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

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

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.

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

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]

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?

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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