Friday, June 29, 2007

Prevent Your Child Needing Health Care for Chronic Disorders By Fathering Babies Earlier In Life

It has been disasterous for offspring of the many, many men who father older and older in the Western World and elsewhere. Why are first borns smarter? Did they even ask about paternal age? No, the study did ask about maternal age.

'What can I do?' - SiCKO

It’s Waning Men,
June 14, 2007
First Published: 00:48 IST(14/6/2007)
Last Updated: 03:16 IST(14/6/2007)

This Father’s Day (June 18) will be observed with a difference. So say the western media that have been running a series of articles to celebrate men as “elaborately engineered gamete vectors”. In fact, the focus seems to be more on the “elaborately engineered” gametes themselves: the sperm. And rightly, too, considering male sperm cells are specialised ones that are only formed after puberty. It is the ability to produce sperm that makes men — well, arguably — such an invaluable resource for the human species. As it is with the male in every other species.

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.

But perhaps there’s a more important reason to ponder the future of “man” this Father’s Day. Researchers recently successfully prompted embryonic stem cells (that could turn into any type of cell in the body) in mice to become sperm, which fertilised a mouse egg. Once this success is replicated in humans, it would be entirely possible to produce sperm without men. Not quite a man’s world, is it?

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Monday, June 25, 2007

the rates of birth defects such as achondroplasia (short stature) and autism is higher among children with older fathers.

Irish Health Headlines

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.

Posted Monday 25th June 2007


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Angus Clarke, "I am aware of the paternal age effect in many disorders and in clearly this is the case in autism..."

Professor Angus Clarke
Principal Investigator and Professor in Clinical Genetics

Angus Clarke was born in 1954. He studied Medical and Natural Sciences in Cambridge, taking his Part II in Genetics, and then qualified in Medicine from Oxford University in 1979. After registration, he worked in general medicine and then paediatrics. As a research registrar in the Department of Medical Genetics in Cardiff, he studied the clinical and molecular genetic aspects of ectodermal dysplasia. Subsequently, he worked in clinical genetics and paediatric neurology in Newcastle upon Tyne, developing an interest in Rett syndrome and neuromuscular disorders.

He returned to Cardiff in 1989 as Senior Lecturer in Clinical Genetics. He is now Professor in Clinical Genetics. As well as teaching he also works as a clinician. With his colleague, Peter Harper, he wrote the book, Genetics, Society and Clinical Practice. He directs the Cardiff MSc course in Genetic Counselling.

Research interests:
social and ethical issues raised by advances in human genetics
the genetic counselling process

"I am aware of the paternal age effect in many disorders - and clearly in the case of autism, as with this one family. I am not aware of it in relation to autism in general - but there are cerainly a number of grounds for discouraging the deferral of child bearing to older ages (for men and women) including gene mutations, chromosome anomalies and reduced fertility. Education about the disbenefits of deferring child bearing is important but it is unclear how to achieve this as education is probably a weak force when it is asked to effect major change in a powerful social force.

Don't think that the problems of later child bearing are unrecognised - but if you have useful ways of addressing this then of course do share these"

Best wishes,

Angus Clarke

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Wednesday, June 20, 2007

Survey Up and Running on Autism

Advanced Grandparental Age as a Risk Factor for Autism
This study is currently recruiting patients.
Verified by University of Mississippi Medical Center June 2007

Sponsored by: University of Mississippi Medical Center
Information provided by: University of Mississippi Medical Center Identifier: NCT00464477


The Division of Medical Genetics at the University of Mississippi Medical Center is recruiting parents of children with a pervasive developmental disorder (including autism, autistic spectrum disorder, PDD-NOS, Asperger syndrome, childhood disintegrative disorder, and Rett syndrome) to participate in a study to help determine potential causes of the increasing prevalence of these disorders. The study is being conducted using an anonymous on-line survey available to parents through a secure link.

The study consists of approximately 90 questions about the affected child, siblings, parents, and grandparents, which will take roughly 10-15 minutes to complete. Several families will also be invited to participate in a phone interview. Both the survey and the phone interview are conducted using a self-designated code to protect anonymity and patient privacy. No identifying information such as name, date of birth, address, or phone number will be asked. Only questions regarding the year of birth of family members will be asked.

Autistic Disorder
Pervasive Developmental Disorder
Asperger Syndrome
Childhood Disintegrative Disorder
Rett Syndrome

MedlinePlus related topics: Asperger's Syndrome; Autism; Mental Health; Rett Syndrome
Genetics Home Reference related topics: Rett syndrome

Study Type: Observational
Study Design: Natural History, Cross-Sectional, Random Sample, Retrospective Study

Official Title: Advanced Grandparental Age as a Risk Factor for Autism and Other Pervasive Developmental Disorders

Further study details as provided by University of Mississippi Medical Center:

Total Enrollment: 100
Study start: June 2007; Expected completion: December 2007

Autism is a genetically heterogeneous entity. Although numerous studies have demonstrated a strong genetic basis, no clear etiology has been identified to date. Recently, two studies have demonstrated an increased risk of autism in children born to fathers over the age of 40. However, given the large male-to-female predominance of autism, it is likely that new mutations on the X chromosome account for a significant number of affected cases. Due to the maternal origin of the X chromosome in males, we hypothesize that advanced maternal-grandpaternal age may also be a risk factor for autism. Precedence for this theory exists with other X-linked disorders such as Duchenne muscular dystrophy and Rett syndrome. Additionally, it has been demonstrated that maternal psychiatric illness, but not paternal psychiatric illness, is more prevalent among parents of children with autism. Using anonymous surveys of families with autistic children, we seek to identify the ages of grandparents at the time the parents were born in order to determine if advanced maternal-grandpaternal age is associated with an increased risk for autism when adjusted for advanced maternal and paternal age. Additionally, we will seek out sister-pairs in order to identify any statistical significance between the ages of the maternal grandfather at delivery of each sister. If advanced maternal-grandpaternal age is, in fact, a risk factor, it would help direct molecular researchers towards genes on the X chromosome as potential etiologies for autism. Also, further study of potential mutagenic exposures in the environment of grandparents may help elucidate the reason for the increasing incidence of autism in recent decades.

Genders Eligible for Study: Both
Inclusion Criteria:

Individuals of any age with autism, autistic disorder, autistic spectrum disorder, Asperger syndrome, pervasive developmental disorder, PDD-NOS, Rett syndrome, or Childhood disintegrative disorder
Location and Contact Information

Please refer to this study by identifier NCT00464477

Omar Abdul-Rahman, MD 601-984-1900

United States, Mississippi
University of Mississippi Medical Center, Jackson, Mississippi, 39216, United States; Recruiting
Omar Abdul-Rahman, MD 601-984-1900

Study chairs or principal investigators

Omar Abdul-Rahman, MD, Principal Investigator, University of Mississippi Medical Center
More Information

If you would like to participate in this anonymous on-line survey, please go to NCT site

Study ID Numbers: 2007-0023
Last Updated: June 18, 2007
Record first received: April 20, 2007 Identifier: NCT00464477
Health Authority: United States: Institutional Review Board processed this record on June 20, 2007

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Wednesday, June 13, 2007

Found in the Hindustan Times, June 14, 2007

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.

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Friday, June 08, 2007

A Link Between Older Age of Fatherhood and An Increased Risk of Schizophrenia Was Detected in 1958 -From 10 Studies Done, age 35 is the Threshold

1: Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4. Links
Paternal ages below or above 35 years old are associated with a different risk of schizophrenia in the offspring.Wohl M, Gorwood P.
INSERM U675, 16 rue Henri Huchard 75018 Paris, France.

BACKGROUND: A link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies attempted to replicate this result with different methods, on samples with different origins, using different age classes. Defining a cut-off at which the risk is significantly increased in the offspring could have an important impact on public health. METHODS: A meta-analysis (Meta Win) was performed, assessing the mean effect size for each age class, taking into account the difference in age class references, and the study design. RESULTS: An increased risk is detected when paternal age is below 20 (compared to 20-24), over 35 (compared to below 35), 39 (compared to less than 30), and 54 years old (compared to less than 25). Interestingly, 35 years appears nevertheless to be the lowest cut-off where the OR is always above 1, whatever the age class reference, and the smallest value where offspring of fathers below or above this age have a significantly different risk of schizophrenia. CONCLUSION: No threshold can be precisely defined, but convergent elements indicate ages below or above 35 years. Using homogeneous age ranges in future studies could help to clarify a precise threshold.


Was father's age a factor in Va. Tech shootings? I've struggled this week about just how to write this. Several news outlets have reported that the father of Virginia Tech gunman Cho Seung-Hui is 61. The shooter was 23, which would mean the father was in his late 30s when his son was born. Not old by the standards around here, but it does bring home the seriousness of what the decision to delay childbearing can mean. It's unclear to me what exactly Cho was diagnosed with in the past, but two things I have seen have been schizophrenia and autism.

The link between advanced paternal age and schizophrenia has been recognized for a long time now. And just what is advanced paternal age in this case? Late last year, a French researcher concluded that while "no threshold can be precisely defined," there did seem to be a difference in risks for those younger than 35 and those older than 35. There also studies that show an association between both maternal and paternal age in autism. In fathers, there may be an increased risk with each advanced decade of the father's age. Without knowing anything more than the father's age and the son's reported behaviors and ultimate violent act, it's impossible to say here if the father's age had any effect whatsoever. But I think we can conclude it was one, and only ONE, of the potential risk factors involved in this tragic case.

That said, it's important to note that Cho's actions could not be explained away by either a diagnosis of schizophrenia or autism. Obviously, most people with those disorders never do anything like he did. I don't think we'll ever know what got in him to do what he did. To say "he did this because he was autistic" - or whatever - does more to stigmatize those with disorders than it does to satisfy the need to explain why it happened.

It also doesn't mean that older dads are destined to have violent, angry kids. As I've stated many times before, the vast majority of our kids will turn out to be just as quote-unquote normal as our younger-parenting counterparts, though there are some increased risks. Those risks are real and should be taken seriously when making family-planning decisions.

Thanks to concerned heart for posts about the research on advanced paternal age.

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Thursday, June 07, 2007

Men 40 and over are nearly six time more likely to have offspring with autism and other genetic defects, also schizophrenia rates are increased etc.

Scientific Evidence Points to Male Biological Clock
Symptoms Include Declining Fertility, Lowered Testosterone Levels and Increased Risk of Heart Disease, Diabetes and Genetic Abnormalities Such as Autism
NEW YORK (Nov 15, 2006)

It is well known that women have a "biological clock" associated with declining fertility, increasing risk for fetal birth defects, and altered hormone levels. Now an increasing body of scientific evidence points to the existence of a similar male biological clock, according to a retrospective review article by NewYork-Presbyterian Hospital and Columbia University Medical Center researchers published in the Nov. 15 Journal of the American Medical Association (JAMA). Conditions associated with the male phenomenon include declining fertility, lowered testosterone levels, diabetes, heart disease, depression, erectile dysfunction (ED) and an increased risk of fetal birth defects.

"Similar to women, aging is associated with declines in sex hormone levels in men. Testosterone decrease is not as steep or as sudden as that associated with estrogen declines during menopause in women, but its effects can be significant," says Dr. Harry Fisch, the study's senior author and director of the Male Reproductive Center and director of urologic microsurgery at NewYork-Presbyterian/Columbia, and professor of clinical urology at Columbia University College of Physicians and Surgeons. Dr. Fisch is also the author of The Male Biological Clock (Free Press), published earlier this year.

Low testosterone level (hypogonadism) affects between two million and four million American men. Symptoms include decreased muscle mass and bone mineral density; decreased libido and energy; obesity; insulin resistance; and mental and emotional problems. Other associated medical conditions and specific findings chronicled in Dr. Fisch's article include:

Male Infertility. Male infertility increases with the man's age. Men older than 35 are twice as likely to be infertile (defined as the inability to initiate a pregnancy within 12 months) compared to men younger than 25.

Birth Defects. As with advanced maternal age, advanced paternal age is associated with an increased incidence of birth defects due to decreased genetic quality of sperm. Men 40 and older are nearly six times more likely to have offspring with autism than men younger than 30, even after controlling for maternal age and other variables. Other defects associated with elevated paternal age include schizophrenia, Down syndrome and genetic abnormalities.

Type 2 Diabetes and Metabolic Syndrome. Both Type 2 diabetes and metabolic syndrome (which involves pre-diabetes symptoms as well as cardiovascular risk factors) are strongly associated with below-normal levels of testosterone. Of men aged 40 to 49 with Type 2 diabetes, 40 percent had decreased testosterone; the rate was nearly 55 percent among men in their 70s.

Erectile Dysfunction (ED)-Related Conditions. Broadly speaking, ED is strongly related to age-related biological changes and, hence, the male biological clock is also implicated in these other chronic, frequently progressive, and disruptive conditions:

Cardiovascular Disease. Prevalence of ED is significantly higher among patients being treated for heart disease and hypertension. Treatments for hypertension may contribute to erectile dysfunction, which may help explain the increased incidence of ED in these patients. However, the reverse relationship is also true: ED should be considered a marker for hypertension and other cardiovascular complications.

Depression. Depression may both contribute to and link erectile dysfunction and cardiovascular disease. Erectile dysfunction is associated with well-established negative psychological effects, primarily depression and anxiety. Furthermore, patients with ED who are depressed are more likely to develop cardiovascular disease.

Mortality. In one study, men with low testosterone had a mortality rate of 35 percent during the eight-year study period compared with a mortality rate of only 20 percent among men with normal testosterone levels. This trend persisted even after controlling for all reasonable variables in the study population.

The most common available treatment for hypogonadism is testosterone replacement therapy.

The study reports that prescription testosterone use in the United States has increased significantly in recent years with approximately 2.3 million prescriptions written in 2005; this represents a 50-percent increase from 2001 and a 210-precent increase from 1999. (In another ill-advised practice, testosterone therapy is prescribed "off label" for physical enhancement, such as for boosting muscle mass or "energy" in otherwise healthy men.)

"An improved understanding of the associated cellular and biochemical mechanisms of 'gonadal' aging is needed so that safe and effective ways to delay this process, or, in effect, 'rewind' the clock, might be possible," says Dr. Fisch.

The article's co-authors include Dr. Marianne Legato, founder and director of the Partnership for Gender Specific Medicine at NewYork-Presbyterian/Columbia and professor of clinical medicine at Columbia University College of Physicians and Surgeons; and Dr. Benjamin H. Lewis, cardiologist at NewYork-Presbyterian/Columbia and associate clinical professor of medicine at Columbia University College of Physicians and Surgeons.

For more information, patients may call (866) NYP-NEWS.

NewYork-Presbyterian Hospital
NewYork-Presbyterian Hospital – based in New York City – is the nation's largest not-for-profit, non-sectarian hospital, with 2,224 beds. It provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine at five major centers: NewYork-Presbyterian Hospital/Weill Cornell Medical Center, NewYork-Presbyterian Hospital/Columbia University Medical Center, Morgan Stanley Children's Hospital of NewYork-Presbyterian, NewYork-Presbyterian Hospital/Allen Pavilion and NewYork-Presbyterian Hospital/Westchester Division. One of the largest and most comprehensive health-care institutions in the world, the Hospital is committed to excellence in patient care, research, education and community service. It ranks sixth on U.S.News & World Report's guide to "America's Best Hospitals," has the greatest number of physicians listed in New York magazine's "Best Doctors" issue, and is included among Solucient's top 15 major teaching hospitals. The Hospital has academic affiliations with two of the nation's leading medical colleges: Joan and Sanford I. Weill Medical College of Cornell University and Columbia University College of Physicians and Surgeons.

Columbia University Medical Center
Columbia University Medical Center provides international leadership in pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future leaders and includes the dedicated work of many physicians, scientists, nurses, dentists, and public health professionals at the College of Physicians and Surgeons, the College of Dental Medicine, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. For more information, visit

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Yq microdeletions are the most prevalent cause of spermatogenic failure in men with azoospermia or severe oligozoospermia

Male Endocrinology

The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 1995-2004
Copyright © 2007 by The Endocrine Society


Approach to the Infertile Man
Shalender Bhasin
Boston University School of Medicine, and Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, Massachusetts 02118

Address all correspondence and requests for reprints to: Shalender Bhasin, M.D., Professor of Medicine, Boston University School of Medicine, Chief, Section of Endocrinology, Diabetes, and Nutrition, Boston Medical Center, Boston, Massachusetts 02118. E-mail:

Introduction: Infertility is one of commonest disorders to afflict young men and women. The evaluation of infertility is initiated typically after 1 yr of failure to conceive.

Diagnostic Evaluation: The couple should be evaluated together to determine whether the problem resides in the male partner, the female partner, or both. The objectives of evaluation are to exclude treatable conditions—gonadotropin deficiency, obstruction, and coital disorders—and identify those who are candidates for assisted reproductive technologies, those who are sterile and should consider adoption or artificial insemination using donor sperm, and those who should undergo genetic screening. All infertile men should undergo several semen analyses according to the World Health Organization manual, as well as measurements of testosterone, LH, and FSH levels. Hormone measurements can help determine whether the patient has gonadotropin deficiency (low testosterone and low or inappropriately normal LH and FSH), primary testicular failure (low testosterone, elevated LH and FSH), spermatogenic failure (normal testosterone and LH, elevated FSH), or androgen However, ICSI is expensive and associated with a higher risk of multiple gestation, low birth weight, preterm delivery, perinatal complications, and chromosome aneuploidy than naturally conceived pregnancies. Men considering ICSI should be offered karyotyping, Yq microdeletion testing, and genetic counseling by counselors experienced in reproductive disorders. resistance (high testosterone, elevated LH). A majority of infertile men have normal testosterone, LH, and FSH levels. Obstruction should be ruled out in azoospermic men with normal testosterone, LH, and FSH levels.

Genetics: Yq microdeletions are the most prevalent cause of spermatogenic failure in men with azoospermia or severe oligozoospermia. Infertile men with azoospermia or severe oligozoospermia should undergo karyotyping and testing for Yq microdeletions. Men with congenital absence of vas should be tested for cystic fibrosis transmembrane conductance regulator mutations.

Therapy: Gonadotropin therapy is highly effective in gonadotropin-deficient men. Intracytoplasmic sperm injection (ICSI) has emerged as the treatment of choice for idiopathic male factor infertility.

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Wednesday, June 06, 2007

There is a strong positive association between paternal age and schizophrenia

2004;329:1070 (6 November), doi:10.1136/bmj.38243.672396.55 (published 22 October 2004)

Paternal age and schizophrenia: a population based cohort study
Attila Sipos, honorary senior clinical lecturer in psychiatry1, Finn Rasmussen, senior clinical lecturer and associate professor of epidemiology2, Glynn Harrison, professor of mental health1, Per Tynelius, senior statistician2, Glyn Lewis, professor of psychiatric epidemiology1, David A Leon, professor of epidemiology3, David Gunnell, professor of epidemiology4

1 Academic Unit of Psychiatry, Cotham House, University of Bristol BS6 6JL, 2 Department of Public Health Sciences, Karolinska Institute, Norrbacka, SE-17176 Stockholm, Sweden, 3 Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, 4 Department of Social Medicine, Canynge Hall, Bristol BS8 2PR

Correspondence to: F Rasmussen


Objective To investigate the association of paternal age at conception with the risk of offspring developing schizophrenia.
Design A population based cohort study.

Setting Sweden.

Subjects 754 330 people born in Sweden between 1973 and 1980 and still alive and resident in Sweden at age 16 years.

Main outcome measures Hospital admission with schizophrenia or non-schizophrenic, non-affective psychosis.

Results After adjustment for birth related exposures, socioeconomic factors, family history of psychosis, and early parental death the overall hazard ratio for each 10 year increase in paternal age was 1.47 (95% confidence interval 1.23 to 1.76) for schizophrenia and 1.12 (0.98 to 1.29) for non-schizophrenic non-affective psychosis. This association between paternal age and schizophrenia was present in those with no family history of the disorder (hazard ratio for each 10 year increase in paternal age 1.60, 1.32 to 1.92), but not in those with a family history (0.91, 0.44 to 1.89) (P = 0.04 for interaction).

Conclusions Advancing paternal age is an important independent risk factor for schizophrenia. The stronger association between paternal age and schizophrenia in people without a family history provides further evidence that accumulation of de novo mutations in paternal sperm contributes to the overall risk of schizophrenia.


Our findings confirm an association between increased paternal age and schizophrenia in offspring, which remained even after we controlled for a wide range of potential confounding factors. The association seems to be relatively specific to schizophrenia compared with non-schizophrenic non-affective psychosis and was stronger in those with no family history of the disorder and those with normal Apgar scores at birth.
Strengths and weaknesses of study
We used routinely recorded data on variables related to birth, parents, and adulthood collected before the onset of disease. Furthermore, as cases were ascertained from a national inpatient register the possibility of selection bias was reduced. The large number of cases gives us statistical power to control for a wide range of important confounding factors and investigate whether the associations differ in relation to family history of psychosis or environmental risk factors.

The main limitation of our analysis is that case ascertainment was based on people admitted to hospital only with diagnoses recorded on an administrative database. Though we will have missed people who were not admitted to hospital, studies in the United Kingdom indicate that in the first three years after presentation over 80% of patients are admitted, even in areas with community oriented services.18 Furthermore, analyses of diagnoses recorded on the Swedish inpatient discharge register indicate that schizophrenia is diagnosed with reasonable accuracy.19-20 Another limitation is that a family history of admission with schizophrenia is only a marker for and not the equivalent of genetic vulnerability.

Comparison of findings with earlier research
In comparing our findings with those of earlier studies1-3 5 6 it is important to bear in mind that we were able to distinguish between narrowly defined schizophrenia (ICD-10 F20) and other non-schizophrenic non-affective psychosis (ICD-10 F21-29). One previous study1 also reported a stronger association with paternal age in relation to narrowly defined schizophrenia.

We found a pattern of association across the categories of paternal age that suggested a J shaped rather than a linear association, in line with the initial unadjusted findings of Byrne et al.2 In our study this pattern remained even after we controlled for possible confounders. Two other studies also investigated the possibility of a stronger association of increased paternal age in people with schizophrenia without a family history as opposed to those with a family history, as this would provide further evidence to support the hypothesis that this association is due to accumulating de novo mutations in the germ cells of older fathers. Malaspina et al showed that paternal age was significantly higher for people with schizophrenia without a family history in a small study that compared 35 familial cases with 68 sporadic cases.12 Zammit et al found no evidence for such effects, but their study lacked statistical power.6

The finding that the association between increased paternal age and schizophrenia was evident only in people with normal Apgar scores was based on a relatively small number of cases in people with low scores (n = 31) and should be viewed as preliminary until replicated in other studies.

Our findings confirm advancing paternal age as a strong independent risk factor for schizophrenia and indicate that 15.5% of cases of schizophrenia in our cohort could be due to the patient having a father who was aged > 30 years at birth. We found a stronger association in subjects without a family history of schizophrenia, providing further evidence to support the theory that accumulating de novo mutations in the germ cells of older fathers might contribute to an increased risk of schizophrenia in their offspring.

What is already known on this topic
Increased paternal age is associated with several diseases, possibly due to the age associated increase in sporadic de novo mutations in male germ cells

Several studies have reported an association between paternal age at conception and their offspring's risk of schizophrenia

If this association was due to de novo mutations one would expect to find a stronger association between paternal age and schizophrenia in cases with no family history of the disorder

What this study adds

There is a strong positive association between paternal age and schizophrenia that is not due to sociodemographic, birth related, or socioeconomic factors or family history or early parental death

Paternal age is only weakly associated with other non-affective, non-schizophrenic psychosis

This association is stronger in those with no family history of schizophrenia, supporting the hypothesis that accumulating de novo mutations in the germ lines of older fathers could play an important part in the aetiology of schizophrenia

In England and Wales the average paternal age has increased from 29.2 years in 1980 to 32.1 in 2002.21 Using our data we can estimate the hazard ratio associated with an average increase of paternal age by 2.9 years as 1.12. Assuming a conservative background annual incidence rate for schizophrenia of 10/100 00022 for the whole of the UK population (59.2 million in 2002) and that the observed associations are truly causal, this increase in paternal age since 1980 could have led to an additional 710 cases of schizophrenia in 2002 over and above the 5923 cases due to the background incidence rate.

Two extra tables of data can be found on
We thank Christina Dalman, Peter Allebeck, and Susanne Wicks for their helpful comments, Stan Zammit for his help with accessing all the relevant literature, and Geoff Adams for statistical/database support.

Contributors: DG, FR, and GH developed the core idea, and FR, AS, DG, GH, GL, DAL, and PT were involved in the design of the study. DG, FR, GH, GL, and DAL raised the research funds. PT prepared the cohort data and did the database linkages. AS carried out the statistical analysis and literature search and wrote the first draft of the paper. DG, DAL, and GL gave advice on statistical methodology. All authors critically reviewed and contributed to the final draft of the paper. FR and AS are guarantors.

Funding: Stanley Medical Research Institute.

Competing interests: None declared.

Ethical approval: The ethics committee at the Karolinska Institute, Stockholm, Sweden approved this study.

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Sunday, June 03, 2007

Sporadic Autism, Diabetes, Schizophrenia, Alzheimer's, Prostate Cancer, Breast Cancer etc. all increase with Paternal Age

Non-Verbal Intelligence Decreases with Increasing Paternal Age
Older paternal age was exclusively associated with a decrement in nonverbal (performance) intelligence IQ, without effects on verbal ability, suggestive of a specific effect on cognitive processing. In controlled analyses, maternal age showed an inverted U-shaped association with both verbal and performance IQ, suggestive of a generalized effect. From Schizophrenia Risk and the Paternal Germ Line


Men's And Women's Fertility Facts--Explained

Guys, Listen Up
But it's not just women who need to pay attention to the ticking of the clock, says Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center and author of The Male Biological Clock.

Men over 35 are twice as likely to be infertile as those under 25. Studies also are showing that, as with older women, older men are more likely to have children with birth defects due to the decreased genetic quality of their sperm.

"Every cell in the body ages," Fisch says. "Why would you think the sperm or testicles don't age?"

Proc. Natl. Acad. Sci. USAVol. 94, pp. 8380-8386, August 1997
ReviewThe high spontaneous mutation rate: Is it a health risk?
James F. Crow
Genetics Laboratory, University of Wisconsin, Madison, WI 53706

"I don't find this nonlinear effect at all surprising. Everything gets worse with age, so I fully expect fidelity of replication, efficiency of editing, and error correction to deteriorate with age. For a man of age 20, the male mutation rate is about 8 times the female rate. With a linear increase, in a man at age 30, the ratio is 430/24 = 18, at age 45 it is 770/24 = 32. With nonlinearity, these ratios are much larger, some 30-fold at age 30 and as much as two orders of magnitude at age 40. Examples such as MEN2A, MEN2B, and Apert syndrome, in which a total of 92 new mutations were all paternal, are therefore not so surprising. Whatever selective forces reduced the mutation rate in our distant past, at a time when most reproduction must have been very early, were not effective for older males.
I conclude that for a number of diseases the mutation rate increases with age and at a rate much faster than linear. This suggests that the greatest mutational health hazard in the human population at present is fertile old males. If males reproduced shortly after puberty (or the equivalent result were attained by early collection of sperm and cold storage for later use) the mutation rate could be greatly reduced. (I am not advocating this. For one thing, until many more diseases are studied, the generality of the conclusion is not established. Furthermore, one does not lightly suggest such socially disruptive procedures, even if there were a well-established health benefit.)"

"The optimal time for a man to father a healthy child is the same as for a woman — 25 or so," says Dolores Malaspina, a psychiatry professor at New York University and coauthor of the study.

Genetic Defects Linked to Sperm of Older Fathers
McGillivray, Katrina katrina at
Wed Apr 14 10:00:40 EDT 2004


Biological Clock Ticks for Men, Too
Genetic Defects Linked to Sperm of Older Fathers
Paul D. Thacker

JAMA. 2004;291:1683-1685.

Women approaching middle age have long been aware that the consequences of a
ticking biological clock include not only decreased fertility but also a
sharp increase in the odds of delivering a child with Down syndrome. Older
men, seemingly untouched by such biological constraints, felt free to father
children as they entered middle, and even old, age.

But now it is becoming increasingly clear that the biological clock ticks
for men as well as women, as researchers turn up evidence that as would-be
fathers get older, they have an increased chance of passing on genetic
defects to their children.

"New point mutations in humans are introduced through the male line," says
Dolores Malaspina, MD, professor of clinical psychiatry at Columbia
University and the New York State Psychiatric Institute. Furthermore, she
adds, the number of mutations in sperm increases as men age.

"This has been known since the 50s," said Malaspina. "What is intriguing is
why society chooses to ignore this."

Society is starting to pay attention. With many couples now deferring
childbearing until they are older, the issue of paternal age and increased
risk for birth defects is gaining a higher profile. It is also possible, say
some experts, that if current trends of older fatherhood continue, it could
someday become a public health problem as well as a personal one.

According to the latest birth statistics released in December by the Centers
for Disease Control and Prevention (CDC), the average age of motherhood is
at an all-time high of 25.1 years compared with 21.4 years in 1971. Although
some of this increase can be explained by the drop in teen births, another
reason was an increase in older women having children. Women in two age
groups-35 to 39 years and 40 to 45 years-now have children at the highest
levels in 3 decades. Statisticians find that women tend to marry men of
similar ages, so it can be surmised that the ages of fathers have also

Interestingly, while news reports on the CDC figures by various news outlets
mentioned the link between increased female age and disease risk to infants,
none reported the vulnerabilities posed by aging fathers that researchers
have turned up in recent years, such as the association between increased
paternal age and genetic diseases such as Apert syndrome (a disorder
characterized by craniofacial and limb abnormalities) and achondroplasia (a
skeletal disorder that causes dwarfism). Furthermore, studies show that 2%
of children born to men 50 years or older will have schizophrenia, three
times the incidence of schizophrenia in offspring born to fathers in their
early 20s.

Some experts in this field speculate that as the mean age of fathers
increases, the accumulation of mutations in the human gene pool could
heighten the risk of some recessive genetic disorders in future generations.

Malaspina notes that some European countries now ban men from becoming sperm
donors after reaching certain ages.

"I wouldn't discourage a man from having a child because the risk for many
of these diseases is quite small for an individual," she says. "But it's
quite meaningful at the population level." The Human Fertilisation and
Embryology Authority in the United Kingdom revised the upper age of sperm
donors downwards from 50 to 45 in 2000, based on the evidence that older men
are more likely to pass on genetic defects to offspring.

EARLY HINTS Wilhelm Weinberg

The first hint of a link between paternal age and incidence of birth defects
was noted in 1912 by Wilhelm Weinberg, MD, who found that achondroplasia, an
inherited skeletal disorder occurred more often in younger siblings than
older ones, suggesting that as parents aged, the likelihood of the disorder
increased. Decades later, L. S. Penrose, MD, discovered that only the
father's age that correlated with de novo incidence of the autosomal
dominant disorder.

Lionel Penrose
There are now approximately 20 different disorders that are correlated with
paternal age. The effect is quite prominent for de novo diseases such as
Apert, Crouzon, and Pfeiffer syndromes, for which frequency increases
rapidly with paternal age. Fathers of children with these syndromes are, on
average, 5 years older than the mean age of fathers in the population or
those of similarly affected children with familial forms of the same

The increase in such genetic disorders probably has multiple causes,
including differences in how sperm are produced as well as environmental
factors. In 1955, Penrose hypothesized that mutations in sperm cause
disease. The copy-error hypothesis posits that mutations arise
disproportionately in the male germ line, because these cells undergo many
more replications than do the germ cells that give rise to eggs. Also,
because the number of replications leading to sperm formation increases as
men age, there are more possibilities for genetic mistakes.

Abnormal expression of paternally imprinted genes is another possible
mechanism linking advancing paternal age and offspring health, suggests
Malaspina. Imprinting is a phenomenon affecting certain genes that causes
such genes to be expressed differently in offspring, depending on whether
they are inherited from the mother or the father.

Men thus add more mutations to the gene pool than women simply because their
germ cells pass through more mitotic replications. Women have only about 24
divisions in the cells that give rise to their eggs, and these divisions all
occur before birth. In men, germ line cells have already passed through 30
rounds of mitosis before puberty, and then continue to divide every 16
days-a total of 23 replications per year.

By the time a man reaches age 30, the cells that create sperm will have
passed through 380 mitotic divisions. At age 40, the number has climbed to
610, and at age 50, it reaches 840 rounds of replication. Each round of
division creates another opportunity for an error to enter into the germ

"When I worked in industry before [going to] medical school, women were
closely watched for their exposure to toxins in case they were pregnant,"
says Malaspina. Such an approach ignores the fact that men, with their
dividing germ cells, also should be protected from benzenes and other
chemicals, as well as radiation.

Multiple studies have examined aging's effect on sperm DNA. Narendra Singh,
MBBS, of the bioengineering department at the University of Washington, in
Seattle, and colleagues found in a study of 66 men aged 20 to 57 years,
there were significantly more breaks in the DNA of sperm from older men (="
src="/math/ge.gif" border=036 years) than from younger men (Fertil Steril.

"There is a gradual increase in DNA damage with age," Singh says. "But the
change was most remarkable at age 35."

Older stem cells might simply be creating more damaged sperm. Another
possibility is that protection from free radicals, which damage DNA, might
decrease with age. The researchers also found that both motility and the
rate of apoptosis, or programmed cell death, in sperm also fell. Apoptosis
is one mechanism to keep damaged sperm from fertilizing an egg.

"This is the first study showing that apoptosis goes down as a function of
age," notes Singh. "This finding is troubling because it shows that aging
predisposes the offspring for transmission of damaged DNA." Future research
might uncover strategies for either selecting healthy sperm or helping the
body to cull the sperm with damaged DNA, he says.

Other studies have found high rates of point mutations in the genes
associated with disease in offspring. Ethylin Jabs, MD, a professor of
pediatric genetics at Johns Hopkins University, in Baltimore, found that 99%
of the Apert syndrome cases were caused by mutations from the male germ line
(Am J Hum Genet. 2003;73:939-947). The incidence of these mutations
increases as men age, but the higher predicted incidence of Apert syndrome
in society suggests that some other process may be at work.

"It's more complex than just the number of mutations in the sperm," said
Jabs. "There may be some sort of selection process for sperm with mutations
that we can't yet explain."

A similar trend has been found by Norman Arnheim, PhD, professor of
molecular and computational biology at the University of Southern
California, Los Angeles. Achondroplasia closely correlates with male age,
but its incidence is higher than can be accounted for by the frequency of
mutated sperm (Proc Natl Acad Sci U S A. 2002;99:14952-14957). He has
posited a number of theories to explain why sperm selection might be

"There's a big field on sperm competition and we know that it happens in a
number of animals," he says. Some scientists suggest, for example, that it
is possible that a mutation that increases the odds of a birth defect will
also allow the particular sperm possessing that mutation to outcompete other
sperm to fertilize the egg. "Some think it might have to do with the
mitochondria that power the sperm's flagella. I don't know if that's the
right hypothesis, but it's one that's out there."

Although researchers have attempted to conduct epidemiological studies to
look for correlations of disease with paternal age, such studies can be
difficult to perform. For one thing, data sets often lack information about
paternal age. Statistics from the CDC, for example, indicate that 13.4% of
birth certificates from 2002 did not list the father's age.

This lack of information makes it difficult to ask questions about paternal
age and birth defects, says Mathias Forrester, a data consultant for the
Hawaii Birth Defects Program. "We've looked at maternal age, but we've never
even asked the question about paternal age because it's difficult to get
good denominators out of birth certificates."

Even when information about the father's age is provided on a birth
certificate, birth defects might be missed; they are often underreported
because they are sometimes identified after the birth certificate is filled
out, notes Thomas Mathews, a CDC demographer. In some cases, conditions with
a genetic component have a late onset, which further complicates linking
paternal age to a disorder in offspring.

To overcome this problem in a study that found a strong association between
paternal age and risk of developing schizophrenia, Malaspina anonymously
linked data from a population-based birth cohort to the records of the
Israeli Psychiatric Registry (Arch Gen Psychiatry. 2001;58:361-367).
"Ours was the first study to show this," she says. "The problem is that
people never asked about paternal age."

There are many reason why paternal contribution to birth defects has a low
profile. James F. Crow, PhD, emeritus professor of genetics and medical
genetics at the University of Wisconsin in Madison, mentions that most of
these defects occur at low levels, on the order of 1 in tens of thousands.
In contrast, the odds of having a child with Down syndrome are about 1 in
350 when the mother is age 35 years and 1 in 100 at age 40 years. However,
some scientists hint that society may not be ready to hear that older men,
like older women, run the risk of passing on birth defects.

But the risk of having a child who later develops schizophrenia, Malaspina
notes, is about 1 in 110 when the father is age 40-similar to a 40-year-old
woman's risk of having a child with Down syndrome.

Malaspina says she believes her findings met resistance because of a
reluctance by men to accept that fathering children later in life poses
increased health risks to their children.

"Despite the fact that our paper received excellent reviews it was rejected
by two medical journals," she said, noting that the study results now have
been replicated five times with similar results. "And these biases really
hold us back from scientific advances."

Katrina McGillivray
Information Coordinator
Best Start/OHPRS
180 Dundas Street W., Suite 1900
Toronto, ON M5G 1Z8
phone: 416-408-2249 x263
fax: 416-408-2122
toll-free 1-800-397-9567
email: katrina at

A New Key to Autism

By Michael Craig Miller, M.D. Harvard Mental Health Letter
The risk was smallest for children of fathers younger than 20 and greatest for children of fathers older than 50. A man in his 40s, for example, was almost 6 times as likely to have an autistic child as a man age 20. This relationship held even after researchers adjusted the results for the year of the person's birth, their socioeconomic status, or the mother’s age.

This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Convincing Evidence .................................................

Until recently, health care professionals have focused almost exclusively on the mother's age as a risk factor for health problems in the child. But we now know that the father's age also adds to the risk of potentially devastating diseases. And there is no practical way to detect these illnesses during pregnancy. For those weighing the risks, the decision can be wrenching. Adoption and in some instances a sperm donation may be acceptable alternatives to older fathers wanting to build a healthy family.

Michael Craig Miller, M.D. is Editor in Chief of the Harvard Mental Health Letter. He is also associate physician at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School. He has been practicing psychiatry for more than 25 years and teaches in the Harvard Longwood Psychiatry Residency Program.

'Infertility time bomb' warning
By Michelle Roberts
BBC News health reporter in Copenhagen

Infertility rates 'could threaten Europe's population'
Infertility is set to double in Europe over the next decade, a leading UK fertility expert has warned.
One in seven couples now has trouble conceiving naturally, but Professor Bill Ledger from Sheffield University warned this could rise to one in three.

He told a European fertility conference that women should be offered career breaks so they could have children younger, when they are more fertile.

Obesity and sex infections were also increasing infertility, he said.

The incidence of chlamydia, a sexually transmitted infection which carries a risk of infertility, has doubled over the last decade - and 6% of girls under the age of 19 are currently classed as obese.

A potential rise in male infertility could also affect couples, Professor Ledger said. Both the quality and quantity of sperm appeared to be in decline.

Time bomb

"Young people of today will become tomorrow's patients in infertility clinics," Professor Ledger said.

The sustainability of the population of Europe is at risk because there are too few children being born

Professor Bill Ledger, Sheffield University

He warned the rise in sexually transmitted infections in young teenagers was likely to cause blocked fallopian tubes in some.

"Later, when these young women want to become mothers, they find they can't conceive."

Professor Ledger added: "The obese child is almost certain destined to become an obese adult. Many women who are overweight will not ovulate as efficiently."

'Too few children'

Inflexible working hours and financial and career aspirations mean many women are putting off having a family until they are in their late 30s and early 40s, he said.

"The sustainability of the population of Europe is at risk because there are too few children being born. It is a threat to the future."

Nature designed women to have children in probably their late teens and early twenties
( maybe really 22-32 like men 22-32)

Dr Allan Pacey

But he said it was not too late to reverse the trend, with many countries, such as those in Scandinavia, introducing policies to encourage women to have children earlier.

He suggested the UK also follow the lead of France by introducing tax relief and giving greater support to women who want to take career breaks to start a family.

"Women are simply not as fertile after 35," Professor Ledger said.

"It's easier and more straightforward to do whatever you can to encourage women to have children naturally, rather than waiting to the point at which IVF may be needed."

'Growing concern'

Dr Allan Pacey, of the British Fertility Society, said: "Nature designed women to have children in probably their late teens and early twenties, and many women are now waiting until they are over 35.

"The message has to be driven home that the sooner you do it, the more likely it is you will be able to conceive without medical assistance."

Dr Pacey said the NHS was unlikely to be able to fund a huge increase in demand for fertility treatment. He also stressed that treatment was not without risk.

Dr Becky Lang, from the Association for the Study of Obesity said the issue of fertility and obesity was often overlooked.

"Being obese can significantly reduce your fertility as well as causing more complications when they do become pregnant.

"We have just been asked by the NHS to conduct more research into this as it is of growing concern to health professionals."

A spokesperson for the Department of Health said: "The government is committed to improving the health of nation, reducing obesity, promoting healthy living, increasing physical activity and tackling sexually transmitted infections."


Dr. Allan Pacey is well aware that the DNA of sperm making cells of older guys, past their early 30s, can become increasingly mutated. He would like to promote a new curriculum so that highschool students learn the correct time for both sexes to have children in order to prevent paternal age related genetic disorders and infertility problems. At this point kids are only taught about not having children too early in life. Of course teachers would have to study the subject of the male biological clock first.

Dear XXX,

Many thanks for your e-mail.
Yes I am aware of these articles which is the main reason I advise both men and women to have their children as early in their life as possible.

Kind regards,

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