Older Fathers: Increased risk of having children with autism, schizophrenia

Older Fathers: Increased risk of having children with autism, schizophrenia
Older fathers: link to autism, schizophrenia.
By Paul Raeburn on January 28, 2009 - 1:52pm in About Fathers

Just after my two-year-old son, Henry, was born, I was surprised and disturbed to learn that he was at increased risk of autism, schizophrenia, bipolar disorder and other ills-because of my age.


My wife, Elizabeth, and I knew about the risks associated with the children of older mothers, with Down syndrome being the most widely recognized. She was tested for whatever was testable while she was pregnant with Henry, and he seemed to be healthy in every respect.

There is, however, no pre-natal test for autism or schizophrenia. And yet the risks are substantial: A 40-year-old man has the same chance of fathering a child with schizophrenia as does a 40-year-old woman of giving birth to a child with Down syndrome.

Why do we know so much about the genetic ailments associated with older mothers, but almost nothing about the diseases associated with older fathers?

In an article I've just written for Scientific American Mind, I note that the number of older fathers is on the rise, meaning the number of children at increased risk for autism and schizophrenia is also on the rise.

Nobody understand why this should be true. A woman's eggs are constructed and stored before she is born. It's reasonable to think that as they age, they might acquire genetic errors that could lead to disease. But sperm are freshly manufactured whenever they're needed; they are not stored. So what could be going on there?

The speculation is that something is going wrong with the so-called spermatogonial cells, the factories that make sperm. It's unclear what is happening, but the situation clearly deserves further research.

And why are older fathers not told of the risks?

That seems wrong to me. Some time ago, I called Charles J. Epstein, past president of the college of medical genetics, and Marilyn C. Jones, the current president, and asked them if they could explain why this don't ask-don't tell policy made sense, especially considering the new findings. "To put it out there every time somebody comes to you for counseling probably engenders more fear than light," Epstein said.

Jones agreed. "Paternal age is usually not addressed in counseling couples of advanced age because there is no simple test to address the risk," she said. "If there is nothing to offer a couple but increasing anxiety, many counselors and physicians do not bring the issue up."

Why then all the fuss about Down syndrome in the children of older women, when the risks for the children of older fathers are about the same? "You bring up Down syndrome, because you get sued if you don't," Epstein said. "And there are options. You can go through prenatal diagnosis, you have the option to terminate."

Epstein points out that the general rate of abnormalities of all kinds in newborns is about 2-4%. So even a 3% risk of schizophrenia in the children of men over 50 is not out of line with other risks. And it sounds less frightening when put this way: A 50-year-old man has a 97% chance of having a child without schizophrenia.

Still, I wish I had known what the risks were before we decided to have children. Would we have gone ahead anyway? That's difficult to say. But at least we would have had all the information we needed to make an intelligent decision.

Increased Paternal Age is a Risk Factor For Alzheimer's Disease in the Absence of a Major Gene

Neurogenetics. 1998 Aug;1(4):277-80. Links
Paternal age is a risk factor for Alzheimer disease in the absence of a major gene.Bertram L, Busch R, Spiegl M, Lautenschlager NT, Muller U, Kurz A.
Department of Psychiatry, Technical University Munich, Germany.

We compared the parental age at birth of patients with Alzheimer disease (AD) with that of cognitively healthy control subjects. Within 206 carefully diagnosed AD patients, two groups were distinguished according to the likelihood of carrying a major gene for AD (MGAD). This likelihood was calculated by applying a Bayesian approach which incorporates data on aggregation of the disease, age at onset, and "censoring" ages within the family. All AD patients were ranked by MGAD probability. According to the sample's quartiles, two subgroups were defined representing the 52 individuals with the lowest and the 52 with the highest MGAD probability. Age at onset of dementia, education, and apolipoprotein E epsilon4 allele frequencies were not statistically different between the two groups. Fathers of patients with a low MGAD probability were significantly older (35.7+/-8.1 years) than fathers of both other groups (high MGAD probability 31.3+/-6.9 years, P=0.004; controls 32.6+/-6.8 years, P=0.04, n=50). The differences for mothers were less pronounced and not statistically significant. These findings suggest that increased paternal age is a risk factor for AD in the absence of a major gene, whereas increased maternal age and AD are associated only weakly and independently of genetic disposition.

PMID: 10732803 [PubMed - indexed for MEDLINE]





George Bartzokis,M.D.


Visiting Professor

Laboratory of Neuro Imaging,
Department of Neurology, UCLA School of Medicine
635 Charles Young Drive South, Suite 225
Los Angeles, CA 90095-7332



Education

1975-1979, BA Harvard University, Cambridge, MA
1979-1983, MD Yale Medical School, New Haven, CT
1983-1984, Internship, UCLA/WLA VA, Los Angeles, CA
1984-1987, Psychiatry Residency, UCLA NPI, Los Angeles, CA
1987-1990, Schizophrenia Research Fellow, UCLA Dept of Psychology, Los Angeles, CA


Research

Development of brain imaging biomarkers for use in diagnosis of neuropsychiatric disorders and medication development
Assessing brain maturation and degeneration trajectories over the life-span in normal populations and how neuropsychiatric disorders interact with these processes


Projects

Myelin breakdown in aging and Alzheimer's disease
In vivo quantification of age-related increases in brain iron levels
Evaluation of brain maturational trajectories in normal adults and patientss with neuropsychiatrc diseases


Skills

Quantification of brain iron levels
Quantification of limbic structures volumes
Quantification of brain myelination
Quantification of myelin integrity
Clinical trials
Administration of multidisciplinary teams


Honors

U.S. Patent, Method for Quantitatively Measuring Stored Iron in Tissue Using MRI



This quote is not from a published paper.
I had asked Dr. Bartzokis why risk of non-familial autism, schizophrenia, MS, and Alzheimer's risk increases with the age of the father at a person's birth.


"The issue is that the older man will have sperm that has undergone more divisions and therefore had more chances to have mutations.
The COMPLEXITY of the myelination process makes it more vulnerable to mutations. I am not talking of one specific mutation. Many things could MANIFEST in the myelination or myelin breakdown process because it is so vulnerable - something going slightly wrong will impact it while it will not impact bone growth or the heart. A good example is ApoE4 - whatever else it may affect, it manifests in the reduced capacity of myelin repair and earlier onset of AD."


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



Charles Lee, Ph.D.

This analysis of so-called copy number variation (CNV) has now revealed some startling results.

It would seem the assumption that the DNA of any two humans is 99.9% similar in content and identity no longer holds.

The researchers were astonished to locate 1,447 CNVs in nearly 2,900 genes, the starting "templates" written in the DNA that are used by cells to make the proteins which drive our bodies.

This is a huge, hitherto unrecognised, level of variation between one individual and the next.

"Each one of us has a unique pattern of gains and losses of complete sections of DNA," said Matthew Hurles, of the UK's Wellcome Trust Sanger Institute.

"One of the real surprises of these results was just how much of our DNA varies in copy number. We estimate this to be at least 12% of the genome.

"The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."

Evolving story

The new understanding will change the way in which scientists search for genes involved in disease.


"Many examples of diseases resulting from changes in copy number are emerging," commented Charles Lee, one of the project's leaders from Brigham and Women's Hospital and Harvard Medical School in Boston, US.

"A recent review lists 17 conditions of the nervous system alone - including Parkinson's disease and Alzheimer's disease - that can result from such copy number changes."

Scientists are not sure why the copy variations emerge, but it probably has something to do with the shuffling of genetic material that occurs in the production of eggs and sperm; the process is prone to errors.

As well as aiding the investigation of disease and the development of new drugs, the research will also inform the study of human evolution, which probes genetic variation in modern populations for what it can say about their relationship to ancestral peoples.

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

285 of the approximately 3,000 CNVs are already known to be
associated with disease, and copy number variations of some of
these genes have been or are now being speculated as risk
factors for ailments such as AIDS, inflammatory bowel disease, lupus, cataracts, arterial disease and
schizophrenia.
One interesting observation that the researchers made during this study was that many of the CNVs have
population-specific characteristics and frequencies, which could explain increased prevalence of some diseases in
certain populations. For example, previous research found that the deletion of the UGT2B17 gene may lead to an
increased risk of prostate cancer in African American men. As a result of this and other research, the consortium is
expanding their studies to thousands of healthy individuals from populations outside of the HapMap collection.


....................................................................................



WHAT ARE THE DANGERS TO SOCIETY OF MEN FATHERING BABIES LATER AND LATER IN LIFE?
IS THE AUTISM EPIDEMIC CAUSED IN LARGE PART BY SO MANY MEN FATHERING BABIES PAST THE AGE OF 35?
IS THE DIABETES TYPE 1 EPIDEMIC ALSO CAUSED BY THE EPIDEMIC OF LATER FATHERING OF BABIES?




IS ANYONE LOOKING FOR A PATERNAL AGE EFFECT IN THE MUTATIONS TO GENES IN TYPE 2 DIABETES? OR CROHN'S, OR LUPUS, OR RHEUMATOID ARTHRITIS, OR FIBROMYALGIA, ETC. ETC.

ADVANCED PATERNAL AGE: How old is too old?
Isabelle Bray, David Gunnel and George Davey Smith
Department of Social Medicine, University of Bristol, UK
Journal of Epidemiology amd Community Health 2006;60:851-853

"Average paternal age in the UK is increasing. The public health implications of this trend have not been widely anticipated or debated. .....Accumulated chromosomal aberrations and mutations occurring during the maturation of the male germ cells are thought to be responsible for the increased risk of certain conditions with older fathers. Growing evidence shows that the offspring of older fathers have reduced fertility and an increased risk of birth defects, some cancers and schizophrenia." ......

July 2001 to April 2007 and No One Knows About the Male Biological Clock. Why?

Judy Foreman is a Lecturer on Medicine at Harvard Medical School. Her column appears every other week. Past columns are available on www.myhealthsense.com

07/03/2001

For years, many prospective parents - and doctors as well - have blithely assumed that, if an older couple's baby has birth defects, it's most likely because of the woman's advancing age.



But, increasingly, scientists are discovering that, by focusing almost exclusively on mothers-to-be, they might have been barking up the wrong genome. A man, or more accurately his sperm, also has a biological clock. And it's ticking can be just as spooky as a woman's, perhaps even more so because its virtually impossible to do prenatal tests to pick up all the possible genetic mutations in sperm.

"There's always been this myth that fathers can be fathers until they die, and that would be fine. It's always the mother who had to be young," said Dr. Eric Vilain, a geneticist and pediatrician at the University of California at Los Angeles. But that's because the risks associated with advancing paternal age have been routinely "underestimated."
Over the years, geneticists have linked a number of other diseases to advancing paternal age, including achondroplasia, or dwarfism; Marfan's syndrome, which can lead to the fatal rupture of a major blood vessel; and Apert's syndrome, or the malformation of the skull, hands and feet.

Retinoblastoma, an eye cancer; neurofibromatosis, or fleshy growths of abnormal nerve tissue; and some types of prostate cancer also have been linked with older fathers. And some diseases caused by genes on the X-chromosome, among them hemophilia, Duchenne muscular dystrophy and Hunter syndrome, have been linked to advanced age not of a child's father but of his maternal grandfather. In these cases, an older man passes on a defective gene on the X chromosome to his daughter, who, like Queen Victoria, becomes an unaffected carrier who can pass the disease to her sons.

When certain diseases caused by genetic defects show up in a family for the first time, the odds are seven to 10 times greater that the mutation has occurred in the DNA of the father rather than that of the mother, said Dr. Victor McKusick, professor of%2

THE OPTIMAL TIME FOR A MAN TO FATHER A CHILD IS 25 OR SO

"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.

Do the benefits of loving older fathers outweigh the risks? Take a survey of the street people, of the victims and see. Who else could answer this questions except the offspring?


Is the firm that hired the firm that produced and wrote this video selling something?

The Father's Age as a Risk Factor for Autism

Published and should be read on the EBD Blog
part of the paper is republished below, the entire paper contains excellent links to research papers pertaining to this subject.


The average age of fatherhood is increasing in the US and in Western Europe. Some research shows f older fathers are at increased risk for diseases and conditions (Bray et al., 2006). Some experts predict an upswing in cases of schizophrenia will accompany the increasing average paternal age. “The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent” (Malaspina et al., 2006). Approximately 25-33% of all cases of schizophrenia may be due to the father’s age at conception, according to Malaspina (2006). Malaspina sees a connection between advancing paternal age and neural functioning difficulties in people with autism and with schizophrenia. According to Tarin et al. (1998), there are well over 30 known conditions that the offspring of older fathers are more at risk for (see chart on paternal aging in the linked article).

The diagnosis of autism is increasing in the US and elsewhere (Centers for Disease Control, 2006). In a population study of 1990 through 1999, a total of 669,995 children, Atladóttir and colleagues (2007) reported increased diagnosese of autism, Torrette Syndrome, and hyperkinetic disorder. Is there a connection between increased cases of disorders such as autism and increased average paternal age? Psychiatrist Michael Craig Miller (2006), editor of the Harvard Mental Health Letter is convinced there is. Although a connection between the two would be corelational (not causal), the relationship encourages examination of the possibility that something related to paternal age (e.g. mutations in gametes) may contribute to the occurrence of autism. If there is a potential causal relationship, the new study by the Centers for Autism and Developmental Disabilities Research and Epidemiology (CADDRE) Network would provide a valuable opportunity to test the hypothesis.

Observations of a connection between advanced paternal age and difficulties for offspring go way back. Earlier research looking for a link between maternal age and autism also found the average paternal age (34) was much higher than the average age in the general population (Gillberg, 1980). Geneticist James F. Crow (1997) cites Wilhelm Weinberg (1862-1937) as noticing, during his 42 years of medical practice and helping 3,500 births, that the mutation rate might be a function of paternal age.James F. Crow said,in 1997and on other occasions that the greatest mutational health hazard in the population is fertile old men.

The Paternal Age Effect

From Wikipedia

Paternal Age Effect
Scientists know that a woman’s age at the time she conceives can affect her offspring’s genetic make-up. Women age 35 and older are at greater risk of delivering a child with a genetic disorder, such as Down Syndrome, due to an incorrect number of chromosomes. Less well known is that a man’s age also affects his offspring. In what is called the paternal age effect, men 35 years and older have a greater probability than younger men of fathering a child with some kind of genetic defect.

Dr. Nancy Snyderman and The Male Biological Clock on the Today Show

http://allday.msnbc.msn.com/archive/2007/03/13/88225.aspx
caught up with Dr. Nancy after her segment on the male biological clock this morning. I asked her what the one take-away point should be from the segment, and she said quite simply: "There is one." That is, there IS a male biological clock, and it's something that everyone should take into account when family planning and deciding to have children. The female biological clock often receives the attention because it's a clear and simple fact -- women cannot have children after a certain age. However, men can still reproduce at any age, and that's the reason that the male risk factors often drop off the radar screen.

Some of the statistics are quite alarming, however. Of the nearly 6 million fertility problems in the US each year, roughly 40% of them are attributed to the man. Of all the babies born with Down Syndrome to women over the age of 35, HALF of them are actually sperm-related. (Source for both statistics: Dr. Harry Fisch, director of the Male Reproductive Center at New York-Presbyterian Hospital/Columbia University Medical Center.) There are other studies out there that are still being discussed, with possible links between the male biological clock and diseases such as autism and schizophrenia.

And both men and women should be aware of the male biological risk factors, rather than solely focusing on the woman's age. She was emphatic about this story, and wants as many people to listen up as possible. WATCH VIDEO.

Dr. Emily Senay on the Early Show

Evidence Of Male Biological Clock Mounts
Senay: More Studies Show Men's Ability To Father Healthy Kids Diminishes With Age
NEW YORK, March 5, 2007


Senay observed that the notion of a male biological clock isn't as new as many people think.

A leading researcher in the field says basic knowledge of age-related changes in men's sperm goes back to the 1950s. She says it's intriguing that society chooses to ignore this information.

Senay herself told Smith, "I think there's a resistance, if you will, or even a measure of denial."

The NY Times science section On the male biological clock

Older fathers appear to raise risks of genetic disorders

By Roni Rabin Published: February 28, 2007





When it comes to fertility and the prospect of having normal babies, it has always been assumed that men have no biological clock — that unlike women, they can have it all, at any age.

But mounting evidence is raising questions about that assumption, suggesting that as men get older, they face an increased risk of fathering children with abnormalities. Several recent studies are starting to persuade many doctors that men should not be too cavalier about postponing marriage and children.

Until now, the problems known to occur more often with advanced paternal age were so rare they received scant public attention. The newer studies were alarming because they found higher rates of more common conditions — including autism and schizophrenia — in offspring born to men in their middle and late 40s. A number of studies also suggest that male fertility may diminish with age.

Ageless Fatherhood? Maybe Not--- a very good article

KATHLEEN DOHENY
c. 2007 HealthDay News
Distributed by The New York Times Syndicate
This is the first of four recent article or TV spots on this vitally important topic.
Here are some extensive excerpts:


.............."Several studies have found that older fathers risk having children with medical problems, including Down syndrome. Fisch and his colleagues evaluated more than 3,400 cases of Down syndrome, finding that if the woman and the man were both over age 35 at the time of conception, the father's age played a role in prevalence of the disorder. This effect was most pronounced when the woman was over 40, the researchers found. And, in those cases, the incidence of Down syndrome was about 50 percent attributable to the sperm, the researchers said. The study was published in 2003 in The Journal of Urology.

In another study, Dr. Avraham Reichenberg, of Mount Sinai School of Medicine in New York City, found that advanced age for fathers is associated with an increased risk of autism. His team gathered data on the age of fathers of more than 318,000 people born in Israel during the 1980s. The researchers found that the chances of having a child with autism or a related disorder were about six times greater if the father was 40 or older, compared to men 29 or younger. The findings were published in the September 2006 issue of The Archives of General Psychiatry.

Still another study found that the risk of schizophrenia in children was tied to older age of the father. In the study, which included about 90,000 people, the researchers discovered that children whose fathers were 50 or older when they were born were nearly three times more likely to have the disorder than those born to younger fathers. That study was published in 2001 in The Archives of General Psychiatry.

Another study, published in 2002 in Human Reproduction, found a higher risk of miscarriage in mothers 35 and older and fathers 40 and older.

And, in 2004, The Journal of the American Medical Association reported that 20 different disorders in children, ranging from schizophrenia to skeletal disorders, have been linked to the advanced age of the father......................

Orignally published February 27, 2007