Saturday, May 31, 2008

Scientists reveal dangers of older fathers

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.


Tuesday, May 13, 2008

Marfan syndrome occurs in offspring of older fathers

Nigeria: Marfan Syndrome

11 May 2008
Posted to the web 12 May 2008


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.

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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.


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.

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
Fibrodysplasia ossificans progressiva
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
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.

Monday, May 12, 2008

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.

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.

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

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.


© 2008 Newswise. All Rights Reserved.

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Saturday, May 3, 2008

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

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.

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]

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