack of habituation pattern, deficit in short-term spatial memory and age-dependent hypolocomotion in an open field test), the appearance of mesenchyme tumors, premature aging and a shortened lifespan. These results are supported by clinical data [8] and have profound implications for the safety of ICSI, which must frequently involve the use of DNA-damaged spermatozoa [12]. Currently, both the nature of this genetic damage and its origins are a matter of intense investigation. In terms of etiology, the ensuing paragraphs summarize data suggesting that paternal age, environmental toxicants, errors of endogenous metabolism and exposure to electromagnetic radiation are all potential contributors to DNA damage in the male germ line.

As men age they do not lose their capacity to generate spermatozoa; however, the quality of these gametes deteriorates. This change can be visualized as an age-dependent increase in DNA fragmentation in spermatozoa [13,14]. Paternal age is also widely recognized as a key factor in the etiology of dominant genetic diseases, such as Apert syndrome or achondroplasia [15]. Furthermore, genetic damage to the spermatozoa of aging males is thought to contribute to the etiology of more complex polygenic conditions such as autism, spontaneous schizophrenia and epilepsy [8]. Since older men tend to be married to older women it is significant that as oocytes age in the ovary, they suffer the depletion of several key genes involved in protection against oxidative stress and the maintenance of DNA integrity, including genes with a probable role in DNA repair [16]. Thus, age-related changes to the integrity of DNA in the spermatozoa are compounded by age-related declines in the oocytes’ capacity for DNA stabilization and repair. In combination, these factors could well make a significant contribution to the elevated incidence of birth defects associated with assisted conception therapy. Whichever way you look at it, aging and reproduction are incompatible bedfellows.

An impact of environmental pollutants on DNA integrity in spermatozoa has been known for some time. For example, men who smoke heavily produce spermatozoa suffering from high levels of oxidative DNA damage. This does not necessarily impair the capacity of these cells for fertilization, however, it does impact upon the subsequent ability of the fertilized egg to develop normally. As a result, the children of heavy smokers stand a four- to fivefold increased chance of developing childhood cancer: a fact that is not often appreciated in the antismoking debate [9].

Recently, exposure of mice to particulate air pollution in an urban/industrial location has also been shown to induce high levels of DNA damage in spermatozoa [17]. Analyses of young men exposed to high levels of air pollution as a result of excessive coal combustion during Eastern European winters have substantiated these results in a clinical context [18]. Similarly, toxicological studies have demonstrated elevated levels of DNA damage in human spermatozoa, which are linked to the presence of metabolites of insecticides or persistent organochlorine pollutants in blood or urine [19,20]. Exposure to environmental endocrine disruptors, such as nonylphenol [21], as well as heavy metals [22], have also been demonstrated to induce oxidative DNA damage in human spermatozoa. Further resolution of the kinds of environmental pollutant that might be damaging to human spermatozoa is clearly needed. Elucidation of the significance of enzyme polymorphisms in defining an individual’s susceptibility to toxicant exposure is also required, as exemplified by a recent study demonstrating that men who are homozygous null for glutathione-S-transferase M1 are more likely to respond to air pollution with high levels of DNA damage in their spermatozoa than men possessing this isoform [23].

Induction of DNA fragmentation in human spermatozoa is not solely due to exposure to environmental toxins, it can also result from errors of endogenous metabolism. An extremely important observation in this context is a recent preliminary report indicating that young male patients suffering from diabetes mellitus exhibit high levels of DNA damage in their spermatozoa [24]. These results have been confirmed in animal studies demonstrating that the experimental induction of diabetes in male mice is associated with oxidative stress and a postmeiotic genotoxic effect reflected in high rates of embryonic resorption in mated females [25]. Our laboratory has also demonstrated that endogenously generated estrogens, particularly catechol estrogens, can have a profound effect on DNA integrity in human spermatozoa, as a consequence of their inherent redox cycling activity [26]. Such studies reinforce the generally held view that most endogenously generated DNA damage in human spermatozoa is a consequence of oxidative stress [8,28]. If this is the case, then any ion (lead or cadmium), organic compound (phthalate ester), enzyme (NADPH oxidase), organelle (mitochondria) or cell (neutrophil), capable of generating reactive oxygen species in the vicinity of human spermatozoa is potentially capable of contributing to DNA damage in the male germ line [8–10,22,28]. In addition to oxidative damage, it is possible that in some patient’s sperm DNA is cleaved by the sequential action of topoisomerase IIB and an uncharacterized nuclease in a process analogous to apoptosis in somatic cells [29]. The relative significance of nuclease- and free radical-mediated mechanisms in the cleavage of sperm DNA, is a key issue that awaits resolution.

Various forms of electromagnetic radiation are also known to have a detrimental effect on DNA integrity in the male germ line. A classic example is heat. The scrotum is designed to maintain the testes and epididymis slightly below core body temperature. It has been known for some time that elevated testicular temperature impairs spematogenesis. However, recent data have also indicated the ability of mild scrotal heat stress (42°C for 30 min) to induce DNA damage in epididymal mouse spermatozoa [30]. Radiofrequency electromagnetic radiation has also been demonstrated to induce DNA damage in epididymal sperm in animal models [31] and there are some reports of mobile phone exposure having a detrimental effect on semen quality in men [32]. Thus, any practice that elevates testicular temperature, such as wearing clothes or a sedentary occupation, or exacerbated exposure to other forms of electromagnetic radiation, such as excessive mobile phone use, are possible contributors to DNA damage in human spermatozoa.

In some couples, the damage brought into the oocyte by the fertilizing spermatozoon may be epigenetic rather than genetic. These epigenetic factors are reviewed in an article in this edition of Expert Review of Obstetrics and Gynecology [31] and include: a functional centrosome to regulate cell division in the embryo; an appropriate pattern of chromatin remodeling; an appropriate population of mRNA and miRNA species that are carried into the zygote by the fertilizing spermatozoon and may play a role in the regulation of early embryonic development; and an appropriate pattern of DNA methylation. There are several recent papers indicating that the DNA methylation profile is dramatically altered in the spermatozoa of infertile men and we already know that the incidence of imprinting defects is elevated in children born as a result of ART [31,32]. The importance of epigenetic defects in the male germ line has recently been highlighted by analyses of vinclozolin, a fungicide used in the wine-making industry [33]. Transient embryonic exposure to vinclozolin in utero resulted in the birth of male offspring exhibiting a spermatogenenic defect. This defect was epigenetic in origin and was vertically transmitted through at least four generations.

Given the evidence that both IVF and ICSI are associated with a significant increase in birth defects, should ART be regarded as safe? On one hand, there is no denying that ART, and particularly ICSI, is an effective form of treatment for infertility. After 12 months approximately 90% of couples submitting to this form of therapy walk away with a baby. Furthermore, even though the risk of birth defects is significantly elevated following ART, the incidence is still relatively rare and should decrease as the field moves towards single-embryo transfers, thereby eliminating complications created by multiple births. Moreover, several clinical groups have trumpeted their ability to successfully perform ART in couples where the male partner’s spermatozoa exhibit high levels of DNA damage, without any obvious consequences as far as the health and wellbeing of the offspring are concerned [34]. These and other data tell us that even if DNA-damaged spermatozoa are used for assisted human conception, the risk of generating a visible phenotypic change in the offspring is extremely low.

However, we should also recognize that the absence of a pathological phenotype in the vast majority of children born as a result of ART, does not mean that the genome has not been damaged, or that the damage will not emerge in some future generation, as a result of mechanisms such as haploid insufficiency, the expression of X-linked defects in male offspring or the future creation of double-recessive combinations. It also does not mean that we will not find defects if we look hard enough. The controversial discovery of fertility-threatening Y-chromosome deletions in the offspring of genotypically normal males as a consequence of ART, is an example of a condition that may take 25–30 years to surface even though the mutation was probably created shortly after fertilization [35].

Clearly, we must continue to be vigilant in our long-term monitoring of the health and wellbeing of children produced by ART. Given recent advances in our understanding of epigenetic defects in the spermatozoa of infertile male patients, we should also extend this surveillance to the DNA methylation profiles of children born as a result of assisted conception. It is also incumbent upon embryologists to optimize the quality of the gametes that are used for ART, particularly where ICSI is involved. The development of prophylactic antioxidant therapies [36], improved culture conditions [37], novel gamete selection technologies [38] and noninvasive methods for the assessment of embryo quality [39] will all contribute to the future evolution of ART as a safe, effective means of treating human infertility.

Financial & competing interests disclosure
Aitken is a Consultant for NuSep. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

References ChooseTop of pageINTRODUCTIONThe male factorParental ageEnvironmental pollutionErrors of endogenous meta...Electromagnetic radiation...Epigenetic damageIs ART a dangerous form o...References <<

Papers of special note have been highlighted as: • of interest •• of considerable interest

1 Van Voorhis‌ BJ. Clinical practice. in vitro fertilization. N. Engl. J. Med. 356, 379–386 (2007). [CrossRef] [Medline]
2 Adamson‌ GD, de Mouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild F; International Committee for Monitoring Assisted Reproductive Technology. World collaborative report on in vitro fertilization, 2000. Fertil. Steril. 85, 1586–1622 (2006). [CrossRef] [Medline]
3 Hansen‌ M, Bower C, Milne E, de Klerk N, Kurinczuk JJ. Assisted reproductive technologies and the risk of birth defects – a systematic review. Hum. Reprod. 20, 328–338 (2005)
•• Meta-analysis suggesting a 30–40% increased risk of birth defects associated with assisted reproductive technology (ART).

[CrossRef] [Medline]
4 Jensen‌ TK, Sobotka T, Hansen MA, Pedersen AT, Lutz W, Skakkebæk NE. Declining trends in conception rates in recent birth cohorts of native Danish women: a possible role of deteriorating male reproductive health. Int. J. Androl. 31(2), 81–92 (2007).
• Recent review highlighting the declining fertility rates typical of the Danish population.

[CrossRef] [Medline]
5 Jorgensen‌ N, Carlsen E, Nermoen I et al. East–West gradient in semen quality in the Nordic–Baltic area: a study of men from the general population in Denmark, Norway, Estonia and Finland. Hum. Reprod. 17, 2199–2208 (2002). [CrossRef] [Medline]
6 Andersen‌ AN, Erb K. Register data on assisted reproductive technology (ART) in Europe including a detailed description of ART in Denmark. Int. J. Androl. 29, 12–16 (2006). [CrossRef]
7 McLachlan‌ RI, de Kretser DM. Male infertility: the case for continued research. Med. J. Aust. 174, 116–117 (2001). [Medline]
8 Aitken‌ RJ, De Iuliis GN. Origins and consequences of DNA damage in male germ cells. Reprod. Biomed. Online 14, 727–733 (2007)
•• Recent review of the causes and consequences of DNA damage in the male germ line.

[Medline]
9 Aitken‌ RJ, Koopman P, Lewis SE. Seeds of concern. Nature 432, 48–52 (2004).
• Review of potential environmental impacts on DNA damage in the germ line.

[CrossRef] [Medline]
10 Aitken‌ RJ, Krausz C. Oxidative stress, DNA damage and the Y chromosome. Reproduction 122, 497–506 (2001). [CrossRef] [Medline]
11 Fernández-Gonzalez‌ R, Moreira P, Pérez-Crespo M et al. Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring. Biol. Reprod. 78(4), 761–72 (2008).
•• Important recent paper providing experimental evidence that the performance of intracytoplasmic sperm injection (ICSI) with DNA-damaged spermatozoa can have long-lasting impacts on the health and wellbeing of the offspring.

[CrossRef] [Medline]
12 Irvine‌ DS, Twigg JP, Gordon EL, Fulton N, Milne PA, Aitken RJ. DNA integrity in human spermatozoa: relationships with semen quality. J. Androl. 21, 33–44 (2000). [Medline]
13 Schmid‌ TE, Eskenazi B, Baumgartner A et al. The effects of male age on sperm DNA damage in healthy non-smokers. Hum. Reprod. 22, 180–187 (2007). [CrossRef] [Medline]
14 Singh‌ NP, Muller CH, Berger RE. Effects of age on DNA double-strand breaks and apoptosis in human sperm. Fertil. Steril. 80, 1420–1430 (2003). [CrossRef] [Medline]
15 Crow‌ JF. The origins, patterns and implications of human spontaneous mutation. Nat. Rev. Genet. 1, 40–47 (2000). [CrossRef] [Medline]
16 Hamatani‌ T, Falco G, Carter MG et al. Age-associated alteration of gene expression patterns in mouse oocytes. Hum. Mol. Genet. 13, 2263–2278 (2004). [CrossRef] [Medline]
17 Yauk‌ C, Polyzos A, Rowan-Carroll A et al. Germ-line mutations, DNA damage, and global hypermethylation in mice exposed to particulate air pollution in an urban/industrial location. Proc. Natl Acad. Sci. USA 105, 605–610 (2008).
•• Important recent paper clearly demonstrating the impact that air pollution has on the epigenetic programming and integrity of sperm DNA.

[CrossRef] [Medline]
18 Rubes‌ J, Selevan SG, Evenson DP et al. Episodic air pollution is associated with increased DNA fragmentation in human sperm without other changes in semen quality. Hum. Reprod. 20, 2776–2783 (2005). [CrossRef] [Medline]
19 Rignell-Hydbom‌ A, Rylander L, Giwercman A et al. Exposure to PCBs and p,p´-DDE and human sperm chromatin integrity. Environ. Health Perspect. 113, 175–179 (2005). [Medline]
20 Meeker‌ JD, Singh NP, Ryan L et al. Urinary levels of insecticide metabolites and DNA damage in human sperm. Hum. Reprod. 19, 2573–2580 (2004). [CrossRef] [Medline]
21 Anderson‌ D, Schmid TE, Baumgartner A, Cemeli-Carratala E, Brinkworth MH, Wood JM. Oestrogenic compounds and oxidative stress (in human sperm and lymphocytes in the COMET assay). Mutat. Res. 544, 173–178 (2003). [CrossRef] [Medline]
22 Xu‌ DX, Shen HM, Zhu QX et al. The associations among semen quality, oxidative DNA damage in human spermatozoa and concentrations of cadmium, lead and selenium in seminal plasma. Mutat. Res. 534, 155–163 (2003). [Medline]
23 Rubes‌ J, Selevan SG, Sram RJ, Evenson DP, Perreault SD. GSTM1 genotype influences the susceptibility of men to sperm DNA damage associated with exposure to air pollution. Mutat. Res. 625, 20–28 (2007). [Medline]
24 Agbaje‌ IM, Rogers DA, McVicar CM et al. Insulin dependant diabetes mellitus: implications for male reproductive function. Hum. Reprod. 22, 1871–1877 (2007).
• Sentinel paper indicating that diabetic patients possess high levels of DNA damage in their spermatozoa.

[CrossRef] [Medline]
25 Shrilatha‌ B, Muralidhara. Early oxidative stress in testis and epididymal sperm in streptozotocin-induced diabetic mice: its progression and genotoxic consequences. Reprod. Toxicol. 23, 578–587 (2007). [CrossRef] [Medline]
26 Bennetts‌ LE, De Iuliis GN, Nixon B et al. Analysis of the impact of estrogenic compounds on DNA integrity in the male germ line. Mutat. Res. (2007) (In Press).
27 Wang‌ X, Sharma RK, Sikka SC, Thomas AJ Jr, Falcone T, Agarwal A. Oxidative stress is associated with increased apoptosis leading to spermatozoa DNA damage in patients with male factor infertility. Fertil. Steril. 80, 531–535 (2003). [CrossRef] [Medline]
28 Aitken‌ RJ, Baker HW. Seminal leukocytes: passengers, terrorists or good samaritans? Hum. Reprod. 10, 1736–1739 (1995).
•• Discussion of the significance of leukocytic infiltration in the origins of oxidative stress in the male reproductive tract.

[Medline]
29 Shaman‌ JA, Yamauchi Y, Ward WS. Sperm DNA fragmentation: awakening the sleeping genome. Biochem. Soc. Trans. 35, 626–628 (2007). [CrossRef] [Medline]
30 Banks‌ S, King SA, Irvine DS, Saunders PT. Impact of a mild scrotal heat stress on DNA integrity in murine spermatozoa. Reproduction 129, 505–514 (2005). [CrossRef] [Medline]
31 Carrell‌ DT. Paternal genetic and epigenetic influences on IVF outcome. Expert Rev. Obstet. Gynecol. 3(3), 359–367 (2008). [Abstract]
32 Houshdaran‌ S, Cortessis VK, Siegmund K, Yang A, Laird PW, Sokol RZ. Widespread epigenetic abnormalities suggest a broad DNA methylation erasure defect in abnormal human sperm. PLoS ONE 2, e1289 (2007). [CrossRef]
33 Anway‌ MD, Cupp AS, Uzumcu M, Skinner MK. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308, 1466–1469 (2005). [CrossRef] [Medline]
34 Gandini‌ L, Lombardo F, Paoli D et al. Full-term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum. Reprod. 19, 1409–1417 (2004). [CrossRef] [Medline]
35 Feng‌ C, Wang LQ, Dong MY, Huang HF. Assisted reproductive technology may increase clinical mutation detection in male offspring. Fertil. Steril. (2008) (Epub ahead of print).
• Recent publication indicating that the treatment of male infertility patients with ART is associated with the de novo appearance of Y chromosome deletions in the offspring.

36 Greco‌ E, Iacobelli M, Rienzi L, Ubaldi F, Ferrero S, Tesarik J. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J. Androl. 26, 349–353 (2005). [CrossRef] [Medline]
37 Friedler‌ S, Schachter M, Strassburger D, Esther K, Ron El R, Raziel A. A randomized clinical trial comparing recombinant hyaluronan/recombinant albumin versus human tubal fluid for cleavage stage embryo transfer in patients with multiple IVF-embryo transfer failure. Hum. Reprod. 22, 2444–2448 (2007). [CrossRef] [Medline]
38 Ainsworth‌ C, Nixon B, Jansen RP, Aitken RJ. First recorded pregnancy and normal birth after ICSI using electrophoretically isolated spermatozoa. Hum. Reprod. 22, 197–200 (2007). [CrossRef] [Medline]
39 Patrizio‌ P, Fragouli E, Bianchi V, Borini A, Wells D. Molecular methods for selection of the ideal oocyte. Reprod. Biomed. Online 15, 346–353 (2007). [Medline]
Website 101 Australian Babies. 4102.0. Australian Social Trends. Australian Bureau of Statistics (2007). www.abs.gov.au/AUSSTATS

Affiliations
R John Aitken
Laureate Professor of Biological Sciences, Faculty of Science and IT, University of Newcastle, Callaghan, NSW 2308, Australia. john.aitken@newcastle.edu.au
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the story last week about the increase in death rates of the offspring brings out the hidden risks associated with fathering children at an older age.

2008-06-12T22:51:00.000-07:00

Genetic clock ticks for men Les Sheffield

June 12, 2008 12:00am
MOST men would have been surprised to read that overseas researchers had found the death rate of young adults was higher if they had been born to older fathers.

This is no surprise to me. It has been scientifically established that genetic changes occur more often in the sperm of older fathers than younger fathers.

As men age there is a higher chance of changes in the genes in the sperm.

These changes can cause genetic conditions in their offspring, such as birth defects, autism and schizophrenia.

Their partners can also have an increased risk of miscarriages.

The presumed reason for the increase occurrence of all of these conditions is that they are all due to a new genetic change in the sperm of the older father.

Genetic changes are occurring all the time. Sometimes they have a beneficial effect, such as making the individual stronger, taller or smarter.

This is part of the concept of "survival of the fittest".

Sometimes, when the gene change is in a non-coding part of the genome, they have no effect. At other times, they can be harmful.

The problem is that these harmful effects are extremely varied because they can affect any one of the 20,000 or so human genes.

For example, they often change the structure of the body. One example is dwarfism, where the arms and legs are short due to a genetic change. The commonest type of dwarfism is achondroplasia.
An individual with this condition will have a 50 per cent risk of having an affected child themselves.

Indeed, about 20 per cent of the parents of achondroplastic babies have one of the parents with this condition, but the remaining 80 per cent do not.

If you look at the parents of babies with achondroplasia, who do not have the condition themselves, you find their average age is older than other people having babies in the population.

Significantly, statistics show it is the father's age which is important and not the mother's.
Achondroplasia is rare and it is only one of the many genes that can go wrong. Collectively, any of the 20,000 genes can change and this causes an increase in risk from about the age of 40.

The risk in men for any single gene change is one in 200 at age of 40, 20 at age 50 and rises steeply after that.

This increase in risk with paternal age is no surprise to me, but it is a surprise to practically everyone else.

The increase risk for older mothers for Down syndrome is well-known.

As part of my work as a clinical geneticist, I see couples every week who come to ask about the risk of having babies because of the age of the mother.

We talk about this and often, as the male partner is also older, we talk about the risk of his age. Most of the partners are quite surprised and even taken aback with this news.

In today's society, delaying pregnancy until later is often done for career and other purposes but usually only the age of the mother is taken into account in planning when to start a family. Why is the increased risk in relation to a father's age not widely known?

There are many possible reasons. Some of the information - such as increased death rates of adults - is new.

But information about single gene changes, such as achondroplasia, has been around for many years.

I think the real reason for the lack of knowledge is the conditions that can be caused are varied and can't really be prevented by a screening program like the one offered for Down syndrome.

In fact, most of the conditions, such as achondroplasia, can't even be picked up by the normal ultrasound scan for abnormalities done at 18-20 weeks of a pregnancy.

So, if you're a male, the only way not to be exposed to this increased risk of genetic defects in your offspring is to plan your children early and regard the increasing risks of the woman in her late 30s and early 40s as also applying to you.

In other words, stop your child bearing at the same sort of age that women stop child bearing. This may not be what older men want to hear, but they need to seek information about what the risks actually are before making child-bearing decisions.

We hear about the positive sides of parenthood in some older celebrity fathers but the story last week about the increase in death rates of the offspring brings out the hidden risks associated with fathering children at an older age.

Associate Professor Les Sheffield is a clinical geneticist with the Victorian Clinical Genetics Services

Scientists reveal dangers of older fathers

2008-05-31T17:25:00.000-07:00

Scientists reveal dangers of older fathers
By Laura Donnelly, Health Correspondent
Last Updated: 10:18PM BST 31/05/2008
Children are almost twice as likely to die before adulthood if they have a father over 45, research has shown.
A mass study found that deaths of children fathered by over-45s occurred at almost twice the rate of those fathered by men aged between 25 and 30.

Scientists believe that children of older fathers are more likely to suffer particular congenital defects as well as autism, schizophrenia and epilepsy. The study was the first of its kind of such magnitude in the West, and researchers believe the findings are linked to the declining quality of sperm as men age.

A total of 100,000 children born between 1980 and 1996 were examined, of whom 830 have so far died before they reached 18, the majority when they were less than a year old.

The deaths of many of the children of the older fathers were related to congenital defects such as problems of the heart and spine, which increase the risk of infant mortality. But there were also higher rates of accidental death, which the researchers believe might be explained by the increased likelihood of suffering from autism, epilepsy or schizophrenia.

Most research into older parents has, until now, focused on the risks passed on by older mothers. But the new study, published in the European Journal of Epidemiology, was adjusted to take account of maternal age and socio-economic differences.

The research also found higher death rates among children of the youngest fathers, especially those below the age of 19. However, the study said these differences were explained by the risks of teenage motherhood and poorer diet and lifestyle.

Previous research using the same data found that older men were four times as likely to father a child with Down's syndrome, while other studies have found that the genetic quality of sperm deteriorates as men age.

More than 75,000 babies in Britain are born to fathers aged 40 and over each year, or more than one in 10 of all births. This includes more than 6,000 born to fathers aged 50 or over. The average age of fathering a child in this country is 32.

Dr Allan Pacey, senior lecturer in andrology – the medical specialty dealing with male reproduction – at the University of Sheffield, said: "A lot of people know that there are risks for the child that come from having an older mother, but children of older fathers also carry an increased risk. These sorts of results provide another good reason to have children early, when possible."

Dr Pacey, who is secretary of the British Fertility Society, said scientists were unsure exactly what impact the ageing process had on the quality of sperm, making it impossible to detect defects before conception.

Dr Jin Liang Zhu, from the Danish Epidemiology Science Centre, which carried out the research, said: "The risks of older fatherhood can be very profound, and it is not something that people are always aware of."

The mother's age still has the bigger impact on child health, however. About one in 900 babies born to women under 30 have Down's syndrome – a figure which reaches one in 100 by the age of 40. The number of over-40s giving birth in Britain each year has doubled in the past decade to 16,000. The risk of miscarriage rises sharply with age.

Marfan syndrome occurs in offspring of older fathers

2008-05-13T13:20:00.000-07:00

Nigeria: Marfan Syndrome

COLUMN
11 May 2008
Posted to the web 12 May 2008

Lagos

Marfan Syndrome is an inherited connective tissue disorder where individuals are characteristically very tall, slender, have a narrow face, loose joints and associated spinal or chest wall abnormalities.

It is caused by a defect in the gene that enables the body to produce fibrillin which is a protein that helps give connective tissue its strength and elasticity. Most people with Marfan Syndrome inherit the abnormal gene from an affected parent passed on in an autosomal dominant fashion. Autosomal dominant means that only a defective gene from one parent is required to pass the disease on. Each child of an affected parent has a 50% chance of inheriting the defective gene. About 25% of cases are as a result of a mutation occurring for the first time in the egg or sperm of a parent that does not have Marfan Syndrome. The disorder affects connective tissue comprised of fibres that provide the framework and support for the body. Marfan syndrome affects many sytems in the body since connective tissue is widespread.

It may affect the blood vessels and heart, eyes, skeleton and skin. Severity of damage varies on an individual basis ranging from mild to severe. The most serious and potentially fatal effects of Marfan Syndrome involve the Aorta which is the large artery that carries blood from the heart to the rest of the body. The connective tissue in the walls of the aorta are weakened which may lead to enlargement, tear or rupture. Marfan Syndrome is a serious condition. Fortunately, advances in treatment, early diagnosis and close, careful management makes it possible for individuals to live full productive lives.

The signs and symptoms of Marfan Syndrome vary greatly because so many body systems are affected. Some individuals have mild symptoms while others have severe effects. In most cases the condition progresses and worsens with age. The most commonly seen traits and problems associated with Marfan Syndrome include the Physical Characteristics of Tall slender build, spidery fingers and toes (Arachnodactyly), and long arms and legs which are disproportionate to the rest of the body.

Individuals may also have Scoliosis (Curvature of the spine), Loose and excessively flexible joints, An abnormally shaped sternum (breastbone) which may protrude outward (pectus carinatum) or bend inward (pectus excavatum), A high arched palate and crowded teeth, Flat feet and a Narrow Face. In the majority of cases the Cardiovascular system (heart and blood vessels) are affected. This involvement is the most serious and accounts for the majority of Marfan related deaths. An aortic aneurysm may occur which is a bulge in the vessel. The aneurysm usually originates at the point where the aorta leaves the heart and it may extend to the abdominal portion of the aorta. Over a period of time constant pressure of the blood passing through this weakened vessel may cause the aneurysm to further enlarge. This enlargement may become more complicated leading to aortic dissection or rupture. Aortic rupture leads to life-threatening internal bleeding which requires immediate surgical intervention. The larger an aneurysm, the more likely the risk of dissection or rupture. Doctors check for aneurysms and monitor the size periodically.

A weakened enlarged aorta doesn't usually cause symptoms but breathlessness may occur if there is a leak of blood back into the heart. Aortic dissection however may cause a sudden, severe stabbing or ripping pain just under the sternum that radiates to the back. Less than half of individuals with Marfan Syndrome survive an Aortic dissection. Marfan syndrome may also affect the mitral valve of the heart causing it to prolapse. This is the valve on the left side of the heart that separates the left atrium from the left ventricle. In Marfan Syndrome the valve is long and floppy and as a result fails to close completely when the left ventricle contracts. This may lead to backflow (Mitral Regurgitation) and associated breathlessness, abnormal heart rhythms (arrhythmias), endocarditis (valve infection) and congestive heart failure.

Most individuals with Marfan Syndrome have problems with their eyes and vision. They often are nearsighted (Myopic), may have Dislocation or shifting of the lens in one or both eyes due to weak suspensory ligaments, Glaucoma (high pressure in the eye), Cataract (cloudy lens) and Retinal Detachment. Unusual bone growth and weak ligaments lead to problems such as scoliosis (curvature of the spine which may be "S" or "C" shaped), Spondylolisthesis where one spinal vertebra slips forward over another leading to back pain and stiffness and Foot Pain as a result of delicate feet. Individuals with Marfan Syndrome develop stretch marks because the skin lacks the proper connective tissue to keep it resilient. These marks usually develop over areas of stress such as the shoulders, hips and low back. Dural Ectasia describes the weakening and expansion of the Dura which is the membrane (composed of connective tissue) that encloses the brain and spinal cord.

With time the enlarged membrane may press on the lower vertebrae of the spine leading to low back pain

and possibly abdominal pain, headache and pain or numbness in the legs.

Relevant Links

West Africa
Health and Medicine
Nigeria

Marfan syndrome is one of the most common of over 100 inherited connective tissue disorders. It affects men and women equally and it occurs in all races and ethnic groups. A team of specialists are usually required to evaluate and manage individuals with Marfan Syndrome. Specialists include Ophthalmologists, Orthopaedic Surgeons, Cardiologists and Medical Geneticists. Treatment is given based on signs, symptoms and presentation.

Clinical history, Family history, Physical examination and Medical investigations are required to make a diagnosis.

Women with aortic aneurysms are advised not to get pregnant because there is an increased risk of aortic dissection and rupture during pregnancy.

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http://en.wikipedia.org/wiki/Paternal_age_effect

The paternal age effect describes the influence that a father's age has on the chances of conferring a genetic defect to his offspring. Generally, older men have a greater probability of fathering children with a genetic defect than younger men do.[citation needed] This is seen as likely due to genetic copying errors which may increase in number after repeated spermatogenesis cycles over a man's lifetime.

Contents
1 Disorders correlated with paternal age
2 See also
3 References
4 External links

Disorders correlated with paternal age
Achondroplasia (dwarfism); craniofacial disorders such as Apert syndrome and Crouzon Syndrome; mental retardation of unknown etiologies; autism; and 25% of schizophrenia cases are correlated with advanced paternal age.

Other disorders related to advanced paternal age are:

Wilms' tumor
Thanatophoric dysplasia
Retinitis pigmentosa
Osteogenesis imperfecta type IIA
Acrodysostosis
Fibrodysplasia ossificans progressiva
Aniridia
Bilateral retinoblastoma
Multiple exostoses
Marfan Syndrome
Lesch-Nyhan syndrome
Pfeiffer Syndrome
Wardenburg Syndrome
Treacher-Collins Syndrome
Soto’s basal cell nevus
Cleidocranial dysostosis
Polyposis coli
Oculodentodigital syndrome
Costello syndrome
Progeria
Recklinghausen’s neurofibromatosis
Tuberous sclerosis
Polycystic kidney disease
Hemophilia A
Duchenne muscular dystrophy
Athetoid Cerebral Palsy
Dystonic Cerebral Palsy
Congenital Hemiplegia

[edit] See also
Maternal age effect

[edit] References
Crow JF (1997). "The high spontaneous mutation rate: Is it a health risk?". PNAS 94: 8380–6.
Bertram L, Busch R, Spiegl M, Lautenschlager NT, Müller U, Kurz A (1998). "Paternal age is a risk factor for Alzheimer disease in the absence of a major gene". Neuroscience 1 (4): 277–80.
Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, Gunnell D (2004). "Paternal age and schizophrenia: a population based (sic) cohort study". BMJ Online.
DNA repair activity linked to paternal age effect. University of Texas Health Science Center at San Antonio (2000-08-28).
Bray I, Gunnell D, Smith GD (2006). "Advanced paternal age: How old is too old?". Journal of Epidemiology and Community Health 60: 851–3.
Montgomery SM, Lambe M, Tomas O, Ekbom A (2004). "Paternal age, family size, and risk of multiple sclerosis". Epidemiology 15 (6): 717–23.
Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap S, Rabinowitz J, Shulman C, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E (2006). "Advancing paternal age and autism". Archives of General Psychiatry 63 (9): 1026–32.
Sanders L (2005). College scientist named Ellison Senior Scholar. University of Southern California College of Letters, Arts & Sciences.
Fisch H, Hyun G, Golden R, Hensle TW, Olsson CA, Liberson GL (2003). "The influence of paternal age on down syndrome (sic)". J Urol 169 (6): 2275–8. PMID 12771769.
Rami B, Schneider U, Imhof A, Waldhör T, Schober E (1999). "Risk factors for type I diabetes mellitus in children in Austria" 158 (5): 362–6. PMID 10333115.
Singh NP, Muller CH, Berger RE (2003). "Effects of age on DNA double-strand breaks and apoptosis in human sperm". Fertility and sterility 80 (6): 1420–30.
Lauritsen MB, Pedersen CB, Mortensen PB (2005). "Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study". J Child Psychol Psychiatry 46 (9): 963–71. PMID 16108999.
Wohl M, Gorwood P (2007). "Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring". Eur Psychiatry 22 (1): 22–6. PMID 17142012.
Schizophrenia Research Forum: Current Hypotheses (2006-03-28).
Choi J-Y, Lee K-M, Park SK, Noh D-Y, Ahn S-H, Yoo K-Y, Kang D (2005). "Association of paternal age at birth and the risk of breast cancer in offspring: a case control study". BMC Cancer 5: 143.
NW Andrology & Cryobank.
Croen LA, Najjar DV, Fireman B, Grether JK (2007). "Maternal and paternal age and risk of autism spectrum disorders". Archives of Pediatrics and Adolescent Medicine 161 (4): 334–40.
Tarin JJ, Brines J, Cano A (1998). "Long-term effects of delayed parenthood". Human Reproduction 13 (9): 2371–6.

when females who carry one good copy and one bad copy of the gene, they are actually affected, whereas males, even when they carry only a bad copy of

2008-05-12T07:37:00.000-07:00

the gene, they are not affected.

researchers discover epilespy mutant geneThe World Today - Monday, 12 May , 2008 13:48:00
Reporter: Nance Haxton
ELEANOR HALL: Researchers in Adelaide have discovered the mutant gene responsible for epilepsy in women.

It’s a groundbreaking discovery and the team from the University of Adelaide and the Adelaide Women's and Children's Hospital has had its findings published today in the journal, Nature Genetics.

One of the lead researchers, Dr Leanne Dibbens, has been speaking to Nance Haxton.

LEANNE DIBBENS: We came across a number of families in which only the females in the family suffered from epilepsy and intellectual disability, and it showed a very unusual inheritance pattern in these families, and that led us to look at what the genetic defect in these families was.

NANCE HAXTON: And what did you find?

LEANNE DIBBENS: We found that these families carry different mutations in the one gene, protocadherin 19, and that when females who carry one good copy and one bad copy of the gene, they are actually affected, whereas males, even when they carry only a bad copy of the gene, they are not affected.

NANCE HAXTON: Is the research now looking at why men don't seem to be affected by this condition, even though they carry the gene that's responsible?

LEANNE DIBBENS: Exactly. We're looking at why males aren't affected with this condition, and we have a lead in that we know that there's a related gene on the Y chromosome, and only males carry a Y chromosome, and so we think that this gene is perhaps protecting or rescuing the males in these families from this condition.

NANCE HAXTON: What sort of ramifications would that have once you actually confirm those reasons? Could it be a possible treatment or a prevention for this disorder, and also for epilepsy in a wider range of people?

LEANNE DIBBENS: The most immediate ramification is that we can now offer genetic counselling to these families that suffer ESMR and people can choose to have pre-natal testing if that's what they desire and make decisions on whether they have daughters with this condition.

And the wider implications are that we now know that this gene family is involved in epilepsy and intellectual disability, and so we'll be looking to see whether this gene or other related genes also play a role in these more common disorders.

NANCE HAXTON: So it's really opened up a whole new realm of research into other related disorders, even such as autism or obsessive disorders as well?

LEANNE DIBBENS: That's right. We'll now be looking at larger groups of patients with epilepsy, intellectual disability, and a number of the females affected in these families have autistic features and obsessive features, and so we'll also be looking at patient cohorts with those features.

NANCE HAXTON: The cause of many of these disorders has ultimately been a mystery for a while hasn't it?

LEANNE DIBBENS: That's right. Very little is known about the genetic causes of epilepsy, even the common epilepsies, intellectual disability. We have come a way in understanding causes of that, but in particular, autism and obsessive traits really, very little is known about the genetic causes of those disorders.

NANCE HAXTON: And particularly given that there's a rise in the occurrence of these conditions, that this has certainly come at a very pivotal or interesting time?

LEANNE DIBBENS: That's right. It gives us a chance now to dive in and look at the roles of the types of genes and what roles are playing in the brain and what happens when these processes go wrong, and why it leads to autism and obsessive traits.

NANCE HAXTON: So it could lead to a treatment and a prevention, or would it be really concentrating on one of those two options?

LEANNE DIBBENS: It's always difficult to predict where the research will go and what it would lead to, but we hope that it will enable more genetic counselling and possibly treatments and ultimately prevention. But that's a few years off yet.

ELEANOR HALL: Dr Leanne Dibbens speaking to Nance Haxton in Adelaide.

Mutant Gene Causes Epilepsy, Intellectual Disability in Women although men carry the ‘bad’ gene, only women are affected.

2008-05-12T07:25:00.000-07:00

Mutant Gene Causes Epilepsy, Intellectual Disability in Women

A mutated gene has been discovered as the key behind epilepsy and mental retardation specific to women, thanks to new research at Adelaide’s Women’s & Children’s Hospital and the University of Adelaide, Australia.

Newswise — A mutated gene has been discovered as the key behind epilepsy and mental retardation specific to women, thanks to new research at Adelaide’s Women’s & Children’s Hospital and the University of Adelaide, Australia.

The world-first discovery, published today in Nature Genetics, shows that although men carry the ‘bad’ gene, only women are affected.

The research has been led by Dr Leanne Dibbens and Associate Professor Jozef Gecz from the Department of Genetic Medicine, Women’s & Children’s Hospital, and the Discipline of Paediatrics at the University of Adelaide. The discovery is a result of a major international collaboration involving the Sanger Institute in Cambridge (UK), Wellcome Trust (UK) and many other collaborators in Australia, the United States, Ireland and Israel.

Their work has linked, for the first time, a large family of genes known as protocadherins with a condition known as “epilepsy and mental retardation limited to females” (EFMR).

Although a relatively uncommon disorder, the condition is hereditary, with successive generations of women affected. In just one of seven families studied across the world, 23 women were affected by the disorder across five generations. This discovery will now enable such families to benefit from genetic counselling, including screening for the genetic mutation at pregnancy.

“This is the first time this type of gene has been found to be involved in epilepsy,” Dr Dibbens says.

“One of the most important discoveries we’ve made is that women in families affected by EFMR carry both a 'good' gene and a 'bad' (mutated) gene, while the men carry only the bad gene. For some reason, the men remain unaffected by the condition,” Dr Dibbens says.

“We suspect this may have something to do with the male Y chromosome, but more research will be needed to find out exactly how or why.”

Dr Dibbens says the gene involved in this discovery is important for cell-to-cell communication in the brain, and could also hold the key to better understanding related issues, such as autism and obsessive disorders.

“With 100 related proteins involved in this gene family, this study could lead to many new areas of research, with the need to understand the role and function of each protein,” she says.

Clinically, the disorder EFMR was first described more than 10 years ago, but the cause of EFMR has been unknown until now. Why females rather males are affected – as is usual for X chromosome associated disorders – makes this a unique disorder among the epilepsies and mental retardations.

For this study, seven families were studied in Australia, the United States, Israel and Ireland. The genetic mutation was discovered in each family.

Crucial to this research was access to state-of-the-art technological support including the sequencing of 737 genes on the X chromosome, which was conducted by collaborators at the Wellcome Trust Sanger Institute in the UK.

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© 2008 Newswise. All Rights Reserved.

Some Autism Could Be Caused by a Single Gene "paternal age is increased among fathers of affected children"

2008-05-03T15:41:00.000-07:00

Nat Rev Genet. 2008 May;9(5):341-55. Links
Advances in autism genetics: on the threshold of a new neurobiology.Abrahams BS, Geschwind DH.
Neurology Department, and Semel Institute for Neuroscience and Behaviour, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769 USA. brett.abrahams@gmail.com

Autism is a heterogeneous syndrome defined by impairments in three core domains: social interaction, language and range of interests. Recent work has led to the identification of several autism susceptibility genes and an increased appreciation of the contribution of de novo and inherited copy number variation. Promising strategies are also being applied to identify common genetic risk variants. Systems biology approaches, including array-based expression profiling, are poised to provide additional insights into this group of disorders, in which heterogeneity, both genetic and phenotypic, is emerging as a dominant theme.

PMID: 18414403 [PubMed - in process]

Related ArticlesThe genetics of autism. [Pediatrics. 2004] What is known about autism: genes, brain, and behavior. [Am J Pharmacogenomics. 2005] Safety and nutritional assessment of GM plants and derived food and feed: The role of animal feeding trials. [Food Chem Toxicol. 2008] Techniques for the identification of genes involved in psychiatric disorders. [Aust N Z J Psychiatry. 2005] Autism: the quest for the genes. [Expert Rev Mol Med. 2007] » See all Related Articles...

A father's legacy to a child's health may start before conception and last generations

2008-04-24T20:23:00.000-07:00

A father's legacy to a child's health may start before conception and last generations
Tina Hesman Saey
Pregnant women know the drill. Don't drink. Don't smoke. Don't eat too much fish. Take vitamins. Mothers have long shouldered the responsibility, and the blame, for their children's health. Fathers don't usually face the same scrutiny.

How a man lives, where he works, or how old he is when his children are conceived doesn't affect their long-term health, scientists used to think. But growing evidence suggests that a father's age and his exposure to chemicals can leave a medical legacy that lasts generations.

Animal studies demonstrate that drugs, alcohol, radiation, pesticides, solvents, and other chemicals can lead to effects that are handed from father to son. Human studies are less clear, but some show that fathers play a role in fetal development and the health of their children.

Teenage dads face increased risk that their babies will be born prematurely, have low birth weight, or die at birth or shortly afterward, a new study in Human Reproduction shows.

Babies of firefighters, painters, woodworkers, janitors, and men exposed to solvents and other chemicals in the workplace are more likely to be miscarried, stillborn, or to develop cancer later in life, according to a review in the February Basic & Clinical Pharmacology & Toxicology.

Fathers who smoke or are exposed at work to chemicals called polycyclic aromatic hydrocarbons put their children at risk of developing brain tumors.

And, older fathers are more likely to have children with autism, schizophrenia, and Down syndrome and to have daughters who go on to develop breast cancer.

Though some of these observations are decades old, attitudes lag even further behind, says Cynthia Daniels, a political scientist at Rutgers University–New Brunswick in New Jersey. Dads aren't held accountable if something goes wrong during fetal development.

Matter of math
Since men make new sperm every 74 days, people used to reason, the genetic slate is wiped clean every couple of months. And even if a man makes defective sperm, the "all-or-nothing" view of reproduction holds that damaged sperm don't fertilize eggs. No harm. No foul.

So no one bothers to remind men to protect themselves against environmental toxins. There are no images of "crack dads" and "crack babies" in the media like those of women who harm developing fetuses with drug and alcohol use, Daniels said in February at a meeting of the American Association for the Advancement of Science held in Boston.

When someone does study fathers-to-be, the focus is usually on fertility, not on the consequences for children's health, she says.

Yet even fertility messages meet resistance from many men.

Harry Fisch, director of the Male Reproductive Center and a urologist at Columbia University Medical Center, found that out when he suggested that men, like women, have ticking biological clocks.

Men can produce sperm throughout life, but that doesn't mean their cells are forever young.

"Every cell in the body ages," says Fisch. "Every cell. The older you get, the more chance of an abnormality. The same thing goes for sperm."

Men younger than 20 and older than 30 make more abnormal sperm than men in their 20s. These damaged sperm could create an unhealthy embryo or pass on damage that could lead to birth defects or illness in offspring.

It is not a popular message.

"Men do not want to hear this," Fisch says. "When my book came out, I got e-mails. I got faxes saying, 'How dare you say this? How can you say this? We know that there are men in their 70s having healthy children.'"

Despite these anecdotal accounts of elderly dads, studies demonstrate that older men are at increased risk of passing on genetic abnormalities. It's a matter of math.

Women are born with all the eggs they will produce in their lifetime. The cells that give rise to eggs divide 24 times, all before birth. But the cells that produce sperm continue to divide throughout a man's lifetime. Each year after puberty, a man's sperm-producing cells replicate about 23 times. Every time the cells divide is another chance for error.

As a result, the sperm produced by a 40-year-old man have gone through about 610 rounds of replication. That's 610 chances of introducing a mutation in the DNA, or improperly divvying up genetic material.

Parents over age 40 are six times more likely to have children with Down syndrome than 25-year-old parents, Fisch and colleagues showed in a 2003 study in the Journal of Urology. An extra copy of chromosome 21 causes Down syndrome. This extra chromosome is just as likely to come from dad as mom in the older couples.

Older dads also have a higher risk of fathering children with rare mutations that cause dwarfism or a premature aging disease called Hutchinson-Gilford progeria syndrome.

But sometimes aging fathers pass along traits that can't be traced to only a single mutation. Fathers 40 and older have an increased chance that their children will develop complex disorders such as autism or schizophrenia. There is growing evidence that those disorders are caused by defects in many genes and the way genes are turned off and on.

Scientists don't yet understand the changes that age induces in sperm-making germ cells, and environmental exposure presents an even bigger mystery. People come in contact with a plethora of chemicals every day. But it is no easy task to sort out exactly which ones, or which combinations, cause heritable problems. The effects chemicals and radiation may have on offspring don't always follow predictable patterns either.

And when researchers do find a clear link between a father's lifestyle and his children's health, it's not always clear what the data mean.

"What we can say is that we identified a group of fathers with adverse outcomes for their fetuses, but we don't have an idea of the mechanism," says Shi Wu Wen of the University of Ottawa in Canada and one of the lead authors of the study showing that babies of teenage fathers have a greater risk of birth problems.

Wen and his colleagues examined birth records for more than 2.6 million babies born between 1995 and 2000 to married, first-time, 20-something mothers in the United States. Looking at the husbands' ages, the team found that babies of teenage fathers, but not middle-age men, had an elevated risk of still birth, low birth weight, and other birth problems. The study was published online Feb. 6 in Human Reproduction.

'Preposterous' inheritance
Some animal studies showing paternal effects emerged years ago but were roundly dismissed, says Gladys Friedler, professor emeritus at Boston University.

OLDER AGE, HIGHER RISK. As men age, they stand a greater chance of fathering children who will develop schizophrenia by age 34. Paternal age is only one of many factors linked to schizophrenia.
E. Roell, (Source: D. Malaspina, et al., Arch. of Gen. Psychiatry, 2001)

Four decades ago, Friedler was studying tolerance to narcotics, one of the first steps of addiction. To find out if a mother rat could pass tolerance on to her offspring along with antibodies and other immune factors, as some scientists theorized, Friedler exposed female rats to morphine before pregnancy. Babies of exposed mothers were born much smaller than average. And those babies also went on to give birth to tiny babies, even though the offspring had never encountered the drug.

Friedler also gave male rats morphine before they bred. "To my total disbelief and bewilderment, paternal exposure also affected progeny," Friedler said at the AAAS meeting.

Her adviser dismissed the result. Morphine doesn't cause mutations, so the idea that males could hand down a trait without passing along a mutation seemed preposterous. The whole thing smacked of Lamarckism, the long-rejected idea that environmental influences can change an animal or plant's structure and offspring can inherit that change.

But in recent decades, scientists have discovered that chemical modifications to DNA and proteins can change the way genes are packaged and regulated without changing the genes themselves. Such modifications are known as epigenetic changes.

"What was Lamarckian is now epigenetic," Friedler says.

Epigenetic modifications act as a molecular scrapbook, preserving memories of events in parents' lives and handing them down to the next generation and beyond.

"There's a chromosomal memory," says Anne Ferguson-Smith, a developmental geneticist at Cambridge University in England. "The chromosomes remember whether they came from the mother or the father."

That memory is established in the form of a chemical mark called methylation. Methylation usually turns a gene off. At least 100 genes in humans are turned off only on the chromosome contributed by the mother or only on the chromosome that came from the father. Such genes are called imprinted genes because of the indelible impression parents leave on their offspring's DNA.

Several imprinted genes help build the placenta or encode growth factors that need to be tightly controlled so an embryo will develop correctly. "There's a contribution from both parents that is essential," Ferguson-Smith says. "One can't do without the other. They must work together to have a healthy offspring."

Imprints and other methylation marks are not encoded in the DNA. Instead the epigenetic modifications decorate chromosomes like ornaments on a Christmas tree. But these ornaments are heirlooms of a different type. It's as if a seedling grows straight from the ground already gussied up with tinsel and lights in the same places its parents were decorated. If a chemical or aging alters the epigenetic pattern on a man's chromosomes, his heirs could bequeath mismarked DNA to their children, too. Some mistakes may be as benign as exchanging a red bulb for a blue one. Other alterations, akin to placing the star on the lowest branch instead of the treetop, are likely to have more profound consequences.

Male mice exposed to cocaine, for example, pass memory problems on to their pups, a 2006 study in Neurotoxicology and Teratology shows. The male mice inhaled cocaine in long daily sessions akin to crack binges. When they mated with females never given coke, they had pups that had trouble learning and remembering where to find food in simple mazes. The problem was especially severe for female offspring. The researchers couldn't find any obvious DNA damage in coke-smoking males' sperm, but did find altered levels of two enzymes involved in the methylation of DNA in sperm-producing tissue in the father mice. The result suggests that epigenetic changes may be responsible for the offspring's behavior problems.

Fungicide legacy
Matthew Anway doesn't know whether the rats in his lab at the University of Idaho in Moscow have methylation problems. Some studies suggest they do, but Anway doesn't yet have definitive proof.

He can prove that male rats exposed to a fungicide in the womb can pass tumors and diseases of the prostate and kidney down for at least three generations. The rats could provide the first model for how prostate disease is inherited, he says.

Male babies born to mothers that had been injected with fungicide had prostate problems that mimic those seen during human aging. The second-generation rats also had more tumors, kidney defects, and higher rates of abscesses, cysts, and other infections than unexposed control rats. Germ cells in the testes of exposed rats also died more quickly than those in the control rats.

Subsequent generations of male rats also had the prostate and testes defects, and both male and female offspring developed kidney problems and tumors.

But only male rats could pass along the defects. The exposed rats bequeathed their fungicide legacy to their sons, grandsons, and great-grandsons even though none of the later generations were exposed to the chemical.

Exposed animals decrease production of enzymes that methylate DNA, Anway says. But he hasn't yet found consistent changes in the methylation patterns in exposed rats.

It's not clear whether Anway's results have any implication for human health. The rats were exposed to extremely high doses of fungicide through the completely unnatural route of injection.

What's important is that the male shares experiences with descendants for years to come. Further research could give new insights, Anway says, into how alterations in early development could lead to adult disease in humans.

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If you have a comment on this article that you would like considered for publication in Science News, send it to editors@sciencenews.org. Please include your name and location.

References:

Anway, M.D., A.S. Cupp, M. Uzumcu, and M.K. Skinner. 2005. Epigenetic transgenerational actions of endocrine disruptors and male fertility. Science 308(June 3):1466-1469. Abstract available at http://dx.doi.org/10.1126/science.1108190.

Anway, M.D., S.S. Rekow, and M.K. Skinner. 2008. Transgenerational epigenetic programming of the embryonic testis transcriptome. Genomics 91(January):30-40. Abstract available at http://dx.doi.org/10.1016/j.ygeno.2007.10.002.

Anway, M.D., and M.K. Skinner. 2008. Transgenerational effects of the endocrine disruptor vinclozolin on the prostate transcriptome and adult onset disease. The Prostate 68(April 1):517-529. Abstract available at http://dx.doi.org/10.1002/pros.20724.

Chen, X.K., S.W. Wen, et al. In press. Paternal age and adverse birth outcomes: Teenager or 40+, who is at risk? Human Reproduction. Available at http://dx.doi.org/10.1093/humrep/dem403.

Choi, J.-Y., et al. 2005. Association of paternal age at birth and the risk of breast cancer in offspring: A case control study. BMC Cancer 5(Oct. 31):143. Available at http://dx.doi.org/10.1186/1471-2407-5-143.

Cordier, S. 2008. Evidence for a role of paternal exposures in developmental toxicity. Basic & Clinical Pharmacology & Toxicology 102(February):176-181. Abstract available at http://www.blackwell-synergy.com/doi/
abs/10.1111/j.1742-7843.2007.00162.x.

Cordier, S., et al. 2004. Parental exposure to polycyclic aromatic hydrocarbons and the risk of childhood brain tumors. American Journal of Epidemiology 159(June 15):1109-1116. Available at http://aje.oxfordjournals.org/cgi/content/full/159/12/1109.

Croen, L.A., et al. 2007. Maternal and paternal age and risk of autism spectrum disorders. Archives of Pediatric and Adolescent Medicine 161(April):334-340. Available at http://archpedi.ama-assn.org/cgi/content/full/161/4/334.

El-Saadi, O., et al. 2004. Paternal and maternal age as risk factors for psychosis: Findings from Denmark, Sweden and Australia. Schizophrenia Research 67(April 1):227-236. Abstract available at http://dx.doi.org/10.1016/S0920-9964(03)00100-2.

Fisch, H., et al. 2003. The influence of paternal age on Down syndrome. Journal of Urology 169(June):2275–2278. Abstract available at http://dx.doi.org/10.1097/01.ju.0000067958.36077.d8.

He, F., I.A. Lidow, and M.S. Lidow. 2006. Consequences of paternal cocaine exposure in mice. Neurotoxicology and Teratology 28(March-April):198–209. Abstract available at http://dx.doi.org/10.1016/j.ntt.2005.12.003.

Lewis, B.H., M. Legato, and H. Fisch. 2006. Medical implications of the male biological clock. Journal of the American Medical Association 296(Nov. 15):2369-2371. Abstract available at http://jama.ama-assn.org/cgi/content/short/296/19/2369.

Thacker, P.D. 2004. Biological clock ticks for men, too. Journal of the American Medical Association 291(April 14):1683-1685. Extract available at http://jama.ama-assn.org/cgi/content/extract/291/14/1683.

Further Readings:

Skinner, M.K. 2008. What is an epigenetic transgenerational phenotype? F3 or F2. Reproductive Toxicology 25(January):2–6. Abstract available at http://dx.doi.org/10.1016/j.reprotox.2007.09.001.

Frequently asked questions from the Epigenome Network of Excellence can be found at http://www.epigenome-noe.net/consulting/webconsulting.php.

Sources:

Matthew Anway
University of Idaho
Department of Biological Sciences
Gibb Hall 239
P.O. Box 443051
Moscow, ID 83844-3051

Sylvaine Cordier
INSERM U625,
GERHM, IFR140,
University of Rennes I,
Campus de Beaulieu
Rennes cedex F-35042
France

Cynthia Daniels
Department of Political Science
Rutgers, the State University of New Jersey
Hickman Hall
89 George Street
Douglass College
New Brunswick, NJ 08901

Anne C. Ferguson-Smith
Department of Physiology, Development and Neuroscience
University of Cambridge
Physiology Building, G-floor Downing Street
Cambridge CB2 3EG
United Kingdom

Harry Fisch
Columbia University
College of Physicians and Surgeons
Department of Urology
944 Park Avenue
New York, NY 10028

Gladys Friedler
4 Newport Road #4
Cambridge, MA 02140

Shi Wu Wen
OMNI Research Group
Department of Obstetrics and Gynecology
University of Ottowa
501 Smyth Road, Box 241
Ottowa, Ontario K1H 8L6
Canada

From Science News, Vol. 173, No. 13, March 29, 2008, p. 200.

Basal cell nevus syndrome is an autosomal dominant condition with complete

2008-03-30T17:37:00.001-07:00

Basal Cell Nevus Syndrome: Guidelines for Early Detection

GEORGE J. BITAR, M.D., Fairfax, Virginia
CHARLES K. HERMAN, M.D., Albert Einstein College of Medicine, Bronx, New York
MOHAMMED I. DAHMAN, M.D., Ain Shams University, Cairo, Egypt
MARTIN A. HOARD, M.D., University of Virginia, Charlottesville, Virginia

Basal cell nevus syndrome is an autosomal dominant condition with complete penetrance and variable expressivity. It is characterized by five major components, including multiple nevoid basal cell carcinomas, jaw cysts, congenital skeletal abnormalities, ectopic calcifications, and plantar or palmar pits. Other features include a host of benign tumors, ocular defects, and cleft lip and palate. Guidelines for diagnosis include a family history, careful oral and skin examinations, chest and skull radiographs, panoramic radiographs of the jaw, magnetic resonance imaging of the brain, and pelvic ultrasonography in women. (Am Fam Physician 2002;65:2501-4. Copyright© 2002 American Academy of Family Physicians.)
A PDF version of this document is available. Download PDF now (4 pages/ 144 KB). More information on using PDF files.

Basal cell nevus syndrome, also known as Gorlin's syndrome, was first reported by Jarisch and White in 1894. The spectrum of disease associated with this syndrome was described in detail by Gorlin in 1960.1 The prevalence is estimated to be 1 per 60,000 persons.2 This syndrome is characterized by five major components as well as other features that may be present (Table 1).3,4 Basal cell nevus syndrome is an autosomal dominant condition with complete penetrance and variable expressivity.5,6 The gene responsible has been localized to chromosome 9q22.1-q31.7,8

Paternal Age Increasing Genetic Disorders in Offspring

2008-03-29T23:59:00.000-07:00

There are two types of paternal age effects. One relates to the autosomes and the other to the X chromosome. New autosomalmutations for dominant conditions show up in the children. Their diseases are due directly to advanced paternal age.

New mutations on the X chromosome are usually not evident in the children. They are transmitted to daughters who are at risk for having sons with X-linked diseases. This is an indirect paternal age effect; it is the effect of the age of the maternal grandfather.

Examples of autosomal dominant conditions associated with advanced paternal age include achondroplasia, neurofibromatosis, Marfan syndrome, Treacher Collins syndrome, Waardenburg syndrome, thanatophoric dysplasia, osteogenesis imperfecta, and Apert syndrome.

Examples of X-linked conditions associated with increased maternal grandfather's age include fragile X, hemophilia A (factor VIII deficiency), hemophilia B (factor IX deficiency), Duchenne muscular dystrophy, incontinentia pigmenti, Hunter syndrome, Bruton-type agammaglobulinemia, and retinitis pigmentosa.

One Third Of Hemophilia is Sporadic

2008-03-22T15:53:00.000-07:00

The mutation originates in the maternal grandfather's sperm

Here are 5 things you didn't know about men by Ross Bonander From Ask Men.com

2008-03-21T15:12:00.000-07:00

"2- Men have their own biological clock
We do indeed have a biological clock of sorts, although instead of one that stops, ours becomes increasingly unreliable over time.

As men age they lose approximately 1% of testosterone every year. The consequence of this deficit is that sperm production decreases, and those that are produced are of a lower quality. For this reason, the older we get the greater the chances that the children we spawn suffer from conditions such as autism, schizophrenia and Down syndrome, to name a few.

To explain why, fertility experts point to cell division: About every 16 days the cells that create sperm and determine their genetic code go through the process of dividing. By the age of 50 that division has happened hundreds and hundreds of times, and each time it did the genetic code was vulnerable to changes that can augment genetic deterioration, making birth defects increasingly likely."

Approximately 50% of affected families have a negative family history;in many of these families, the father is older,

2008-03-08T21:02:00.000-08:00

suggesting that advanced paternal age may influence the NF-1 mutation.NF-2 is an autosomal dominant disorder of chromosome 22; however,many patients have a negative family history

Neurofibromatisis
Neurofibromatosis is a group of inherited development disorders of the nervous system,muscles,bones,and skin that causes formation of multiple,pedunculated,soft tumors, and cafe-au-lait spots. The most common types are NF-1 (von Recklinghausen disease) and NF-2 (bilateral acoustic neurofibromatosis). About 80,000 Americans are known to have neurofibromatosis; in many others, the disorder is overlooked because symptoms are mild. the prognosis varies; however, spinal or intracranial tumors can shorten the patient's life span.Causes and IncidenceNF-1 is an autosomal dominant disorder of chromosome 17 that occurs in about 1 in 30,000 births. Approximately 50% of affected families have a negative family history;in many of these families, the father is older,suggesting that advanced paternal age may influence the NF-1 mutation.NF-2 is an autosomal dominant disorder of chromosome 22; however,many patients have a negative family history.

An Article Published by the Executive Editor of the Simons Foundation, Apoorva Mandavill

2008-03-06T18:27:00.000-08:00

AUTISM AND SCHIZOPHRENIA ARE NOT SINGLE GENE DISORDERS BUT THIS ARTICLE IS IMPORTANT TO STUDY

Father's advanced age feeds autism risk
Helen Pearson
25 February 2008 09:00:00 EST

Children of fathers aged 40 or older are nearly six times morelikely to have autism.
Are older fathers more likely to have children with autism? A series of epidemiological studies is giving credence to the idea, suggesting that, with age, sperm may accumulate damage that increases risk in the next generation.
Advancing age of the father is known to be a significant risk factor for schizophrenia1. These studies — along with anecdotal suggestions that fathers of autistic children tend to be older than average — prompted Avi Reichenberg of Mount Sinai School of Medicine, New York, to launch one of the first thorough epidemiological investigations into a link between the two.
Reichenberg and his colleagues had access to a vast database of health information collected from more than 132,000 Israeli adolescents who underwent draft board assessment, including psychiatric screening, before entering the army. The researchers were able to identify those who were diagnosed with autism spectrum disorders (ASD), along with the age of their parents.
Children of fathers in their 30s are about 1.6 times more likely to have ASD than children of fathers below age 30, the study found2. Compared with the youngest group, children of fathers aged 40 or older were nearly six times more likely to have ASD. “It was much stronger than we had thought,” Reichenberg says.
Since then, a handful of other epidemiology studies have backed the autism-paternal age connection. In one of these3, a team led by Lisa Croen of Kaiser Permanente Northern California Division of Research in Oakland, California, mined a health database of more than 130,000 births and found that each decade of paternal or maternal age increased risk of autism spectrum disorder by around 30%.
Paternal age “is still a relatively small contributor,” Croen says, “but when you see something that keeps coming up in different populations and study designs you start thinking there must be something to this.”
The link may be real, but researchers have yet to explain what causes it. Perhaps, says Croen, older parents are simply more attuned to the development of their children and therefore more likely to get a diagnosis. “It could be an artifact,” she says. “We don’t have enough data yet to really rule that out.”
Genetic origins
Another simple explanation is that fathers who themselves have autism or mild social deficits are likely to marry and have children at a later age than other men, and these children inherit factors putting them at high risk of developing the condition themselves.
But Reichenberg says that in his studies he has found no link between traits such as shyness, sensitivity and aloofness in parents and the age at which they have children. “It’s not definitive but the evidence is definitely against such an explanation,” he says.
Many researchers instead favor a genetic origin for the phenomenon. Male germ cells go through multiple rounds of division to manufacture sperm throughout a man’s life and, according to one idea, they may accumulate DNA damage as the molecule is copied again and again.
Sperm produced by older men are more likely to carry genetic defects, and these defects could boost their children’s risk of autism. Female germ cells divide far fewer times.
It is also possible that older sperm are more likely to acquire epigenetic defects: ones that do not change the DNA sequence itself, but that alter the activity of genes due to structural or chemical changes to DNA such as methylation.
These genetic changes arise in the egg or sperm rather than being inherited from the parents. Both concepts fit with the knowledge that the majority of ASD cases have a genetic cause, even though they are also the first in a family.
For precedent, geneticists point to a condition called achondroplasia, a common cause of dwarfism and the textbook example of a genetic condition associated with paternal age. The risk of sperm carrying a single point mutation in the gene for a growth factor receptor is thought to increase with the age of the father.
“It would be overwhelmingly logical,” for something similar to be going on in some cases of autism, says human geneticist Arthur Beaudet at Baylor College of Medicine in Houston, Texas. Perhaps just one or two of the many genes associated with the disorder are susceptible to detrimental point mutations as the germ cells age.
Beaudet says he would like to see genetic and epigenetic analyses of single sperm to see if mutation rates differ in the fathers of autistic children, and between younger and older men. “That would be the approach I’d be enthusiastic about,” he says. Reichenberg says that he is pursuing such studies.
Because there are few clearly defined genes for autism risk, it’s not yet clear where to look for these increased mutation rates. And genome-wide studies looking for differences in the rates of point mutations in many sperm are still too expensive and laborious.
Copy numbers
Last year, molecular studies showed that mutations called copy number variations (CNVs) — genomic chunks that can be deleted or duplicated from one person to the next — appear to be major contributors to sporadic autism.
A group led by Michael Wigler and Jonathan Sebat at the Cold Spring Harbor Laboratory in New York looked for CNVs that were present in autistic individuals, but not in their parents. They found CNVs in 10% of children with sporadic autism, 2% of those with familial autism and 1% of controls4.
This suggests that many more cases of sporadic autism may be attributable to spontaneous mutations — either CNVs or more subtle mutations — than had been realized.
Sebat has not examined whether the frequency of these CNV mutations increases in aging germ cells — but he suspects it might. “We don’t have data one way or the other,” he says, “but it’s a very tantalizing hypothesis.”
Many of the cellular systems that protect DNA from mutation might begin to fail in aging germ cells, so that their mutation rate increases, Sebat suggests. He is planning to test in a larger group of autistic individuals whether the CNV mutations are more common in children of older parents.
Reichenberg and his colleagues are also testing these hypotheses. In one study, they are trying to compare old and young fathers of autistic children, looking for differences in the rate of new mutations and their association to genetic hotspots previously linked to autism.
They are also doing mouse studies to explore whether offspring of older males tend to suffer more behavioral problems that mimic autism.
There remains some debate about whether the mother’s age is as important a risk factor as that of the father, and studies have differed in their findings. A maternal age effect is harder to tease out, partly because women have children within a more limited age range than men: very few over-40 women have children.
In her study, Croen found that maternal age is just as important and says that other studies have lacked the statistical power to tease this out. “Our data show that maternal age is also in the mix,” she says.
The fact that schizophrenia risk also increases with age leads some researchers to wonder whether some of the same genes may contribute to both disorders – and perhaps to other psychiatric conditions as well.
It’s a “feasible hypothesis”, Reichenberg says, “and I believe a worthwhile one to pursue.”
References:
Malaspina D et al. Arch. Gen. Psychiatry 58, 361-367 (2001) PubMed ↩
Reichenberg A. et al. Arch. Gen. Psychiatry 63, 1026-1032 (2006) PubMed ↩
Croen L. et al. Arch. Pediatr. Adolesc. Med. 161, 334-340 (2007) PubMed ↩
Sebat J. et al. Science 316, 445-449 (2007) PubMed ↩
posted by ApoorvaMandavilli
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The paternal component of this parental age effect was the major factor in the occurrence of such mutations

2007-07-05T17:00:00.000-07:00

Genetika. 1984 Oct;20(10):1726-32.Links
[Analysis of the relation of the frequency of new gene mutations for Mendelian diseases to parental age][Article in Russian]

Bazhenova MD, Kozlova SI, Al'tshuler BA, Tatishvili GG.
The effect of parental age on mutation rates of achondroplasia, neurophibromatosis, hereditary gastrointestinal adenomatosis and Duchenne muscular dystrophy loci was studied. A significant parental age effect on the occurrence of new mutations for achondroplasia and neurophybromatosis was shown. The paternal component of this parental age effect was the major factor in the occurrence of such mutations. The risk of the occurrence of new cases of achondroplasia and neurophybromatosis, as compared with their overall frequency, due to new mutations, are increased by a factor of 2 and 3, respectively, up to the paternal age of 50. The possibility of application of the data obtained in genetic counselling is discussed.

PMID: 6149974 [PubMed - indexed for MEDLINE]

Duchenne New Mutants Could Be Prevented With Younger Paternal Age At Conception

2007-07-05T16:27:00.000-07:00

: J Med Genet. 1978 Oct;15(5):339-45.Links
Estimation of proportion of new mutants among cases of Duchenne muscular dystrophy.Davie AM, Emery AE.
Using a number of different methods, it is confirmed that approximately one third of all cases of X-linked Duchenne muscular dystrophy are new mutants, the remainder being sons of carriers.

1: Am J Med Genet. 1980;7(1):27-34.Links
Frequency of new mutants among boys with Duchenne muscular dystrophy.Bucher K, Ionasescu V, Hanson J.
Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explantation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population or intrapedigree controls (29.5 +/- 1.3).PMID: 7211951 [PubMed - indexed for MEDLINE]

CHD7 Gene and Scoliosis Maternal Age??? Or is Paternal Age Involved???

2007-07-02T13:47:00.000-07:00

Physicians have recognized scoliosis, the abnormal curvature of the spine, since the time of Hippocrates, but its causes have remained a mystery -- until now. For the first time, researchers have discovered a gene that underlies the condition, which affects about 3 percent of all children.

The new finding lays the groundwork for determining how a defect in the gene -- known as CHD7 -- leads to the C- and S-shaped curves that characterize scoliosis. The gene's link to scoliosis was identified by scientists at Washington University School of Medicine in St. Louis, working in collaboration with investigators at the University of Texas Southwestern Medical Center and Texas Scottish Rite Hospital for Children, both in Dallas, Rutgers State University of New Jersey and the University of Iowa. The group published its results in May in the American Journal of Human Genetics.

"Hopefully, we can now begin to understand the steps by which the gene affects spinal development," says Anne Bowcock, Ph.D., professor of genetics, of medicine and of pediatrics. "If we understand the genetic basis of the condition, we can theoretically predict who is going to develop scoliosis and develop treatments to intervene before the deformity sets in. It may take many years to accomplish these goals, but I think it will eventually happen."

The researchers have traced a defect in CHD7 to idiopathic scoliosis, the form of the condition for which there is no apparent cause. It is the most common type of scoliosis, occurs in otherwise healthy children and is typically detected during the growth spurt that accompanies adolescence.

Although scientists have known for years that scoliosis runs in families, its pattern of inheritance has remained unclear. That's because the condition is likely caused by several different genes that work in concert with one another -- and the environment -- to cause scoliosis. Bowcock predicts that scientists will soon find other genes involved in the disease.

The CHD7 gene is thought to play a critical role in many basic functions in the cell. The researchers zeroed in on the gene after finding that it is missing or profoundly disrupted in a rare syndrome called CHARGE. Babies born with the syndrome often die in infancy. Those that survive have heart defects, mental retardation, genital and urinary problems, ear abnormalities and deafness, among other problems. They also develop late-onset scoliosis.

"This led us to consider that milder variations of CHD7 may be involved in other types of scoliosis," Bowcock said.

The researchers, led by Carol Wise, Ph.D., at Scottish Rite Hospital, collected data on 52 families with a history of scoliosis in at least two members -- the one who sought treatment and another from earlier generation. The patients had an average spinal curvature of 40 degrees and did not have any illnesses, such as Marfan syndrome or cerebral palsy, which can also involve scoliosis. The researchers performed genome-wide scans that spelled out the 6 billion letters of genetic code in the affected family members and analyzed the data.

They found that patients with scoliosis very often had a defect in the gene's non-coding region, meaning that the error did not disrupt production of the CHD7 protein. The researchers speculate that this particular mutation alters the binding of a molecule that controls whether the gene is turned on. In this case, they think the gene is turned off more often than it should be, which reduces the amount of CHD7 protein produced.

"The change in the amount of the protein produced is subtle, which correlates with the onset of scoliosis, which typically happens very gradually," explains Michael Lovett, Ph.D., professor of genetics and pediatrics. "This particular defect was so highly associated with scoliosis that it is either the real McCoy or is very closely linked to the defect that causes the condition."

The researchers will continue to look for genetic variations involved in scoliosis by studying additional families with the condition.

Severe scoliosis is typically treated by surgery or by wearing an orthopedic brace, which straightens the curvature over time. Most minor spinal curves can be monitored by a doctor and do not progress to the point where treatment is necessary.

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1: J Bone Joint Surg Am. 1990 Jul;72(6):910-3. Related Articles, Links

Influence of parental age on degree of curvature in idiopathic scoliosis.

Henderson MH, Rieger MA, Miller F, Kaelin A.

Department of Medical Education, Alfred I. duPont Institute, Wilmington, Delaware 19899.

One hundred and seventy-seven patients who had adolescent idiopathic scoliosis were followed from the time of the initial evaluation to skeletal maturity or arthrodesis. At that time, we analyzed the degree of curvature to determine if it was related to parental age at the time of the patient's birth. Patients who were born to mothers who were twenty-seven years old or more had a mean curve of 35.2 degrees, which was significantly greater (p = 0.02) than that of patients whose mothers were younger than twenty-seven years, who had a mean curve of 30.4 degrees. More patients whose mothers were twenty-seven years old or older ultimately needed arthrodesis than did those whose mothers were younger than twenty-seven years (26 compared with 12 per cent). Therefore, a maternal age of twenty-seven years old or more is a risk factor for greater progression of the curve and indicates a potential need for arthrodesis. No difference in the degree of curvature was seen when the patients were grouped according to paternal age.

"Common KIBRA alleles are associated with human memory performance

2007-07-02T10:07:00.000-07:00

Genetics of Human Memory Performance

December 2006

Researchers at the Translational Genomics Research Institute (TGen) in Phoenix and the University of Zurich have discovered a genetic variation in the human KIBRA gene associated with short-term memory performance, a finding that may shed light on devastating memory-based diseases such as Alzheimer's and Parkinson's.

"This is a generally applicable association finding," said Dietrich Stephan, head of the Neurobehavioral Research Unit at TGen. "In fact, probably about 50 percent of people worldwide have the at-risk haplotype and about 50 percent have the good haplotype."

The team, led by Stephan and Andreas Papassotiropoulos, made the discovery using the Affymetrix Human Mapping 500K Array Set; the study is the first published research using genotype data from 500,000 SNPs for whole-genome association analyses.

"Whole-genome association works at this density in outbred populations," said Stephan. "The ramifications for understanding disease process and for early diagnostics are huge."

Stephan's team discovered that genetic changes in the gene encoding the KIBRA protein correlated with the ability to perform memory-based tasks in a cohort of 341 students at the University of Zurich. They confirmed this association in additional Swiss and U.S. cohorts.

Gene expression studies showed that the KIBRA transcript is present at high levels in the human brain, especially in the hippocampus, a part of the brain critical in memory function. The team also performed functional magnetic resonance imaging, which showed that activation in the hippocampus during memory retrieval differs depending on the KIBRA allele.

The study, "Common KIBRA alleles are associated with human memory performance," appears in the October 20, 2006, issue of Science.

Rates of birth defects such as achondroplasia (short stature) and autism is higher among children with older fathers. Single and multi gene disorders

2007-07-01T18:56:00.000-07:00

"It is curious that although sperm have been around since the beginning of time, we know so little about what is in them, and what makes them tick, er, swim. So scientists spend a lot of their waking hours trying to compare the structure and content of the proteins of sperm in various species, in order to understand their evolution and origin. For instance, the mutated DNA in the genes of the sperm of older fathers is believed to cause many genetic diseases. It is almost as if a man’s biological clock accelerates mutation in sperm cells in his early ’30s."

and

Birth Defects Higher Among Children with Older Fathers
Older men have an increased risk of having a child with abnormalities, new research suggests.

The common belief is that there is no age limit for men when it comes to fathering a child. Unlike women who undergo menopause, men do not have a fixed “andropause”. However, this view is being challenged as new evidence shows that the rates of birth defects such as achondroplasia (short stature) and autism is higher among children with older fathers.

A recent study carried out at a large Israeli army database found that children of men over 40 were 5.75 times more likely to have an autism disorder than those who had fathers under 30. Another Israeli study suggested that the risk of schizophrenia in children is almost double if the father is in his late 40s.

Prof Sheena Lewis, a consultant in reproductive medicine at Queen's University Belfast, said that as men get older their sperm DNA becomes more fragmented. By the time a man is 50, the cells that create a man’s sperm have replicated up to 800 times, creating many possibilities for error.

According to Prof Lewis:

The impact of the father smoking is even worse than the mother smoking (you can't repair damage caused in sperm DNA)
Viagra can affect fertility by causing the sperm to travel too fast
Cannabis us slows sperm function, resulting in a reduction in fertility
She also warns about the damaging impact of modern lifestyle and environmental factors.

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Most Common Cause of Progeria is a single-letter misspelling in a gene on chromosome 1 codes for lamin A protein key component of nuclear membrane

2007-05-31T21:57:00.000-07:00

Researchers Identify Gene for Premature Aging Disorder
Progeria Gene Discovery May Help Solve Mysteries of Normal Aging
WASHINGTON, D.C., April 16, 2003 - A team led by the National Human Genome Research Institute today announced the discovery of the genetic basis of a disorder that causes the most dramatic form of premature aging, a finding that promises to shed new light on the rare disease, as well as on normal human aging.

In their study, to be released online next week in the journal Nature, researchers identified the genetic mutations responsible for Hutchinson-Gilford progeria syndrome (HGPS), commonly referred to as progeria. Derived from the Greek word for old age, "geras," progeria is estimated to affect one in 8 million newborns worldwide. There currently are no diagnostic tests or treatments for the progressive, fatal disorder.

Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute (NHGRI) and leader of the research team, said, "This genetic discovery represents the first piece in solving the tragic puzzle of progeria. Without such information, we in the medical community were at loss about where to focus our efforts to help these children and their families. Now, we finally know where to begin."

Dr. Collins added, "The implications of our work may extend far beyond progeria to each and every human being. What we learn about the molecular basis of this model of premature aging may provide us with a better understanding of what occurs in the body as we all grow older."

In addition to NHGRI, the multi-institution research team included scientists from the Progeria Research Foundation; the New York State Institute for Basic Research in Developmental Disabilities in Staten Island, N.Y.; the University of Michigan in Ann Arbor; and Brown University in Providence, R.I.

W. Ted Brown, M.D., Ph.D., co-author of the study and chairman of the Department of Human Genetics at the Institute for Basic Research, said, "Many people consider progeria to be the most dramatic example of a genetic disease that clearly resembles accelerated aging. The children appear to have an aging rate that is 5 to 10 times what is normal." Dr. Brown is widely regarded as the world's leading clinical expert on progeria.

Children with progeria usually appear normal at birth. However, within a year, their growth rate slows and their appearance begins to change. Affected children typically become bald with aged-looking skin and pinched noses. They often suffer from symptoms typically seen in elderly people, especially severe cardiovascular disease. Death occurs on average at age 13, usually from heart attack or stroke.

Leslie Gordon, M.D., Ph.D., medical director of the Progeria Research Foundation (PRF) and executive director of the PRF Genetics Consortium, said, "Isolating this gene is just the beginning. It is our goal to find treatments and possibly a cure for this rare, life-threatening disease that robs children of their adulthood. The Progeria Research Foundation will continue to lead the fight against progeria."

In 2001, PRF co-hosted a workshop with various institutes and centers of the National Institutes of Health (NIH), including the National Institute on Aging and the Office of Rare Diseases. The workshop brought together leading scientists from around the world to identify promising areas of research in progeria. This partnership eventually led to funding for progeria research and the formation of the PRF Genetics Consortium, a group of 20 scientists whose common goal is to find the genetic cause of progeria and to develop ways of treating the disease. Six of those scientists are co-authors of the study to be published in Nature.

Dr. Collins commended the collaborative efforts, saying, "The Progeria Research Foundation's commitment and cooperation played a key role in the hunt for the disease gene. They brought the urgent need to find this gene to the attention of the biomedical research community."

Earlier this week, Dr. Collins, as leader of the Human Genome Project, announced the successful completion of the international project's effort to sequence the 3 billion letters that make up the human genetic instruction book. "Free and unrestricted access to the human genome sequence is greatly speeding the pace of disease gene discovery. Finding the gene for progeria would have been impossible without the tools provided by the Human Genome Project," said Dr. Collins, who still spends some of his time in a small research lab at the National Institutes of Health (NIH). "This was a particularly challenging project for the gene hunters, since there are no families in whom the disease has recurred, and geneticists generally depend on such families to track the responsible gene. This was a detective story with very few clues."

Taking advantage of an array of genomic technologies - from whole-genome scans to high-throughput sequencing of targeted DNA regions - researchers determined the most common cause of progeria is a single-letter "misspelling" in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell's nucleus. Specifically, the researchers found that 18 out of 20 children with classic progeria harbored exactly the same misspelling in the lamin A (LMNA) gene, a substitution of just a single DNA base - a change from cytosine (C) to thymine (T) - among the gene's 25,000 base pairs. In addition, one of the remaining progeria patients had a different single base substitution - guanine (G) to adenine (A) - just two bases upstream. In every instance, the parents were found to be normal indicating that the misspelling was a new, or "de novo," mutation in the child.

At first glance, the point substitution in the LMNA gene would appear to have no effect on the production of lamin A protein. "Initially, we could hardly believe that such a small substitution was the culprit. How could these bland-looking mutations lead to such terrible consequences in the body?" said NHGRI's Maria Eriksson, Ph.D., a post-doctoral fellow in Dr. Collins' lab and the first author of the study.

However, when Dr. Eriksson conducted laboratory tests on cells from progeria patients, she found that the minute change in the LMNA gene's DNA sequence dramatically changed the way in which the sequence was spliced by the cell's protein-making machinery. The end result was the production of an abnormal lamin A protein that is missing a stretch of 50 amino acids near one of its ends.

To determine what effect abnormal lamin A has upon cells, the NHGRI-led team used fluorescent antibodies to track lamin A in skin cells taken from progeria patients known to have the common misspelling, as well as skin cells taken from unaffected people. The studies showed that about half of the cells from the progeria patients had misshapen nuclear membranes, compared with less than 1 percent of the cells from the unaffected controls.

"We suspect that this instability of the nuclear membrane may pose major problems for tissues subjected to intense physical stress - tissues such as those found in the cardiovascular and musculoskeletal systems, which are so severely affected in progeria," said Dr. Eriksson, noting that nuclear instability ultimately may lead to widespread death of cells.

Researchers hope to move their new findings into the clinic almost immediately with the development of a genetic test for progeria. Such a test will help doctors diagnose or rule out progeria in young children much earlier than their current method of looking at outward physical changes.

The new findings also may have implications for the treatment of progeria, with the newfound understanding of progeria's molecular roots pointing to possible therapeutic approaches. For example, researchers plan to explore the possibility that statins and/or other drugs known to inhibit a step in protein processing, known as farnesylation, might reduce the production of abnormal lamin A in progeria patients. Another avenue for identifying possible therapies involves screening large libraries of chemical molecules with the hope of finding a compound that can reverse the nuclear membrane irregularities seen in the cells of progeria patients.

"It is impossible to predict how soon our findings will translate into treatments for children suffering from progeria. We and other researchers across the nation will be working hard to find ways of helping them. Unfortunately, as we have witnessed with other genetic discoveries, the road from the lab to the clinic is not always swift or smooth," Dr. Collins said.

More also remains to be done to determine what role the LMNA gene may play in the normal aging process. "Aging clearly has a strong genetic component. Discovery of this key genetic mutation that causes progeria may lead to a much clearer understanding of what causes aging in us all. Eventually, this information may lead to improvements in health care for our aging population," said Dr. Brown.

Researchers plan to look at the LMNA genes of people who are exceptionally long-lived to see if there are any variants of the gene associated with longevity. Other studies might focus on determining whether repeated damage to the LMNA gene over the course of a lifetime may influence the rates at which people age.

"Our hypothesis is that LMNA may help us solve some of the great mysteries of aging," Dr. Collins said. "However, it will probably take more than one genetic key to unlock the secrets to a biological process as complex as aging. There are probably a host of other genes related to aging still waiting to be discovered."

Another interesting footnote to the recent findings is that different mutations in other regions of the LMNA gene previously have been shown to be responsible for a half-dozen other rare, genetic disorders. Those disorders are: Emery-Dreifuss muscular dystrophy type 2; limb girdle muscular dystrophy type 1B; Charcot-Marie-Tooth disorder type 2B1; the Dunnigan type of familial partial lipodystrophy; mandibuloacral dysplasia; and a familial form of dilated cardiomyopathy.

Prior to coming to NIH to lead the Human Genome Project in 1993, Dr. Collins had established a reputation as a relentless gene hunter using an approach that he named "positional cloning." In contrast to previous methods for finding genes, positional cloning enabled scientists to identify disease genes without knowing in advance what the functional abnormality underlying the disease might be. Dr. Collins' lab, together with collaborators, applied the new approach in 1989 in their successful quest for the long-sought gene responsible for cystic fibrosis. Other major discoveries soon followed, including identification of the genes for neurofibromatosis; Huntington's disease; multiple endocrine neoplasia type 1; one type of adult acute leukemia; and Alagille syndrome.

NHGRI is one of the 27 institutes and centers at the NIH, which is an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site: www.genome.gov.

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A DIRECT CAMPAIGN FOR FATHERS TO COMPLETE THEIR FAMILIES BEFORE THE AGE OF 35 MAY HAVE A MEASUREABLE EFFECT IN THE PREVENTION OF DOMINANT MUTATIONS

2007-05-28T16:46:00.000-07:00

1: Am J Med Genet. 1988 Dec;31(4):845-52. Links
Prevalence of dominant mutations in Spain: effect of changes in maternal age distribution.Martinez-Frias ML, Herranz I, Salvador J, Prieto L, Ramos-Arroyo MA, Rodriguez-Pinilla E, Cordero JF.
Estudio Colaborativo Espanol de Malformaciones Congenitas (ECEMC), Facultad de Medicina, Universidad Complutense, Madrid, Spain.
We studied the birth prevalence of autosomal dominant mutations in Spain and estimated how a decrease in maternal age distribution may lead to reduction in dominant mutations. The data were collected by the Estudio Colaborativo Espanol de Malformaciones Congenitas from April, 1976, to December, 1985. Among 553,270 liveborn infants monitored during the period, 66 infants with autosomal dominant conditions were identified. These included Apert, Crouzon, Hay-Wells, Treacher-Collins, Robinow, Stickler, Adams-Oliver, and the blepharophimosis syndromes, achondroplasia, cleidocranial dysostosis, and thanatophoric dysplasia. The overall rate of autosomal dominant conditions was 1.2 per 10,000 liveborn infants. Thirteen (20%) had an affected relative, and 52 (79%) had a negative family history. One case was excluded because of insufficient family data. The rate of autosomal dominant mutations was 0.9 per 10,000 liveborn infants, or 47 per 1 million gametes. A reduction in the maternal age distribution of mothers age 35 years and older from the current 10.8% to 4.9%, as in Atlanta, Georgia, would reduce the rate of Down syndrome in Spain by 33% and through a change in parternal age distribution may lead to a reduction in dominant mutations of about 9.6%. This suggests that a public health campaign to reduce older maternal age distribution in Spain may also lead to a reduction in dominant mutations and emphasizes the potential that a direct campaign for fathers to complete their families before age 35 years may have a small, but measurable, effect in the primary prevention of dominant mutations.

PMID: 3239577 [PubMed - indexed for MEDLINE]

Paternal Age 4 years older than general population in Paternal Germline Origin of PTPN11 Mutations in Noonan Syndrome

2007-05-18T19:35:00.000-07:00

Paternal Germline Origin and Sex-Ratio Distortion in Transmission of
PTPN11 Mutations in Noonan Syndrome
Marco Tartaglia,1,2 Viviana Cordeddu,1 Hong Chang,4 Adam Shaw,5 Kamini Kalidas,5
Andrew Crosby,5 Michael A. Patton,5 Mariella Sorcini,1 Ineke van der Burgt,6 Steve Jeffery,5
and Bruce D. Gelb2,3
1Dipartimento di Biologia Cellulare e Neuroscienze, Istituto Superiore di Sanita`, Rome; Departments of 2Pediatrics and 3Human Genetics,
Mount Sinai School of Medicine, New York; 4Health Institute, Division of Clinical Care Research, Tufts–New England Medical Center, Boston;
5Division of Medical Genetics, St. George’s Hospital Medical School, London; and 6Department of Medical Genetics, University Hospital
Maastricht, Maastricht, The Netherlands
Germline mutations in PTPN11—the gene encoding the nonreceptor protein tyrosine phosphatase SHP-2—represent
a major cause of Noonan syndrome (NS), a developmental disorder characterized by short stature and facial
dysmorphism, as well as skeletal, hematologic, and congenital heart defects. Like many autosomal dominant disorders,
a significant percentage of NS cases appear to arise from de novo mutations. Here, we investigated the
parental origin of de novo PTPN11 lesions and explored the effect of paternal age in NS............

For comparison with other studies of
advanced paternal age, we noted that the average paternal
age of the PTPN11-related cohort was 35.6 years,
which was 6.1 years older than the population average
for the children’s average year of birth (1980). For the
PTPN11-negative cohort, the average paternal age was
33.4 years, which was 4.0 years older than the population
average for the children’s average year of birth
(1981)........

The data presented here provide the first evidence for
a paternal origin of de novo PTPN11 mutations in NS
and for their association with advanced paternal age.
This finding confirms previous studies supporting a predominance
of paternal origin of point mutations in the
majority of autosomal dominant diseases. It is clear that
this predominance does not reflect some genetic quirk
isolated to the FGFR genes, nor does it necessitate a
restricted molecular diversity of mutations, as observed
in some disorders (e.g., achondroplasia). The higher level
of DNA methylation in spermatagonia—compared with
that in oogonia—which would predict increased substitutions
at CpG dinucleotides, has been suggested as an
important contributing factor. .....

Our results show some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation

2007-05-18T08:28:00.000-07:00

1: Am J Hum Genet. 1994 Jun;54(6):989-1003. Links
Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.Pegoraro E, Schimke RN, Arahata K, Hayashi Y, Stern H, Marks H, Glasberg MR, Carroll JE, Taber JW, Wessel HB, et al.
Department of Molecular Genetics, University of Pittsburgh, School of Medicine, PA 15261.

Duchenne muscular dystrophy is one of the most common lethal monogenic disorders and is caused by dystrophin deficiency. The disease is transmitted as an X-linked recessive trait; however, recent biochemical and clinical studies have shown that many girls and women with a primary myopathy have an underlying dystrophinopathy, despite a negative family history for Duchenne dystrophy. These isolated female dystrophinopathy patients carried ambiguous diagnoses with presumed autosomal recessive inheritance (limb-girdle muscular dystrophy) prior to biochemical detection of dystrophin abnormalities in their muscle biopsy. It has been assumed that these female dystrophinopathy patients are heterozygous carriers who show preferential inactivation of the X chromosome harboring the normal dystrophin gene, although this has been shown for only a few X:autosome translocations and for two cases of discordant monozygotic twin female carriers. Here we study X-inactivation patterns of 13 female dystrophinopathy patients--10 isolated cases and 3 cases with a positive family history for Duchenne dystrophy in males. We show that all cases have skewed X-inactivation patterns in peripheral blood DNA. Of the nine isolated cases informative in our assay, eight showed inheritance of the dystrophin gene mutation from the paternal germ line. Only a single case showed maternal inheritance. The 10-fold higher incidence of paternal transmission of dystrophin gene mutations in these cases is at 30-fold variance with Bayesian predictions and gene mutation rates. Thus, our results suggest some mechanistic interaction between new dystrophin gene mutations, paternal inheritance, and skewed X inactivation. Our results provide both empirical risk data and a molecular diagnostic test method, which permit genetic counseling and prenatal diagnosis of this new category of patients.

PMID: 8198142 [PubMed - indexed for MEDLINE

It is confirmed that approximately 1/3 of all cases of X-linked Duchenne muscular dystrophy are new mutants, the remainder being sons of carriers

2007-05-18T08:24:00.000-07:00

1: J Med Genet. 1978 Oct;15(5):339-45. Links
Estimation of proportion of new mutants among cases of Duchenne muscular dystrophy.Davie AM, Emery AE.
Using a number of different methods, it is confirmed that approximately one third of all cases of X-linked Duchenne muscular dystrophy are new mutants, the remainder being sons of carriers.

PMID: 739522 [PubMed - indexed for MEDLINE]

6/10 cases of haemophilia-B the de novo mutations in the carriers mothers were found to be of paternal origin

2007-05-18T07:52:00.000-07:00

1: Eur J Haematol. 1992 Mar;48(3):142-5. Links
Origin of mutation in sporadic cases of haemophilia-B.Kling S, Ljung R, Sjorin E, Montandon J, Green P, Giannelli F, Nilsson IM.
Department for Coagulation Disorders, University of Lund, Malmo General Hospital, Sweden.

Of the 45 haemophilia-B patients registered at the haemophilia centre in Malmo, Sweden, 24 are the sole members of their families to be affected, and in 13 of these 24 cases, ascendant relatives are available for study. Detection of the gene defect showed the mutation to be de novo in the proband in 3 of these 13 cases, and inherited from a carrier mother in the remaining 10 cases. All 10 carrier mothers were shown to have de novo mutations, as the patients' grandfathers were phenotypically and/or haematologically normal, and the grandmothers were non-carriers. Seven restriction fragment length polymorphisms (RFLPs) of the factor IX gene were used to determine whether the de novo mutations of the 10 carrier mothers were of paternal or maternal origin. In 6/10 cases, the RFLP patterns were informative, and indicated the mutation to be of paternal origin.

HEMOPHILIA B A PATERNAL AGE EFFECT COULDN'T BE EXCLUDED

2007-05-18T07:45:00.000-07:00

1: Am J Hum Genet. 1992 Jan;50(1):164-73. Links
Parental origin of factor IX gene mutations, and their distribution in the gene.Ludwig M, Grimm T, Brackmann HH, Olek K.
Institute of Experimental Haematology and Blood Transfusion, Bonn, Germany.

Genomic amplification followed by direct sequencing enabled us to establish the causative mutation in 67 unrelated hemophilia B patients of predominantly German origin. With the detection of the mutation, extensive pedigree analysis has become feasible. We therefore anticipated that determination of the origin of mutation could be achieved in a comparatively great number of families. Although these investigations often were restricted by the availability of blood samples from the maternal grandparents or great-grandparents, we were able to prove a de novo mutation in 9 of 20 families with sporadic hemophilia B and in 3 of 20 families with a history of the disease. This could be achieved with the aid of RFLP analysis and, in one case, where the mutation is still unknown, with the aid of biochemical and immunological factor IX assays. Since the maternal grandfather was decreased in two of these families, the germ line of origin could not be determined precisely. In the remaining families, the female and male germ lines turned out to be the origin of mutation in six and four cases, respectively, and an effect of paternal age on the mutations observed could not be excluded. Furthermore, our data indicate that the hemophilia B gene pool is mainly renewed byvariable mutations.

8 of the 61 Hemophilia A Families Found to Have a Somatic Mosaicism (0.2-25%)

2007-05-18T07:06:00.000-07:00

IS THE QUESTION OF MOSAICISMS VS. MUTATIONS IN A SINGLE GERM CELL A BIG ONE? WHAT ABOUT MANY GERMS CELLS HAVING THE INVERSION?

-----------------------------------------------------------------------
: Am J Hum Genet. 2001 Jul;69(1):75-87. Epub 2001 Jun 14. Links
Somatic mosaicism in hemophilia A: a fairly common event.Leuer M, Oldenburg J, Lavergne JM, Ludwig M, Fregin A, Eigel A, Ljung R, Goodeve A, Peake I, Olek K.
Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.

Mutations in the large gene of clotting factor VIII (FVIII) are the most common events leading to severe human bleeding disorder. The high proportion of de novo mutations observed in this gene raises the possibility that a significant proportion of such mutations does not derive from a single germ cell but instead should be attributed to a germline or somatic mosaic originating from a mutation during early embryogenesis. The present study explores this hypothesis by using allele-specific PCR to analyze 61 families that included members who had sporadic severe hemophilia A and known FVIII gene defects. The presence of somatic mosaicisms of varying degrees (0.2%-25%) could be shown in 8 (13%) of the 61 families and has been confirmed by a mutation-enrichment procedure. All mosaics were found in families with point mutations (8 [25%] of 32 families). In the subgroup of 8 families with CpG transitions, the percentage with mosaicism increased to 50% (4 of 8 families). In contrast, no mosaics were observed in 13 families with small deletions/insertions or in 16 families with intron 22 inversions. Our data suggest that mosaicism may represent a fairly common event in hemophilia A. As a consequence, risk assessment in genetic counseling should include consideration of the possibility of somatic mosaicism in families with apparently de novo mutations, especially families with the subtype of point mutations.

PMID: 11410838 [PubMed

SOMATIC OR GERMLINE MOSAICISMS WERE EXCLUDED IN MANY MOTHERS SUGGESTING SUCH MOSAICISMS ARE A RARE EVENT IN FAMILIES WITH INVERSION OF INTRON 22

2007-05-18T06:50:00.000-07:00

THE INVERSIONS ORIGINATED ALMOST EXCLUSIVELY IN THE MALE GERM LINE

Haemophilia. 2003 Sep;9(5):584-7. Links
Exclusion of mosaicism in Spanish haemophilia A families with inversion of intron 22.Tizzano EF, Cornet M, Domenech M, Baiget M.
Department of Genetics, Hospital of Sant Pau, Barcelona, Spain. etizzano@hsp.santpau.es

Inversion of intron 22, the most frequent mutation event in haemophilia A (HA), was tested in our HA families to diagnose the females at risk of being carriers, to trace the origin of the mutation and to investigate the presence of germinal or somatic mosaicism. A total of 166 females belonging to 54 families with inversion, were analysed. All but one of the mothers tested were carriers and the inversion originated almost exclusively in male germ cells. Somatic or germline mosaicisms were excluded in 53 of these women and in 20 grandfathers, suggesting that such mosaicisms may be a rare event in families with inversion of intron 22.

DNA HAPLOTYPE ANALYSIS IN 8 FAMILIES WITH GRANDPARENTS AVAILABLE DEMONSTRATED THAT THE INVERSION ORIGINATED ALMOST EXCLUSIVELY IN MALE GERM CELLS

2007-05-18T06:43:00.000-07:00

Thromb Haemost. 1995 Jan;73(1):6-9. Links
Inversion of intron 22 in isolated cases of severe hemophilia A.Tizzano EF, Domenech M, Baiget M.
Molecular Genetics Unit, Santa Creu i Sant Pau Hospital, Barcelona, Spain.

Inversion involving intron 22 is the commonest type of mutation causing severe hemophilia A (HA). We investigated 15 families with isolated cases and 5 families with two or three brothers as the only affected members with hemophilia A, in order to determine the carrier status of the mothers, the origin of the mutation and the presence of germinal mosaicism. Our results show that all mothers tested were carriers of the inversion. In addition, three families whose unique hemophilic member was not available for analysis, were screened for the inversion. In one of these last families, the mother was diagnosed as a carrier and her sister and her niece as non-carriers. DNA haplotype analysis in 8 families with grandparents available for study demonstrated that the inversion originated almost exclusively in male germ cells. These findings have important relevance for genetic counselling in families with an isolated case or to exclude germinal mosaicism. Inversion analysis should constitute the first step in molecular diagnosis of severe hemophilia A.

PMID: 7740498 [PubMed - indexed for MEDLINE]

Hemophilias and the Age of the Maternal Grandfather at the carrier Mother Birth

2007-05-18T06:32:00.000-07:00

Haemophilia. 2003 Nov;9(6):717-20. Links
Germ-line origin of intron 1 inversion in two haemophilia A families.Acquila M, Pasino M, Santoro C, Lanza T, Molinari AC, Bottini F, Bicocchi MP.
Haemostasis and Haemophilia Laboratory, IV Paediatric Department, G Gaslini Institute, Genova, Italy. mauraacquila@ospedale-gaslini.ge.it

Factor VIII gene inversion of intron 1 has recently been reported to be the mutation responsible for haemophilia A in about 5% of severe cases. In our series of patients, which is made up of 77 Italian cases negative for intron 22 inversion, the mutation was found in three sporadic and in one familial patients, with an overall frequency of 5.2%. The carrier status of the patients' female relatives was assessed by mutation analysis and showed that only two-thirds of cases could be considered truly sporadic. The germ-line origin of the mutation was investigated in the two sporadic families by haplotype analysis on genomic DNA of the patients' maternal grandparents. These studies indicated that both mutation events had occurred in the germ cell lines of the patients' healthy grandfather, suggesting that, as already demonstrated for the inversion of intron 22, the male germ cell line is more susceptible to the intrachromosome recombination which leads to the inversion of intron 1.

CHROMOSOMAL DISORDERS SUCH AS KLEINFELTER'S (CLASSIC 47XXY), MIXED GONADAL DYSGENESIS,CHROMOSOMAL TRANSLOCATIONS AND XYY OFFSPRING OF SUBFERTILE MEN

2007-05-17T23:07:00.000-07:00

Genetic concerns for the subfertile male in the era of ICSI
Edward D. Kim 1, Farideh Z. Bischoff 2, Larry I. Lipshultz 1, Dolores J. Lamb 1 3 *
1Scott Department of Urology, Baylor College of Medicine, Houston, TX, U.S.A.
2Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX, U.S.A.
3Department of Cell Biology, Baylor College of Medicine, Houston, TX, U.S.A.

email: Dolores J. Lamb (dlamb@bcm.tmc.edu)

*Correspondence to Dolores J. Lamb, Scott Department of Urology, Baylor College of Medicine, 1 Baylor Plaza, Room 440E, Houston, TX 77030, U.S.A.

Keywords
ICSI • male infertility • genes • genetic defects

Abstract
The treatment of severe male factor infertility has seen remarkable advances in the last five years with the introduction and widespread use of intracytoplasmic sperm injection (ICSI). Although ICSI represents one of the most important advances in the treatment of the subfertile male, significant concerns exist regarding the potential for transmission of abnormal genes to the offspring because many of the natural barriers to conception have been bypassed. Because these couples were not able to conceive prior to ICSI, the long-term genetic consequences in these offspring are largely undefined at this time. Genetic abnormalities related to male infertility need to be considered in terms of being (1) causative for male infertility and (2) potentially transmissible to the offspring. Reasons for pursuing a genetic evaluation include (1) establishing a diagnosis, (2) establishing a possible genetic origin, (3) clarifying the pattern of inheritance, and (4) providing information on natural history, variation and expression. The three most common known genetic factors related to male infertility are cystic fibrosis gene mutations leading to congenital absence of the vas deferens, Y-chromosome microdeletions leading to spermatogenic impairment, and karyotype abnormalities. When congenital bilateral absence of the vas deferens with azoospermia is encountered, cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations are commonly the underlying cause. When testicular failure is manifest by azoospermia or severe oligoszoospermia, Y-chromosome microdeletions may be present in approximately 10-15 per cent of otherwise normal appearing men. Karyotyping can uncover potentially transmissible genetic abnormalities in the infertile male including structural chromosomal disorders such as Klinefelter's (classic 47, XXY), mixed gonadal dysgenesis, chromosomal translocations and XYY syndromes. Finally, potential male infertility genes in animal models are reviewed. Without question, advances in clinical and basic research raise scientific and social issues that must be addressed. Copyright © 1998 John Wiley & Sons, Ltd.

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Digital Object Identifier (DOI)

10.1002/(SICI)1097-0223(199812)18:13<1349::AID-PD504>3.0.CO;2-# About DOI

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Turner Syndrome Scotland had a Paternal Age Effect and England did not ONE MECHANISM OF ORIGIN MAY BE INCREASING PATERNAL AGE

2007-05-14T09:18:00.000-07:00

1: Clin Genet. 1989 Jul;36(1):53-8. Links
An aetiological study of isochromosome-X Turner's syndrome.Carothers AD, De Mey R, Daker M, Boyd E, Connor M, Ellis PM, Stevenson D.
Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, U.K.

In an attempt to resolve conflicting evidence from the literature concerning the existence of a paternal age effect in 46,X,i(Xq) Turner's syndrome, we have analysed data on all known cases ascertained in the main population centres of Scotland and on others ascertained in England, using population controls matched for year of birth. There was a significant (P = 0.02) increase of 2.3 years in the mean paternal age of the Scottish cases, and a smaller and non-significant increase in their mean maternal age. Logistic regression analysis confirmed that the primary association was with paternal, rather than maternal, age. For the English cases, however, there were small and non-significant decreases in their mean maternal and paternal ages. The differences between the two groups were also significant, but cannot be explained by any likely source of ascertainment bias. We therefore conclude that there is no evidence for a universal paternal age effect in this condition, but that at least one mechanism of origin, occurring with variable frequency, may be associated with increased paternal age. Using data from this and earlier published studies, we estimate the incidence of individuals with a 46,X,i(Xq) cell line to be between 3.3 and 13 per 10(5) female livebirths.

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Clin Endocrinol (Oxf). 2004 Feb;60(2):272. Links
The prevalence of diabetes mellitus in the parents of women with Turner's syndrome.Bakalov VK, Cooley MM, Troendle J, Bondy CA.

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J Pediatr Endocrinol Metab. 2002 Sep-Oct;15(8):1203-6. Links
Type 1 diabetes mellitus in a 3 1/2 year-old girl with Turner's syndrome.Gonc EN, Ozon A, Alikasifoglu A, Kandemir N.
Pediatric Endocrinology Unit, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Turner's syndrome is associated with autoimmune disorders. Autoimmune endocrinopathy in Turner's syndrome seems to be limited to autoimmune thyroiditis. A small number of patients with Turner's syndrome has also been associated with celiac disease, inflammatory bowel disease and juvenile rheumatoid arthritis. Type 1 diabetes mellitus in Turner's syndrome has been rarely reported. We present here the youngest patient with Turner's syndrome who developed type 1 diabetes mellitus. At the age of 3.5 years she was hospitalized with diabetic ketoacidosis. Anti-islet cell and anti-insulin antibodies were positive and C-peptide level was low. When she was investigated for recurrent urinary tract infections, horseshoe kidney was detected by ultrasonography. Karyotype analysis revealed 45,XO. She has been followed for 2 years with an insulin dose of 0.9 U/kg per day. The prevalence of type 1 diabetes mellitus associated with Turner's syndrome is still unknown.

PMID: 14725692 [PubMed - indexed for MEDLINE]

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1: Clin Exp Rheumatol. 1998 Jul-Aug;16(4):489-94. Links
Comment in:
Clin Exp Rheumatol. 2000 Mar-Apr;18(2):267-8.
Juvenile arthritis in Turner's syndrome: a multicenter study.Zulian F, Schumacher HR, Calore A, Goldsmith DP, Athreya BH.
Department of Pediatrics, University of Padova, Italy.

OBJECTIVE: Turner's syndrome (TS) is a disorder associated with characteristic defects in the X chromosome. Autoimmune conditions such as thyroiditis, inflammatory bowel diseases and diabetes have been described in association with TS. METHODS: We have studied the association between TS and juvenile arthritis (JA) by using a survey in which 28 pediatric rheumatology centers (15 in the USA, 10 in Europe, and 3 in Canada) participated. RESULTS: Eighteen cases of TS in a population of approximately 15,000 JRA patients have been found. Two different patterns of arthritis were present: polyarticular (7) and oligoarticular (11). Children with polyarticular disease had early onset, seronegative, progressively deforming arthritis and growth retardation. Those with oligoarticular arthritis had a benign course and were ANA+ (8/11). The oligoarticular children had varying karyotypes whereas almost all of the polyarthritic patients shared the same 45X0 karyotype (6/7). The light and electron microscopic studies of synovium performed in two patients showed chronic inflammation and hyperplasia of the synovial lining cells, vascular proliferation and infiltration with lymphocytes, plasma cells and mononuclear phagocytes. CONCLUSION: Juvenile arthritis is a new autoimmune condition association with Turner's syndrome. The prevalence seems to be at least six times greater than would be expected if the two conditions were only randomly associated. This is the first description of the synovium in Turner's syndrome; no differences from other forms of juvenile rheumatoid arthritis were found.
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Clin Exp Rheumatol. 1997 Nov-Dec;15(6):701-3. Links
Delayed diagnosis of juvenile rheumatoid arthritis in a girl with Turner's syndrome.Foeldvari I, Wuesthof A.
University Children's Hospital, Hamburg, Germany.

Although increased risk for autoimmune diseases has been documented in Turner's syndrome (TS), the involvement of juvenile rheumatoid arthritis (JRA) has rarely been reported. A detailed case description of JRA associated with Turner's syndrome is presented as the second such case report in the literature. The arthritis was diagnosed 8 years after its onset due to the confounding of its symptoms with those of TS
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1: Am J Med Genet. 2000 Jun 12;96(3):312-6. Links
Female with autistic disorder and monosomy X (Turner syndrome): parent-of-origin effect of the X chromosome.Donnelly SL, Wolpert CM, Menold MM, Bass MP, Gilbert JR, Cuccaro ML, Delong GR, Pericak-Vance MA.
Department of Medicine and Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA.

We have ascertained and examined a patient with autistic disorder (AD) and monosomy X (Turner syndrome). The patient met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)/International Classification of Diseases (ICD-10) criteria for AD verified by the Autism Diagnostic Interview-Revised. The patient exhibited both social and verbal deficits and manifested the classical physical features associated with monosomy X. Skuse et al. [1997: Nature 387:705-708] reported three such cases of AD and monosomy X in their study of Turner syndrome and social cognition. They observed that monosomy X females with a maternally inherited X chromosome had reduced social cognition when compared with monosomy X females with a paternally inherited X chromosome. All three cases of AD and monosomy X were maternally inherited. Based on their data, they suggested that there was a gene for social cognition on the X chromosome that is imprinted and not expressed when the X chromosome is of maternal origin. Thus, we conducted parent-of-origin studies in our AD/monosomy X patient by genotyping X chromosome markers in the patient and her family. We found that the patient's X chromosome was of maternal origin. These findings represent the fourth documented case of maternal inheritance of AD and monosomy X and provide further support for the hypothesis that parent-of-origin of the X chromosome influences social cognition.

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Nature. 1997 Jun 12;387(6634):705-8. Links
Comment in:
Nature. 1997 Jun 12;387(6634):652-3.
Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function.Skuse DH, James RS, Bishop DV, Coppin B, Dalton P, Aamodt-Leeper G, Bacarese-Hamilton M, Creswell C, McGurk R, Jacobs PA.
Behavioural Sciences Unit, Institute of Child Health, London, UK. dskuse@ich.ucl.ac.uk

Turner's syndrome is a sporadic disorder of human females in which all or part of one X chromosome is deleted. Intelligence is usually normal but social adjustment problems are common. Here we report a study of 80 females with Turner's syndrome and a single X chromosome, in 55 of which the X was maternally derived (45,X[m]) and in 25 it was of paternal origin (45,X[p]). Members of the 45,X[p] group were significantly better adjusted, with superior verbal and higher-order executive function skills, which mediate social interactions. Our observations suggest that there is a genetic locus for social cognition, which is imprinted and is not expressed from the maternally derived X chromosome. Neuropsychological and molecular investigations of eight females with partial deletions of the short arm of the X chromosome indicate that the putative imprinted locus escapes X-inactivation, and probably lies on Xq or close to the centromere on Xp. If expressed only from the X chromosome of paternal origin, the existence of this locus could explain why 46,XY males (whose single X chromosome is maternal) are more vulnerable to developmental disorders of language and social cognition, such as autism, than are 46,XX females.

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Pathol Int. 2007 Apr;57(4):219-23. Links
Sudden death of a young woman due to aortic dissection caused by Turner's syndrome.Mimasaka S, Ohtsu Y, Tsunenari S, Matsukawa A, Hashiyada M, Takahashi S, Funayama M.
Department of Forensic Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Mimasaka9@aol.com

A 24-year-old woman was found dead in her bed. There had been an episode of fainting with cervicodynia 1 day before death but no significant past medical history, except for menstrual irregularities. Post-mortem examination revealed that death was due to hemopericardium caused by rupture of the ascending aorta by thoracic aortic dissection (Stanford type A). Microscopically, weakness of the aorta was due to cystic medial necrosis. On external examination, short stature, a short neck and multiple pigmented nevi were observed, while internal examination revealed coarctation of the aorta and funicular ovaries. Examination of the X chromatin showed a decrease in numbers of Barr bodies in the tissues, and a 45,X/46,XX mosaicism was suspected. It is concluded that the cause of death was aortic dissection due to Turner's syndrome.

PMID: 17316418 [PubMed - indexed for MEDLINE]

4/ 5 LESCH-NYHANS IN WHICH THE MOTHER WAS NEW MUTATION, AGE OF HER PARENTS WAS CONSIDERABLY HIGHER THAN THE MEAN PARENTAL AGE IN THE POPULATION.

2007-05-12T22:05:00.000-07:00

THIS RAISES THE POSSIBILITY OF PATERNAL AGE EFFECT X-LINKED MUTATIONS

The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease.
U Francke, J Felsenstein, S M Gartler, B R Migeon, J Dancis, J E Seegmiller, F Bakay, and W L Nyhan
This article has been corrected. See Am J Hum Genet. 1976 May; 28(3): 311.
This article has been cited by other articles in PMC.
AbstractIn a population at equilibrium for a sex-linked lethal, one-third of the genes for that lethal must arise anew each generation. Therefore, one-third of all cases of Lesch-Nyhan disease, a severe X-linked recessive lethal disorder, should be new mutants. To test this hypothesis, we have collected 47 families, 20 with a single proband and 27 with multiple affected males in which the patients' mothers and other female relatives had been studied for heterozygosity. Available carrier detection tests identify heterozygous for HPRT deficiency in hair roots and skin fibroblasts. Only four mothers were found not to be carriers. This result deviates significantly from expected (P less than .001). Statistical tests for ascertainment effects indicated absence of bias for multiple proband families but strong bias in favor of families with many heterozygous females. When the analysis was limited to single proband families, the deviation from expected was still significant (P less than .01). The incidence of new mutants among the heterozygous mothers, as determined by the ratio of +/+ to +/- maternal grandmothers, should be one-half (see Appendix). Of all 20 maternal grandmothers studied, five were +/+ and 15 were +/- (P less than .05). Considering only the single proband families, the ratio of 5 +/+ to 8 +/- was not significantly different from expected. In four of the five cases in which the heterozygous mother of an affected individual was a new mutation, the age of her parents was considerably higher than the mean parental age in the population. This raises the possibility of a paternal age effect on X-linked mutations. There appears to be a true deficiency of new mutatnts among males but not among females. Data on additional Lesch-Nyhan families are needed before conclusions regarding a possible higher mutation rate in males can be drawn.Full textFull text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (1.6M), or see the PubMed citation or the full text of some References or click on a page below to browse page by page.

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Hagemeijer AM, Dodinval P, Andrien JM. Syndrome de Lesch-Nyhan. Détection des hétérozygotes par sélection biochimique des cellules mutants et autoradiographie. Humangenetik. 1972;15(2):126–135. [PubMed]
de Bruyn CH, Oei TL, ter Haar BG. Studies on hair roots for carrier detection in hypoxanthine-quanine phosphoribosyl transferase deficiency. Clin Genet. 1974;5(5):449–456. [PubMed]
McKeran RO, Andrews TM, Howell A, Gibbs DA, Chinn S, Watts WE. The diagnosis of the carrier state for the Lesch--Nyhan syndrome. Q J Med. 1975 Apr;44(174):189–205. [PubMed]
Felix JS, DeMars R. Detection of females heterozygous for the Lesch-Nyhan mutation by 8-azaguanine-resistant growth of cultured fibroblasts. J Lab Clin Med. 1971 Apr;77(4):596–604. [PubMed]
Fujimoto, Wilfred Y.; Seegmiller, J Edwin. Hypoxanthine-Guanine Phosphoribosyltransferase Deficiency: Activity in Normal, Mutant, and Heterozygote-Cultured Human Skin Fibroblasts. Proc Natl Acad Sci U S A. 1970 Mar;65(3):577–584. [PubMed]
Chase GA, Murphy EA. Risk of recurrence and carrier frequency for X-linked lethal recessives. Hum Hered. 1973;23(1):19–26. [PubMed]
Gartler SM, Francke U. Half chromatid mutations: transmission in humans? Am J Hum Genet. 1975 Mar;27(2):218–223. [PubMed]

MARFANS DISEASE --A DISPLAY OF A PATERNAL AGE EFFECT IN THE SPORADIC CASES

2007-05-12T17:54:00.000-07:00

1: J Genet Hum. 1988 Jun;36(3):239-45. Links
[Marfan disease][Article in French]
Briard ML, Chauvet ML, Kaplan J.
Clinique et Unite de Recherches de Genetique Medicate, INSERM U.12, Hopital des Enfants, Malades, Paris.

After reviewing the main features of the Marfan syndrome (musculoskeletal, ocular, cardiovascular, pulmonary abnormalities), its autosomal dominant inheritance with high penetrance but variable phenotype and presence of "soft" conditions preventing an easy diagnosis, the authors report their own data relevant to 73 probands: ratio of each clinical manifestation, state of 34% of familial cases and display of a paternal age effect in the sporadic cases. The pathogenic defect is unknown as like the location of the gene. The difficulties of the genetic counseling are then approached: unpredictability of the severity and of the prognosis in the unborn children of an affected patient, benefit of the echocardiography in the management of people at risk.

PMID: 3411304 [PubMed - indexed for MEDLINE]

1: Humangenetik. 1972;16(1):77-82. Links
Human mutations and paternal age.Tunte W.
PMID: 4647446 [PubMed - indexed for MEDLINE

ALL CASES OF THANATOPHORIC DYSPLASIA ARE CAUSED BY NEW MUTATIONS IN THE FGFR3 GENE due to ADVANCED PATERNAL AGE

2007-05-12T10:51:00.000-07:00

1: Am J Med Genet. 1995 Nov 6;59(2):209-17. Links
Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta.Orioli IM, Castilla EE, Scarano G, Mastroiacovo P.
Departamento de Genetica, Universidade Federal do Rio de Janeiro, Brazil.

The paternal ages of nonfamilial cases of achondroplasia (AC) (n = 78), thanatophoric dysplasia (TD) (n = 64), and osteogenesis imperfecta (OI) (n = 106), were compared with those of matched controls, from an Italian Indagine Policentrica Italiana sulle Malformazioni Congenite and a South American Estudio Colaborativo Latinoamericano de Malformaciones Congenitas series. The degree of paternal age effect on the origin of these dominant mutations differed among the three conditions. Mean paternal age was highly elevated in AC, 36.30 +/- 6.74 years in the IPIMC, and 37.19 +/- 10.53 years in the ECLAMC; less consistently elevated in TD, 33.60 +/- 7.08 years in the IPIMC, and 36.41 +/- 9.38 years in the ECLAMC; and only slightly elevated in OI in the ECLAMC, 31.15 +/- 9.25 years, but not in the IPIMC, 32.26 +/- 6.07 years. Increased maternal age or birth order in these conditions disappeared when corrected for paternal age. Approximately 50% of AC and TD cases, and only 30% of OI cases, were born to fathers above age 35 years. For AC and TD, the increase in relative incidence with paternal age fitted an exponential curve. The variability of paternal age effect in these new mutations could be due, among other reasons, to the high proportion of germ-line mosaicism in OI parents, or to the localization of the AC gene, mapped to the 4p16.3 region, in the neighborhood of an unstable DNA area

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Reviewed June 2006
What is thanatophoric dysplasia?
Thanatophoric dysplasia is a severe skeletal disorder characterized by extremely short limbs and folds of extra (redundant) skin on the arms and legs. Other features of this condition include a narrow chest, short ribs, underdeveloped lungs, and an enlarged head with a large forehead and prominent, wide-spaced eyes.

Researchers have described two major forms of thanatophoric dysplasia, type I and type II. Type I thanatophoric dysplasia is distinguished by the presence of curved thigh bones and flattened bones of the spine (platyspondyly). Type II thanatophoric dysplasia is characterized by straight thigh bones and a moderate to severe skull abnormality called a cloverleaf skull.

The term thanatophoric is Greek for "death bearing." Infants with thanatophoric dysplasia are usually stillborn or die shortly after birth from respiratory failure; however, a few affected individuals have survived into childhood with extensive medical help.

How common is thanatophoric dysplasia?
This condition occurs in 1 in 20,000 to 50,000 newborns. Type I thanatophoric dysplasia is more common than type II.

What genes are related to thanatophoric dysplasia?
Mutations in the FGFR3 gene cause thanatophoric dysplasia.

What genes are related to thanatophoric dysplasia?
Mutations in the FGFR3 gene cause thanatophoric dysplasia.

Both types of thanatophoric dysplasia result from mutations in the FGFR3 gene. This gene provides instructions for making a protein that is involved in the development and maintenance of bone and brain tissue. Mutations in this gene cause the FGFR3 protein to be overly active, which leads to the severe disturbances in bone growth that are characteristic of thanatophoric dysplasia. It is not known how FGFR3 mutations cause the brain and skin abnormalities associated with this disorder.

How do people inherit thanatophoric dysplasia?
Thanatophoric dysplasia is considered an autosomal dominant disorder because one mutated copy of the FGFR3 gene in each cell is sufficient to cause the condition. Virtually all cases of thanatophoric dysplasia are caused by new mutations in the FGFR3 gene and occur in people with no history of the disorder in their family. No affected individuals are known to have had children; therefore, the disorder has not been passed to the next generation.

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1: Am J Med Genet. 1988 Dec;31(4):815-20. Links
Thanatophoric dysplasia: an autosomal dominant condition?Martinez-Frias ML, Ramos-Arroyo MA, Salvador J.
Estudio Colaborativo Espanol de Malformaciones Congenitas, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

We present 13 cases of thanatophoric dysplasia collected in the Spanish Collaborative Study of Congenital Malformations from a total population of 517,970 births. The incidence (live and stillbirth) was 2.7 per 100,000 births. All cases were sporadic, and there was no evidence of parental consanguinity. Parental age was significantly higher as compared with control parents. These findings suggest the occurrence of autosomal dominant mutation, with an overall mutation rate of 1.34 X 10(-5) in our population, which is close to that observed in achondroplasia.

PMID: 3239573 [PubMed - indexed for MEDLINE]

1998 a 29 YEAR OLD MOTHER AND A SIXTY YEAR OLD FATHER HAVE a SON WITH de novo complex chromosomal rearrangement

2007-05-10T19:56:00.000-07:00

He was hypotonic and he could neither stand
up nor walk. Speech was lacking. A mild facial dysmorphy
was noted, including a long face, a large nose with anteverted
nostrils, micrognathy, a pronounced philtrum, long teeth and
low set ears. There was neither visceral malformation nor
anomaly in standard laboratory investigations such as
electroencephalography, electromyography or skeletal X-ray
examination.

Human Reproduction vol.13 no.7 pp.1801–1803, 1998
CASE REPORT
Advanced paternal age and de-novo complex
chromosomal rearrangement in offspringB.Benzacken1,4, J.P.Siffroi2, B.Straub2,
C.Le Bourhis2, S.Sauvion3, J.Gaudelus3,
J.P. Dadoune2 and J.P.Wolf1
1Laboratoire d’Histologie, Embryologie, Cytoge´ne´tique et Biologie
de la Reproduction, Hoˆpital Jean Verdier, 93140, Bondy,
2Laboratoire d’Histologie, Biologie de la Reproduction et
Cytoge´ne´tique, Hoˆpital Tenon, Paris and 3Service de Pe´diatrie,
Hopital Jean Verdier, 93140, Bondy, France
4To whom correspondence should be addressed
We report one case of a de-novo complex chromosomal
rearrangement (CCR), t(1;5;13)ins(14;13), in an abnormal
19-month-old boy. Clinical features associated were a mild
facial dysmorphy and a psychomotor retardation. Parental
ages were, respectively, 29 years for the mother and
60 years for the father. We point out the usefulness of
fluorescence in-situ hybridization in elucidating CCRs, and
discuss the possible correlation between the existence of a
chromosomal aberration and advanced paternal age.
Key words: complex chromosomal rearrangement/fluorescence
in-situ hybridization/mental retardation/reproduction/paternal
age
Introduction
Complex chromosomal rearrangements (CCRs) are defined as
reciprocal exchanges between three or more chromosomes.
They are rare events in human pathology and only about 100
CCRs have been reported as constitutional findings (Batista
et al., 1994). The involvement of several chromosomes and
the high number of breakpoints can make cytogenetic diagnosis
very difficult when classical banding techniques or highresolution
methods only are used. Here we report the molecular
study by fluorescence in–situ hybridization (FISH) of an
apparently balanced 4-chromosome CCR in an abnormal child.
Advanced paternal age, as a possible causal factor, is discussed.
Case report
The proband was a boy, born from a 29-year-old healthy
mother and from a 60-year-old father. The parents were
unrelated, and they already had a normal child. Pregnancy,
labour and delivery were uneventful; birthweight was 3830 g,
length 53 cm and head circumference 37 cm.
At 19 months, the child was referred for a psychomotor
retardation evaluation. He was 80 cm high and weighed
© European Society for Human Reproduction and Embryology 1801
10.1 kg (–1SD). He was hypotonic and he could neither stand
up nor walk. Speech was lacking. A mild facial dysmorphy
was noted, including a long face, a large nose with anteverted
nostrils, micrognathy, a pronounced philtrum, long teeth and
low set ears. There was neither visceral malformation nor
anomaly in standard laboratory investigations such as
electroencephalography, electromyography or skeletal X-ray
examination.
Cytogenetic investigations were performed on blood cell
cultures using R-banding and bromodeoxyuridine (BrdU)
incorporation. The karyotype revealed a complex chromosomal
rearrangement involving chromosomes 1, 5, 13 and 14 with
at least five breakpoints (Figure 1). Molecular study by FISH,
using whole chromosome paint probes (Biosys®, France),
allowed the precise identification, first, of a complex translocation
implicating the long arms of chromosomes 1, 5 and 13
and, second, of an insertion of a part of the long arm of
chromosome 13 into the long arm of chromosome 14 (Figure 1).
Therefore, the proband’s karyotype was apparently balanced,
46,XY,t(1;5;13)(q32.2;q14;q12).ish t(1;5;13)(wcp131; wcp11;
wcp51)ins(14;13)(q12.2;q12q31).ish ins (14;13)(wcp131;
wcp131).
The parents’ and brother’s karyotypes were normal even
after high-resolution cytogenetic techniques. According to this
result, no analysis by FISH was necessary in the parents.
In order to determine parental origin of this CCR, polymorphisms
of the 13 and 14 acrocentric chromosomes’ short
arms and of the secondary constriction of chromosome 1 were
analysed in the proband and his parents. Only the latter was
informative: indeed, parental chromosomes 1 were distinguishable
by the size of their secondary constrictions, and the
comparison with the translocated chromosome 1 in the proband
allowed us to assume that CCR had arisen during paternal
spermatogenesis (Figure 2).
Discussion
............................................
Since continual divisions of spermatogonia throughout adult
life may result in structural rearrangements of chromosomes
which may persist in a clone, it seems reasonable to consider
that pregnancies from elderly fathers, especially those who are
more than 50 years old, present genetically increased risk and
that fetal karyotype analyses can be proposed in these cases.

AN INCREASING INCIDENCE OF SPORADIC WILM'S TUMOR IN CHILDREN OF FATHERS OVER 55 COMPARED TO CHILDREN OF FATHERS YOUNGER THAN 20

2007-05-09T16:01:00.000-07:00

1: Br J Cancer. 1993 Apr;67(4):813-8. Links
Wilms' tumour and parental age: a report from the National Wilms' Tumour Study.Olson JM, Breslow NE, Beckwith JB.
Department of Biostatistics, University of Washington, Seattle 98195.

Age distributions of parents at birth of patients registered in the National Wilms' Tumour Study were compared to those of the general population. An increasing incidence of sporadic Wilms' tumour with increasing paternal age was found, with a relative risk of 2.1 of tumour in children of fathers over 55 compared to children of fathers younger than 20. A similar effect for maternal age was found, with a relative risk of 1.4 in children of mothers over 40 compared to children of mothers younger than 20. The maternal age effect was much weaker among patients registered later in the study; in the later, more completely ascertained cohort, paternal age appears to be the major contributor to the parental age effect. Little difference in paternal age distribution was found between patients with bilateral and unilateral tumour and between male and female patients. In contrast, patients with reported associated congenital anomalies, patients with evidence of nephrogenic rests, and patients with early or late age-of-onset of tumour had parents who were, on average, substantially older than the remainder. These findings lend support to the idea that many Wilms' tumours result from new germline mutations. Further, the histologic composition of such tumours may

1: Med Pediatr Oncol. 1992;20(4):284-91. Links
Genetics and epidemiology of Wilms' tumor: the French Wilms' tumor study.Bonaiti-Pellie C, Chompret A, Tournade MF, Hochez J, Moutou C, Zucker JM, Steschenko D, Brunat-Mentigny M, Roche H, Tron P, et al.
Unite de Recherche d'Epidemiologie Genetique (U155 INSERM), Paris, France.A complete family history was obtained for 501 patients with Wilms' tumor, treated in departments of pediatric oncology in whole France. The information was collected by self-questionnaire and/or by interview of parents. The proportion of bilateral cases is 4.6% and there are 12 patients (2.4%) with a positive family history of Wilms' tumor. The affected relatives are most often distant and no first degree relative was affected. Apart from the well-known associations with aniridia, hemihypertrophy, genitourinary anomalies, Beckwith-Wiedeemann, and Drash syndromes, there is also a significant excess of congenital heart defects (P = .008) which remains to be explained. Several findings support the bimutational hypothesis such as earlier diagnosis and increased parental age in bilateral cases. No particular anomalies and no increased frequency of childhood cancer were found in patients' relatives. The frequency of Wilms' tumor in relatives was estimated to be less than 0.4% in sibs, 0.06% in uncles and aunts, and 0.04% in first cousins. These figures are very different from those found in retinoblastoma and suggest that the mechanism may be more complex in Wilms' tumor. This conclusion is in agreement with molecular biology studies in tumors and linkage analysis in multiple case families which suggest that more than one locus is involved.

PMID: 1318995 [PubMed - indexed for MEDLINE]

Am J Hum Genet. 1990 July; 47(1): 155–160.
Copyright notice
Parental origin of de novo constitutional deletions of chromosomal band 11p13.
V Huff, A Meadows, V M Riccardi, L C Strong, and G F Saunders
Department of Biochemistry and Molecular Biology, University of Texas, M. D. Anderson Cancer Center, Houston 77030.
This article has been cited by other articles in PMC.
AbstractOne-half of all cases of Wilms tumor (WT), a childhood kidney tumor, show loss of heterozygosity at chromosomal band 11p13 loci, suggesting that mutation of one allele and subsequent mutation or loss of the homologous allele are important events in the development of these tumors. The previously reported nonrandom loss of maternal alleles in these tumors implied that the primary mutation occurred on the paternally derived chromosome and that it was "unmasked" by loss of the normal maternal allele. This, in turn, suggests that the paternally derived allele is more mutable than the maternal one. To investigate whether germinal mutations are seen with equal frequency in maternally versus paternally inherited chromosomes, we determined the parental origin of the de novo germinal 11p13 deletions in eight children by typing lymphocyte DNA from these children and from their parents for 11p13 RFLPs. In seven of the eight cases, the de novo deletion was of paternal origin. The one case of maternal origin was unremarkable in terms of the size or extent of the 11p13 deletion, and the child did develop WT. Transmission of 11p13 deletions by both maternal and paternal carriers of balanced translocations has been reported, although maternal inheritance predominates. These data, in addition to the general preponderance of paternally derived, de novo mutations at other loci, suggest that the increased frequency of paternal deletions we observed is due to an increased germinal mutation rate in males.Full textFull text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (862K), or see the PubMed citation or the full text of some

list contains those references that cite another article in PMC or have a citation in PubMed. It may not include all the original references for this article.Breslow NE, Beckwith JB. Epidemiological features of Wilms' tumor: results of the National Wilms' Tumor Study. J Natl Cancer Inst. 1982 Mar;68(3):429–436. [PubMed]
Breslow N, Beckwith JB, Ciol M, Sharples K. Age distribution of Wilms' tumor: report from the National Wilms' Tumor Study. Cancer Res. 1988 Mar 15;48(6):1653–1657. [PubMed]
Bunin GR, Nass CC, Kramer S, Meadows AT. Parental occupation and Wilms' tumor: results of a case-control study. Cancer Res. 1989 Feb 1;49(3):725–729. [PubMed]
Butler MG, Meaney FJ, Palmer CG. Clinical and cytogenetic survey of 39 individuals with Prader-Labhart-Willi syndrome. Am J Med Genet. 1986 Mar;23(3):793–809. [PubMed]
Chamberlin J, Magenis RE. Parental origin of de novo chromosome rearrangements. Hum Genet. 1980;53(3):343–347. [PubMed]
Compton DA, Weil MM, Jones C, Riccardi VM, Strong LC, Saunders GF. Long range physical map of the Wilms' tumor-aniridia region on human chromosome 11. Cell. 1988 Dec 2;55(5):827–836. [PubMed]
Dao DD, Schroeder WT, Chao LY, Kikuchi H, Strong LC, Riccardi VM, Pathak S, Nichols WW, Lewis WH, Saunders GF. Genetic mechanisms of tumor-specific loss of 11p DNA sequences in Wilms tumor. Am J Hum Genet. 1987 Aug;41(2):202–217. [PubMed]
Dryja TP, Mukai S, Petersen R, Rapaport JM, Walton D, Yandell DW. Parental origin of mutations of the retinoblastoma gene. Nature. 1989 Jun 15;339(6225):556–558. [PubMed]
Ejima Y, Sasaki MS, Kaneko A, Tanooka H. Types, rates, origin and expressivity of chromosome mutations involving 13q14 in retinoblastoma patients. Hum Genet. 1988 Jun;79(2):118–123. [PubMed]
Emanuel BS. Molecular cytogenetics: toward dissection of the contiguous gene syndromes. Am J Hum Genet. 1988 Nov;43(5):575–578. [PubMed]

1981 Genetic Disease in the offspring of older fathers-Good public health policy for both men and women to complete their family before age 40, ...

2007-05-08T23:15:00.000-07:00

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Obstetrics & Gynecology 1981;57:745-749
© 1981 by The American College of Obstetricians and Gynecologists

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Genetic disease in the offspring of older fathers
JM Friedman

Autosomal dominant genetic diseases may result from the transmission of a trait by a carrier parent or from gene mutation in one of the gametes from which the child develops. The mean age of fathers of affected persons has been found to be greater than expected for several autosomal dominant diseases due to new mutations. To assess the clinical importance of this observation, the relative and absolute frequencies of offspring with autosomal dominant diseases due to mutation in the sperm from fathers of various ages have been calculated. The relative frequency of new autosomal dominant mutations in children increases logarithmically with paternal age during the usual years of fatherhood. The absolute frequency of autosomal dominant disease due to new mutations among the offspring of fathers who are 40 years of age or older is estimated to be at least 0.3 to 0.5%. This risk is many times greater than that for children of young fathers and is similar in magnitude to the risk of Down syndrome among the offspring of 35- to 40-year-old mothers. Thus, it is good public health policy to recommend that both men and women complete their family a before age 40, if possible.

J.M. Friedman on the Epidemiology of Neurofibromatosis type 1

2007-05-08T23:11:00.000-07:00

Epidemiology of neurofibromatosis type 1
J.M. Friedman *

email: J.M. Friedman (frid@interchange.ubc.ca) *Correspondence to J.M. Friedman, UBC Department of Medical Genetics, BC Children's Hospital, 4500 Oak Street, Room C201, Vancouver, Canada V6H 3N1

Dr. Friedman is professor and head of the Department of Medical Genetics at the University of British Columbia and Children's and Women's Health Centre of British Columbia. He is a clinical geneticist.

Keywords
NF1 • epidemiology • mutation

Abstract
The prevalence of neurofibromatosis type 1 (NF1) is about 1/3,000. There are no known ethnic groups in which NF1 does not occur or is unusually common. The prevalence is somewhat higher in young children than in adults, a difference that probably results at least in part from the early death of some NF1 patients. NF1 is fully penetrant in adults, but many disease features increase in frequency or severity with age. The reproductive fitness of NF1 patients is reduced by about one-half. About half of all cases result from new mutations. The estimated rate of new NF1 mutations is unusually high, but the basis for this high mutation rate is not known. Am. J. Med. Genet. (Semin. Med. Genet.) 89:1-6, 1999. © 1999 Wiley-Liss, Inc.

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Digital Object Identifier (DOI)

FATHERS OF PATIENTS WITH SPORADIC NEUROFIBROMATOSIS 1, IN A CASE CONTROL STUDY WERE 1.5 YEARS OLDER THAN FATHERS OF THE CONTROL SUBJECTS AT THE BIRTH

2007-05-08T22:55:00.000-07:00

Original Article
Paternal age and sporadic neurofibromatosis 1: A case-control study and consideration of the methodologic issues
Greta R. Bunin 1 *, Michael Needle 1, Vincent M. Riccardi 2
1Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia
2The Neurofibromatosis Institute, La Crescenta, California

email: Greta R. Bunin (bunin@email.chop.edu)

*Correspondence to Greta R. Bunin, Children's Hospital of Philadelphia, Abramson Center, 34th St. & Civic Center Blvd., Philadelphia, PA 19104-4318

Funded by:
National Institutes of Health; Grant Number: HD28376
Texas Neurofibromatosis Foundation

Keywords
epidemiologic methods • germline mutation • maternal age

Abstract
Sporadic neurofibromatosis 1 (NF1) occurs in the absence of a family history of the disease and usually results from a new mutation in the germ cell of one of the parents, most commonly the father. Older paternal age may increase the risk for a new germinal NF1 mutation, but the results of studies to address this question conflict. We investigated paternal age in sporadic NF1 by using a case-control study design. Patients who were seen at two specialty NF clinics in Houston, Texas, born between 1970 and 1992 and living in the Houston area and surrounding counties, were studied. Birth certificates with information on the father were found for 89 cases. For each case, two birth certificates were chosen at random from the same year and county of birth. In this way, the control group of 178 individuals was formed. Fathers of patients with NF1 were 1.5 years older than fathers of control subjects at the birth of the child, but the difference was only of borderline statistical significance (P = 0.07). This paternal age difference was not changed by adjustment for socioeconomic status or maternal age. These and previous data are consistent with either a small paternal age effect in sporadic NF1 or a bias such as that resulting from the selection of cases and/or controls. Genet. Epidemiol. 14:507-516,1997. © 1997 Wiley-Liss, Inc.

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Received: 23 July 1996; Revised: 2 December 1996; Accepted: 2 January 1997
Digital Object Identifier (DOI)

WASSINK SAYS NO PATERNAL AGE EFFECT IN MUTATION OF NEUREXIN 1 GENE ON CHROMOSOME 11

2007-05-07T18:24:00.000-07:00

U-I researchers find genetic link to autism
Monday, May 7, 2007, 4:11 PM
By Darwin Danielson
University of Iowa researchers have found a genetic mutation that contributes to a brain disorder that inhibits a person's ability to communicate and develop social relationships. Dr. Thomas Wassink says the finding involving autism was part of a larger study of families which have children with the disorder.

Wassink says there was one family where they found "a piece of a chromosome missing in the middle of a really interesting gene, in two girls with autism from this family."

Wassink says they did further study to narrow down the gene mutation. Wassink says, "At some point in the embryonic development of the father, an abnormality occurred or a mutation arose in his primordial sperm cell." Wassink says the discovery of the mutation led to more research. He says the screened the gene, called "neurexin one," for mutations in about 400 other individuals with autism, but didn't find any additional mutations of the gene in people with autism. Wassink says it appears the mutations in the gene in this particular family are not a very common cause of autism.

Wassink says the exciting thing is that this is one of a groups of genes where mutations have been found in the proteins in the synapse that send messages between nerve cells. Wassink says this tells researchers that other genes and proteins in this particular synapse are worth looking at to screen for other mutations that might be related to autism.

Wassink says having a clue about where to look for the problem is important. He says there are well over 10,000 genes in the brain, and finding the right ones to look at is not easy. Wassink says this finding helps them look at a more specific set of genes. Wassink says the finding could eventually help with treatments for autism.

Wassink says it may indicate different types of medications to try in treating autism. Wassink, who is an associate professor of psychiatry, says this study does not show any link to an earlier study that indicated that the chances for autism increased with the age of the father. Wassink says age is not a factor in this finding.

DUCHENNE'SMaternal Grandfathers/Mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population

2007-04-30T13:21:00.000-07:00

or intrapedigree controls (29.5 +/- 1.3).

: Am J Med Genet. 1980;7(1):27-34. Links
Frequency of new mutants among boys with Duchenne muscular dystrophy.Bucher K, Ionasescu V, Hanson J.
Haldane's rule states that one-third of the cases of an X-linked recessive lethal should represent new mutations. This rule is derived under the assumptions that there is equilibrium between mutation and selection, that mutation rates in ova and sperm are equal, and that heterozygous and homozygous normal women have the same fitness. To test this rule for Duchenne muscular dystrophy (DMD), we have examined the mothers of 55 boys with DMD (16 familial and 39 isolated cases) and classified them as carriers or noncarriers on the basis of measures of ribosomal protein synthesis (RPS). Of the 55 mothers, only nine (16.4%) are classified as noncarriers, a figure significantly different from the expected one-third. When the analysis is limited to the 39 mothers of isolated cases, 23.1% (9/39) are classified as noncarriers, still significantly different than expected under Haldane's rule. Violation of any of the assumptions under which Haldane's rule is derived could lead to deviations from the expected one-third new mutants. We find the most likely explantation to be a higher male than female mutation rate. This is supported also by the finding that maternal grandfathers in whom a mutation occurred had higher mean age at birth of the carrier daughter (33.7 +/- 1.6) than did the general population or intrapedigree controls (29.5 +/- 1.3).
PMID: 7211951 [PubMed - indexed for MEDLINE]

Increased Paternal Age Found in Neurofibromatosis in 1973

2007-04-26T09:42:00.000-07:00

1: Humangenetik. 1975 Jun 19;28(2):129-38. Links
On the mutation rate of neurofibromatosis.Sergeyev AS.
A genetic study of 124 cases of neurofibromatosis was performed. The contingent of probands was mainly represented by a Russian population, most of the individuals being born in the European part of the RSFSR. Both parents of the probands were examined in only 58 cases, the proportion of sporadic cases in this group being 0.79, as compared to 0.77 for the whole group under study. The existing data evaluated by a direct method are not yet sufficient for a decisive estimation of the penetrance, which, however, cannot be under 80%. Segregation analysis of descendants from particular marriages showed a good correspondance to the hypothesis of Mendelian dominance (32 affected children out of 65). These results analyzed together with those obtained by other authors permit an inference on the full penetrance of neurofibromatosis. The genetic interpretation of sporadic cases as a result of new mutations is presented. The prevalence of neurofibromatosis among the 16-year-old youths was evaluated as 12.8 with 10-(5). This value is suggested to be an estimation of the incidence of the condition in the general population, the mutation rate evaluated by a direct method being equal to 4.4 with 10-(5) divided by 4.9 with 10-minus 5. The increased birth order of probands in sporadic cases (against the theoretical expectation) as well as increased paternal age (as compared with controls) were found to be statistically significant (P equals 0.004 and P equals 0.03, respectively) while the difference in maternal ages was statistically insignificant (P equals 0.008). No statistical relationship between sporadic cases and occupational exposure of parents to deleterious chemical and physical factors was found.

PMID: 125227 [PubMed - indexed for MEDLINE]

Mean Paternal Age Was 32.8 in von Recklinghausen disease

2007-04-26T09:36:00.000-07:00

1: Am J Med Genet. 1984 May;18(1):169-76. Links
The pathophysiology of neurofibromatosis: IX. Paternal age as a factor in the origin of new mutations.Riccardi VM, Dobson CE 2nd, Chakraborty R, Bontke C.
Von Recklinghausen neurofibromatosis is characterized by a relatively large proportion of apparently nonfamilial cases, presumed spontaneous mutations. This paper analyzes the distribution of paternal and maternal ages for 187 patients with von Recklinghausen disease representing the first definite case in their respective families. Mean paternal age was 32.8 years and mean maternal age was 27.4 years, both being significantly greater than for control populations (P equal to or less than .001). The advanced paternal age was not accounted for by the increase in maternal age. The methodology of controlling the general population paternal ages for each patient's birth year is described.

PMID: 6430086 [PubMed - indexed for MEDLINE]

Neurofibromatosis 2 50% de novo mutations Paternal Age ??

2007-04-26T09:27:00.000-07:00

Disease characteristics. Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected persons develop bilateral vestibular schwannomas by the age of 30 years. Affected indivduals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, and rarely, ependymomas and astrocytomas. Posterior subcapsular lens opacities that rarely progress to a visually significant cataract are the most common ocular findings. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy, a squint (third nerve palsy), or hand/foot drop.

Diagnosis/testing. Diagnosis of NF2 is based on clinical criteria. NF2f is the only gene known to be associated with neurofibromatosis type 2. Confirmatory molecular genetic testing of the NF2 gene is clinically available. The main role of molecular genetic testing is in early detection of at-risk individuals (primarily the children of classically affected individuals) for the purpose of medical management and surveillance. Prenatal diagnosis is clinically available.

Management. Treatment of vestibular schwannoma is primarily surgical. Stereotactic radiosurgery, most commonly with the gamma knife, may be an alternative to surgery. Management of individuals with vestibular tumors should include counseling for insidious problems with balance and underwater disorientation, which can result in drowning. Radiation therapy of NF2-associated tumors should be carefully considered since radiation exposure, especially in childhood, may induce, accelerate, or transform tumors. Treatment for hearing loss includes referral to an audiologist, lip-reading and sign language instruction, and possibly hearing aids and/or cochlear or brain stem implants. Individuals with visual impairment require routine, complete eye examinations. Surveillance for affected or at-risk individuals includes annual MRI beginning around age ten to 12 years and continuing until at least the fourth decade of life. Hearing evaluation including BAER testing may also be useful.

Genetic counseling. NF2 is inherited in an autosomal dominant manner. About 50% of individuals with NF2 have an affected parent and 50% have NF2 as the result of a de novo gene mutation. However, 25-30% of those representing simplex cases (i.e., individuals with no family history of NF2) are mosaic for an NF2 mutation. The risk to the sibs of the proband depends upon the genetic status of the parents. If a parent of the proband is affected, the risk to the sibs is 50%. Prenatal testing is clinically available. The disease-causing allele of an affected family member must be identified or linkage established in the family before prenatal testing can be performed.

DAILY PILL TO FIGHT GENETIC DISEASES?

2007-04-24T21:31:00.000-07:00

The drug, known as PTC124, has already had encouraging results in patients with Duchenne muscular dystrophy and cystic fibrosis. The final phase of clinical trials is to begin this year, and it could be licensed as early as 2009.

As well as offering hope of a first effective treatment for two conditions that are at present incurable, the drug has excited scientists because research suggests it should also work against more than 1,800 other genetic illnesses.

PTC124 targets a particular type of mutation that can cause very different symptoms according to the gene that is disrupted. This makes it potentially useful against a range of inherited disorders.

Related Links
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The same drug could be given to patients with Duchenne muscular dystrophy, the most serious form of the muscle-wasting condition, cystic fibrosis, which mainly affects the lungs, and haemophilia, in which the blood does not clot. It can be taken orally, and safety trials have not revealed any major side effects.

“There are literally thousands of genetic diseases that could benefit from this approach,” Lee Sweeney, of the University of Pennsylvania, who is leading the research, said. “What’s unique about this drug is it doesn’t just target one mutation that causes disease, but a whole class of mutations.”

In most genetic conditions, between 5-15 per cent of cases are caused by a defect called a “nonsense mutation”. Genes are instruction manuals for cells to make proteins, but nonsense mutations in effect introduce a command halfway through that stops production. The kind of protein disrupted determines the nature of the disease.

In Duchenne muscular dystrophy, for example, the protein necessary for normal muscle development is not made, and the fatal wasting disease is the result. In haemophilia, it is the gene for the clotting agents factor VIII or factor IX that is disrupted.

PTC124 works by binding to a part of the cell called the ribosome, which translates genetic code into protein, and allows it to ignore nonsense mutations. The gene can be read straight through and a normal protein is produced.

The beauty of the drug is that it should be useful with

APERT SYNDROME MEAN AGE OF FATHERS WAS 34.1YEARS

2007-04-12T12:59:00.000-07:00

ALMOST HALF THE FATHERS WERE OVER 35 WHEN THE CHILD WAS BORN AND 20% OF THE FAMILIES BOTH PARENTS WERE OLDER THAN 35

1: Am J Med Genet. 1997 Nov 12;72(4):394-8. Related Articles, Links

Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome.

Tolarova MM, Harris JA, Ordway DE, Vargervik K.

Department of Growth and Development, School of Dentistry, University of California, San Francisco, 94143-0442, USA.

Apert syndrome was studied to determine birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity among 2,493,331 live births registered in the California Birth Defects Monitoring Program (CBDMP) from 1983 through 1993; 31 affected infants were identified. The sample was completed with an additional 22 cases from the Center for Craniofacial Anomalies (CCA), University of California, San Francisco, for a total of 53 affected children. Birth prevalence, calculated from the CBDMP subsample, was 12.4 cases per million live births (confidence interval [CI] 8.6,17.9). The calculated mutation rate was 6.2 x 10(-6) per gene per generation. Asians had the highest prevalence (22.3 per million live births; CI 7.1,61.3) and Hispanics the lowest (7.6 per million, CI 3.3-16.4). In the large population-based CBDMP subsample, there was an almost equal number of affected males and females, (sex ratio 0.94) but in the clinical CCA subsample, there were more affected females (sex ratio 0.79). For all cases, the mean age of mothers was 28.9+/-6.0 years, and of fathers was 34.1+/-6.2 years. Almost half of fathers were older than 35 years when the child was born; for more than 20% of cases, both parents were older than 35 years. These findings may support the view that point mutations appear to be more commonly associated with paternal than with maternal alleles. Representing the largest systematically ascertained population-based study of Apert syndrome to date, they provide a reliable basis for genetic counseling and decision-making, and for focused research to define the cause of this syndrome.

PMID: 9375719 [PubMed - indexed for MEDLINE]

--------------------------------------------------------------------------------

Sporadic Neurofibromatosis and Advanced Paternal Age

2007-04-07T20:19:00.000-07:00

1: J Child Neurol. 1993 Oct;8(4):395-402. Links
Neurofibromatosis type 1: review of the first 200 patients in an Australian clinic.North K.
Department of Neurology, Children's Hospital, Camperdown, Sydney, Australia.

Neurofibromatosis type 1 is a common multisystem disorder, best managed in a multidisciplinary clinic. In 1991, the first Australian neurofibromatosis clinic was established at the Children's Hospital, Camperdown, and the clinical characteristics of the first 150 families are reviewed. Two hundred individuals were assessed; there was an equal sex distribution, and 55% of cases were sporadic. Advanced paternal age appeared to predispose to new mutations in the neurofibromatosis gene. Cafe-au-lait spots and axillary freckling were important to the diagnosis of neurofibromatosis type 1 during childhood, and neurofibromas and Lisch nodules, although often not appearing until after puberty, were present in almost all patients over 30 years of age. Short stature (27%), macrocephaly (43%), scoliosis (20.5%), and learning disabilities (45%) were common associated features. The prevalence of disease complications was similar to the major US and European studies.

Spontaneous Beta-Thalassemia and Advanced Paternal Age

2007-04-04T16:06:00.000-07:00

: Blood. 1989 Aug 1;74(2):852-4. Links
Characterization of a spontaneous mutation in beta-thalassemia associated with advanced paternal age.Chehab FF, Winterhalter KH, Kan YW.
Howard Hughes Medical Institute, University of California, San Francisco 94143.

We characterized the molecular defect in a Swiss patient with a spontaneous beta-thalassemia mutation. Cloning and DNA sequencing of her beta-globin gene revealed a new frameshift mutation due to a single nucleotide deletion at codon 64 of the beta-globin gene. Restriction site polymorphism showed that the mutation arose on her paternal chromosome. Direct sequencing of a polymerase chain reaction amplified DNA segment showed absence of the lesion in both alleles of her father's beta-globin gene and confirmed the spontaneous nature of this mutation.

PMID: 2665856 [PubMed - indexed for MEDLINE]

Neurofibromatosis(vonRecklinghausen's disease, NF1) paternal age effect

2007-04-04T15:31:00.000-07:00

: Hum Genet. 1992 May;89(3):281-6. Links
Genetics of neurofibromatosis 1 in Japan: mutation rate and paternal age effect.Takano T, Kawashima T, Yamanouchi Y, Kitayama K, Baba T, Ueno K, Hamaguchi H.
Department of Hygiene, Teikyo University School of Medicine, Tokyo, Japan.

We have performed formal genetic studies on 26 patients (14 males, 12 females) with neurofibromatosis 1 (von Recklinghausen's disease, NF1) in Japan. Family studies of 74 members of 18 kindreds revealed that 50% of the cases were caused by a new mutation; the mutation rate was assumed to be 7.3-10.5 x 10(-5). A tendency of paternal age effect, which was not accounted for by the maternal age effect, was observed, but live-birth order had no significant effect. Genetic linkage of neurofibromatosis 1 to the NF1 gene or the genetic marker in the pericentric region of chromosome 17 was established in 3 informative families.

PMID: 1351032 [PubMed - indexed for MEDLINE]

Athetoid/dystonic cerebral or hemiplegic cerebral palsy and Paternal Age

2007-04-04T15:27:00.000-07:00

: J Med Genet. 1993 Jan;30(1):44-6. Links
Parental age, genetic mutation, and cerebral palsy.Fletcher NA, Foley J.
Department of Neurological Sciences, St Bartholomew's Hospital, London.

Parental age and birth order were studied in 251 patients with cerebral palsy. No parental age or birth order effects were observed in spastic quadriplegia or diplegia, but a paternal age effect was detected in those with athetoid/dystonic cerebral palsy and congenital hemiplegia. These observations indicate that some cases of athetoid/dystonic or hemiplegic cerebral palsy might arise by fresh dominant genetic mutation.

PMID: 8423607 [PubMed - indexed for MEDLINE]

The Age of the Father is the Main Factor Determining the Human Spontaneous Mutation Rate

2007-04-04T15:22:00.000-07:00

1: Environ Mol Mutagen. 1993;21(2):122-9. Links
Erratum in:
Environ Mol Mutagen 1993;21(4):389.
How much do we know about spontaneous human mutation rates?Crow JF.
Genetics Department, University of Wisconsin, Madison 53706.

The much larger number of cell divisions between zygote and sperm than between zygote and egg, the increased age of fathers of children with new dominant mutations, and the greater evolution rate of pseudogenes of the Y chromosome than of those on autosomes all point to a much higher mutation rate in human males than in females, as first pointed out by Haldane [Ann Eugen 13:262-271, 1947] in his classical study of X-linked hemophilia. The age of the father is the main factor determining the human spontaneous mutation rate, and probably the total mutation rate. The total mutation rate in Drosophila males of genes causing minor reduction in viability is at least 0.4 per sperm, and may be considerably higher. The great mutation load implied by a rate of approximately 1 per zygote can be greatly ameliorated by quasi-truncation selection. Corresponding data are not available for the human population. The evolution rate of pseudogenes in primates suggests some 10(2) new mutations per zygote. Presumably the overwhelming majority of these are neutral, but even the approximate fraction is not known. Statistical evidence in Drosophila shows that mutations with minor effects cause about the same heterozygous impairment of fitness as those that are lethal when homozygous. The magnitude of heterozygous effect is such that almost all mutant genes are eliminated as heterozygotes before ever becoming homozygous. Although quantitative data in the human species are lacking, anecdotal information supports the conclusion that partial dominance is the rule here as well. This suggests that if the human mutation rate were increased or decreased, the effects would be spread over a period of 50-100 generations.

PMID: 8444142 [PubMed - indexed for MEDLINE]

New Mutations For Huntington's Disease From Advanced Paternal Age

2007-04-04T15:16:00.000-07:00

: Nat Genet. 1993 Oct;5(2):174-9. Links
Comment in:
Nat Genet. 1993 Nov;5(3):215.
Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects.Goldberg YP, Kremer B, Andrew SE, Theilmann J, Graham RK, Squitieri F, Telenius H, Adam S, Sajoo A, Starr E, et al.
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.

Huntington's disease (HD) is associated with expansion of a CAG repeat in a novel gene. We have assessed 21 sporadic cases of HD to investigate sequential events underlying HD. We show the existence of an intermediate allele (IA) in parental alleles of 30-38 CAG repeats in the HD gene which is greater than usually seen in the general population but below the range seen in patients with HD. These IAs are meiotically unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for HD are more frequent than prior estimates and indicate a previously unrecognized risk of inheriting HD to siblings of sporadic cases of HD and their children.

PMID: 8252043 [PubMed - indexed for MEDLINE]

Article

Nature Genetics 5, 174 - 179 (1993)
doi:10.1038/ng1093-174
Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects
Y. Paul Goldberg1, Berry Kremer1, Susan E. Andrew1, Jane Theilmann1, Rona K. Graham1, Ferdinando Squitieri1, Håkan Telenius1, Shelin Adam1, Anaar Sajoo1, Elizabeth Starr1, Arvid Heiberg2, Gerhard Wolff3 & Michael R. Hayden1
1Department of Medical Genetics, University of British Columbia, 416−2125 East Mall Vancouver, British Columbia V6T 2C1, Canada

2Frambu Helsesenter, 1404 Siggerud, Norway

3Institut für Humangenetik und Anthropologie, Universität Freiburg, Breisacherstrasse 33, D-7800 Freiburg, Germany

Correspondence should be addressed to M.R.H.

REFERENCES
Harper, P.S. Huntington's Disease (W.B. Saunders, London, 1991).
Hayden, M.R. Huntington's Chorea (Springer-Vertag, New York, 1981).
Vogel, F. & Motulsky, A. Human Genetics 2nd edn (Springer-Verlag, New York, 1986).
Huntington Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on HD chromosomes. Cell 72, 971−983 (1983).
Andrew, S.E. et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington Disease. Nature Genet. 4, 398−403, (1993).
Wolff, G. et al. New Mutation to Huntington's Disease. J. med. Genet. 26, 18−27 (1989).
Barattser, M., Bum, J. & Fazzone, T.A. Huntington's chorea arising as a fresh mutation. J. med. Genet. 20, 459−460 (1983).
Shaw, M. & Caro, A. The mutation rate to Huntington's chorea. J. Med. Genet. 19, 161−167 (1982).
Chiu, E. & Brackenridge, C.J. A probable case of mutation in Huntington's disease. J. med. Genet. 13, 75−77 (1976).
Stevens, D. & Parsonage, M. Mutation in Huntington's chorea. J. Neurol. Neurosurg. Psychiat. 32, 140−143 (1969).
MacDonald, M.E. et al. The Huntington's disease candidate region exhibits many different haplotypes. Nature Genet. 1, 99−103 (1969).
Andrew, S.E. et al. DNA analysis of distinct populations suggest multiple origins for the mutation causing Huntington Disease. Clin. Genet. 43, 286−294 (1993).
Fu, Y-h. et al. Variation of the CCG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 67, 1047−1058 (1991).
Kremer, E.J. et al. Mapping of DNA instability at the fragile X to a trinucleotide repeat sequence p(CCG)n. Science 252, 1711−1714 (1991).
Mahadevan, M. et al. Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science 255, 1253−1255 (1992).
Fu, Y-H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256−1258 (1992).
Brook, J.D. et al. Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell 68, 799−808 (1992).
Barcelo, J.M. et al. Intergenerational stability of the myotonic dystrophy protomutation. Hum. molec. Genet 6, 705−709,1993.
Brook, J.D. Retreat of the triplet repeat? Nature Genet. 3, 279−281 (1993).
Penrose, L.S. Parental age and mutation. Lancet II, 312 (1955).
Penrose, L.S. Parental age in achondroplasia and mongolism. Am. J. hum. Genet. 9, 167−169 (1957).
Murdoch, J., Walker, B.A. & McKusick, V.A. Parental age effects on the occurrence of new mutations for the Marfan syndrome. Ann. hum. Genet. 35, 331−336 (1972).
Vogel, F. A probable sex difference in some mutation rates.Am. J. hum. Genet. 29, 312−319 (1977).
Kunkel, L.M. et al. Analysis of human Y chromosome specific reiterated DNA in chromosome variants. Proc. natn. Acad. Sci. U.S.A. 74, 1245−1249 (1977).
Goldberg, Y.P., Andrew, S.E., Clarke, L.A. & Hayden, M.R. A PCR method for accurate assessment of trinucleotide repeat expansion in Huntington Disease. Hum. molec. Genet 2, 635−636 (1993).
Zar, J.H. (ed.) Biostatistical Analysis 2nd edn 370−371 (Prentice-Hall, New Jersey, (1984).

Costello Syndrome and Mean Paternal Age of 38 years

2007-04-04T14:51:00.000-07:00

Am J Med Genet. 1994 Sep 1;52(3):358-9. Links
Genetics of the Costello syndrome.Lurie IW.
Department of Pediatrics, School of Medicine, University of Maryland, Baltimore.

Although Costello syndrome is considered to be an autosomal recessive disorder, review of 20 families demonstrated that the 37 sibs of the probands were all normal. In 6 families on whom pedigrees were not available, 2 affected sib-pairs were born. Even if there were no normal offspring in these latter families, the occurrence of the Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal recessive inheritance pattern (P = 0.999). Moreover, a significant increase of mean paternal age (38.0 yr) and paternal-maternal age difference (7.36 yr) suggests sporadic autosomal dominant mutations as a likely cause. The 2 reported cases of affected sibs born to healthy parents may be explained by gonadal mosaicism, although heterogeneity with a small proportion of recessively inherited cases cannot be excluded.

PMID: 7528974 [PubMed - indexed for MEDLINE]

Daughters Of Fathers 50-59 Lose about 4.4 years .......

2007-04-04T14:37:00.000-07:00

Mutat Res. 1997 Jun 9;377(1):61-2. Links
Mutation load and human longevity.Gavrilov LA, Gavrilova NS, Kroutko VN, Evdokushkina GN, Semyonova VG, Gavrilova AL, Lapshin EV, Evdokushkina NN, Kushnareva YE.
Center for Longevity Research at A.N. Belozersky Institute, Moscow State University, Russia. gavrilov@glas.apc.org

Since paternal age at reproduction is considered to be the main factor determining human spontaneous mutation rate (Crow, J. (1993) Environ. Mol. Mutagenesis, 21, 122-129), the effect of paternal age on human longevity was studied on 8,518 adult persons (at age 30 and above) from European aristocratic families with well-known genealogy. The daughters born to old fathers (50-59 years) lose about 4.4 years of their life compared to daughters of young fathers (20-29 years) and these losses are highly statistically significant, while sons are not significantly affected. Since only daughters inherit the paternal X chromosome, this sex-specific decrease in daughters' longevity might indicate that human longevity genes (crucial, house-keeping genes) sensitive to mutational load might be located in this chromosome.

PMID: 9219579 [PubMed - indexed for MEDLINE]

The high spontaneous mutation rate: Is it a health risk?*

2007-04-04T14:32:00.000-07:00

James F. Crow

Proc. Natl. Acad. Sci. USA
Vol. 94, pp. 8380-8386, August 1997

Genetics Laboratory, University of Wisconsin, Madison, WI 53706

My topic is mutation. Mutation is the ultimate source of variability on which natural selection acts; for neutral changes it is the driving force. Without mutation, evolution would be impossible. My concern, however, is not with mutation as a cause of evolution, but rather as a factor in current and future human welfare. Since most mutations, if they have any effect at all, are harmful, the overall impact of the mutation process must be deleterious. And it is this deleterious effect that I want to discuss.

The ideas that I am presenting are not new. Some go back to early in the century, but the evidence has been strengthened in recent times. In this review, I shall draw on the work of many who have contributed to this history.

This lecture is dedicated to three heroes. The first is Wilhelm Weinberg, a busy German physician and obstetrician42 years of practice and more than 3,500 birthswho somehow found time to invent all manner of clever tricks for studying heredity in that recalcitrant species, Homo sapiens. He was the first to suggest that the mutation rate might be a function of paternal age (1). The second hero is J. B. S. Haldane, an eccentric polymath with an enormous number and an incredible diversity of accomplishments. He was one of the first to measure a human mutation rate and was the first to notice a sex difference in the rate (2). The third is H. J. Muller, who made mutation an experimental subject by devising an objective way of measuring it and showing that ionizing radiation is mutagenic. In the later years of his life, Muller spent much of his energy, physical and emotional, in a crusade against unnecessary human exposure to radiation. Interestingly, he gave little attention to what is surely much more important, chemical mutagens. The main reason is that when he was still active there were no known mutagens that were not highly toxic; mustard gas is an example. Had he known of relatively harmless compounds that are highly mutagenic, he would surely have extended his crusade to environmental chemicals. Curiously, although Muller emphasized the high rate of spontaneous mutation, he did not include it in his crusade, mainly, I think, because he saw no feasible way to reduce it (3).

The Nature of Mutations

Older Paternal Age and progeria, basal cell nevus syndrome etc. 1975

2007-04-04T14:22:00.000-07:00

1: J Pediatr. 1975 Jan;. Links
Older paternal age and fresh gene mutation86(1):84-8: data on additional disorders.Jones KL, Smith DW, Harvey MA, Hall BD, Quan L.
Older paternal age has previously been documented as a factor in sporadic fresh mutational cases of several autosomal dominant disorders. In this collaborative study, an older mean paternal age has been documented in sporadic cases of at least five additional dominantly inheritable disorders; the basal cell nevus syndrome, the Waardenburg syndrome, the Crouzon syndrome, the oculo-dental-digital sysdrome, and the Treacher-Collins syndrome. It was also found to be a factor in acrodysostosis and progeria, suggesting a fresh mutant gene etiology for these two conditions in which virtually all cases have been sporadic and the mode of genetic etiology has been unknown