De Novo Point Mutations and Autism

What is the story on the rise of autism? What does Arthur L. Beaudet say about autism? Dolores Malaspina? Abraham Reichenberg, Michael Miller, Raz Gross, etc.? The rise is autism could have been prevented on the genetic level if the public had been told about the nature of the male biological clock and sperm stem cell mutations.



Arthur L. Beaudet, M.D.



The two studies1, 2 greatly strengthen the growing awareness that a substantial fraction of autism is caused by genomic rearrangements. Particularly in the case of deletions, loss-of-function point mutations in genes in these regions are likely to be important as well. Most of these are de novo mutations not present in the parents. The children with identifiable genetic abnormalities are often in the syndromic group, and the sex ratio for these individuals tends to be 1:1, except for X-linked disorders6, 7.

De novo point mutations in such genes could explain the advanced paternal age association that has been reported for autism13. There is no evidence, however, that the risk of a de novo CNV is related to the age of either parent.

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Point Mutation
A point mutation is a simple change in one base of the gene sequence. This is equivalent to changing one letter in a sentence, such as this example, where we change the 'c' in cat to an 'h':


Original
The fat cat ate the wee rat.

Point Mutation The fat hat ate the wee rat.







Paul D. Thacker


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

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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
increased.

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

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.

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
diseases.

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.

DNA DAMAGE IN SPERM
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
line.

"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.
2003;80:1420-1430).

"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
occurring.

"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."

A PUBLIC HEALTH THREAT?
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."

CULTURAL RESISTANCE
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."

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"I have heard this evening that the hearing is to be suspended for three weeks in September because witnesses cannot attend, and because it is not going to be possible to finish on time in October it will be further suspended and not resumed until spring 2008 (who knows on previous form whether it even will then?). There is a general feeling that so far the hearing has gone extremely well for Andy and the prosecution is in disarray.


Profile: Dr Andrew Wakefield

Dr Wakefield stands by his findings
The suggestion that there is a link between MMR and autism has been one of the biggest health controversies of the last 10 years. But just who is the doctor behind the headlines?


Is Wakefield being attacked because his findings of harm from vaccinations are not to be tolerated by the powers that be?

Dr Richard Halvorsen, raises his concerns - warning that the Government "misleads us about vaccines".

Vaccinations: the debate
Saturday, July 28, 2007

By Gabrielle Fagan

Vaccinating our children is a routine part of protecting them from illness in childhood - but a new book queries whether it is worth the risk.


Dr Andrew Wakefield, who challenged the safety of the MMR vaccine because of fears over a possible link to autism, is currently fighting to save his career. Meanwhile the Government insists vaccines are essential and save millions of lives.

The result is that many parents are anxious and confused about the best course of action. And now another doctor, Dr Richard Halvorsen, raises his concerns - warning that the Government "misleads us about vaccines".

Author of a new book, The Truth About Vaccines, he claims that UK children are being used as "guinea pigs" and given "unnecessary" jabs for illnesses such as mumps, and a vaccine for whooping cough which has been "ineffective" in stamping out the illness.................





The pros and cons of vaccinations
DR Halvorsen looks at the case for and against controversial vaccines, but he says firmly: "Before making any final decisions, you are advised to consult a health professional about the specific needs of your child."

MMR (Measles, Mumps and Rubella)

Dr Halvorsen believes the vaccine serves little purpose and points out that: "MMR is the first and only vaccine to contain three live viruses. The studies to look for potential problems that this previously untried combination might cause have never been done."

And he believes that in view of the controversy over suggested links to autism, the MMR should be withdrawn until adequate long-term safety studies on sufficient numbers of children can demonstrate its safety.

He analyses its individual elements:

MEASLES

Measles used to kill more people than smallpox, scarlet fever and diphtheria combined, but improved nutrition and hygiene meant that by the mid-1950s deaths dropped to around 100 per year.

Despite claims vaccination of 95% of the population would eradicate the disease, there have been outbreaks in schools where 99% of children have been vaccinated, writes Dr Halvorsen.

"Measles 4vaccine can cause permanent brain damage and SSPE (rare but fatal brain disease), though almost certainly less commonly than 'naturally caught' measles."

HIS VERDICT: On balance the risks of the disease remain greater than those associated with the vaccine, especially in vulnerable children with chronic illnesses.

MUMPS

It is a mild disease that rarely kills; most people get a slight swelling of the facial and neck glands and are then immune for life.

Because immunity wears off, giving the vaccine has resulted in raising the age which children catch mumps from early childhood to adolescence, where the symptoms are more likely to be severe and can include permanent hearing loss, a painful swelling of testicles and possible infertility, says Dr Halvorsen.

He also suggests that the mumps vaccine is less effective as part of MMR, than the single jab.

HIS VERDICT: This vaccination is unnecessary and the MMR vaccine is making the disease worse.

RUBELLA

The vaccine was introduced to save babies being born with deformities as a result of mothers catching the disease while pregnant, but even before MMR was introduced only 30 babies a year were damaged by rubella.

A Finnish study showed that after two MMR jabs, a third of girls lost all protection by age 15.

HIS VERDICT: Not recommended for children, and it would be more effective to screen teenage girls to check if they've acquired immunity and vaccinate only those who don't have it.

HPV

This is aimed at the "Human Papilloma Virus" which causes genital warts that can result in cervical cancer.

A new HPV vaccination programme has been recommended by health authorities for 12-year-old girls and could start across the UK in autumn 2008, subject to a review. The plan is to vaccinate girls before they have time to become infected with HPV, which is sexually transmitted.

In trials it has only prevented the pre-cancerous changes to cells rather than cancer itself, and it only protects against the two types of HPV that cause 70% of this cancer.

HIS VERDICT: Some women in trials of the vaccine developed potential auto-immune disorders - mainly arthritis-related. This vaccine looks promising but it is too early to introduce it on a national scale.

ALUMINIUM

Dr Halvorsen also has concerns about aluminium which is present in most childhood vaccines. He says: "It's highly toxic, is known to cause brain damage and has been implicated in behavioural problems in children."

On the day of vaccination, young babies are given doses of aluminium that are the equivalent of up to a thousand times the maximum advised daily safety levels, he says.

HIS VERDICT: You can lessen the amount of aluminium your baby receives by spreading out the vaccines over a period of time.

"Spread out the length of time between the Pediacel (5-in-1), meningitis C and pneumococcal vaccines, all of which contain aluminium, so the amount of aluminium your baby receives on any one day will be reduced."

Of the three meningitis C vaccines available, Miningitec has the least aluminium, says Dr Halvorsen.

Where do spontaneous mutations come from?

Who is James F. Crow? 1997 The high spontaneous mutation rate: Is it a health risk?
James F. Crow

"How can we account for a higher mutation rate in males than in females? The most obvious explanation lies in the much greater number of cell divisions in the male germ line than in the female germ line. In the female the germ cell divisions stop by the time of birth and meiosis is completed only when an egg matures. In the male, cell divisions are continuous and many divisions have occurred before a sperm is produced. If mutation is associated with cell division, as if mutations were replication errors, we should expect a much higher mutation rate in males than in females."This makes the strong prediction that the mutation rate should increase with the age of the father, since the older the man, the more cell divisions have occurred. On the other hand, there should be no age effect in females."

"The most important properties of gene mutations, for the purposes of this talk, are: First, to repeat, if they have an observable effect they are almost always harmful. Second, most of the changes are not in the genes, but in the great bulk of so-called "junk" DNA, most of which has no known function. Many of these changes are effectively neutral. Third, most mutations have very minor effects, if any. We usually think of a mutation as an eye color change, a conspicuous disease, or some other phenotypic change that is sharp and striking, and indeed these are the kinds of mutations that have been most useful for classical genetic analysis. But diverse experiments in various species, especially Drosophila, show that the typical mutation is very mild. It usually has no overt effect, but shows up as a small decrease in viability or fertility, usually detected only statistically. Fourth, that the effect may be minor does not mean that it is unimportant. A dominant mutation producing a very large effect, perhaps lethal, affects only a small number of individuals before it is eliminated from the population by death or failure to reproduce. If it has a mild effect, it persists longer and affects a correspondingly greater number. So, because they are more numerous, mild mutations in the long run can have as great an effect on fitness as drastic ones."


"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.)"

Why Do Some Mutations Not Show a Paternal Age Effect?

Autism and Paternal Age

Paul Law, Jonathan Sebat, Michael Wigler, Clara Lajonchere, etc. know it is the older father that transmits the muated genes for autism. They will never tell the public the connection.


The full citation of the paper published in the July 31, 2007 print edition of the Proceedings of the National Academy of Sciences is: "A unified theory for sporadic and inherited autism," by Xiaoyue Zhao, Anthony Leotta, Vlad Kustanovich, Clara Lajonchere, Daniel H. Geschwind, Kiely Law, Paul Law, Shanping Qiu, Catherine Lord, Jonathan Sebat, Kenny Ye and Michael Wigler.


Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.

An Excellent Post on Vaccinations

Congratulations on your new baby! And Welcome to the War on Disease!
By Julie Obradovic
The Rescue Post


I have been wrong to exclude the influence of mercury and other ingredients of vaccinations in causing autism because I am so interested in the subject of how advancing paternal age is a cause of neurological and immunological disorders. Both increasing paternal age and the ingredients of vaccinations cause neurocognitive developmental disorders and detrimental effects.


http://www.youtube.com/watch?v=hq7FSYYVMEU

Correction Dr. Wigler's PNAS Paper Did NOT Attribute Autism to Older Mothers, "Nature" and the Dallas Morning News Reported it Though

. The paper Dr. Wigler wrote and the press release from CSHL did not contain this assertion at all. Nature and The Dallas Morning News contain quotes from Dr. Wigler attributing sporadic autism to older mothers. This assertion of Dr. Wigler's distort the 50 years plus of studies that show that older paternal age is the cause of sporadic genetic disorders because sperm divide hundreds and hundreds and hundreds of time with the age of the man and errors multiply in the sperm precursor cells and sperm. Dr. Wigler knows the public is unaware of this but scientists are not unaware. His paper does not point the finger at the mother's age, but his comments to NATURE and the press do.

Why is Dr.Wigler talking about old eggs when it is clear that older men's sperm stem cells and sperm carry de novo DNA mutations, i.e. probably copy number variations and definitely deletions? There is no evidence that older ovum cause autism. Yes, genetic mutations can be carried in an unaffected female who had an older father or by women who have autistic brothers or relatives. Paternal age derived autism is caused by germ line mutations in the father's sperm and 1:1 male to female. Plenty of males with autism or Asperger's have had older fathers.

.
Michael Wigler's assertions NOT IN HIS paper because scientists would not buy the assertion to blame sporadic autism on the mother's age. The public however does think that the age of the mother is important and these quotes reinforce this misinformation:

"Older mothers, who are more likely to have autistic children, could fall into this class, notes Wigler. Such mothers' eggs have had more time to accumulate mutations."


"The older the mother, the more likely she has acquired spontaneous mutations" in her chromosomes, and will transmit them at conception, Dr. Wigler said. Less frequently, but just as likely, Dr. Wigler said, fathers can transmit autism traits as well. Why mix up Down syndrome and CNVs in autis? 50% of Down Syndrome is due to an older father.

What about the information in this study of grandparents age and autism, especially the maternal grandfather age at the mother birth?

Why does this paper ignore Burd, ignore Gillberg, ignore Reichenberg, Gross, Croen, Cantor, Lauritsen, Malaspinia, Harlap, Crow, Gorwood, Rasmussen, Sipos, Brown, etc. Do you just change the definition of autism in 1994 and ignore paternal age as the major cause of some of the conditions that you now call autism? Japan has found older fathers and PDD and schizophrenia so has Australia, Denmark any country that has looked has found it. Wigler blames the old eggs.

One scientist wrote:
"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."


older papers discussing paternal age etc.:

Anorexia, Greater Maternal and Paternal Age at the Time of Birth

Psychosomatic Medicine Vol. 36, No. 1 (Jan.-Feb. 1974)
Anorexia Nervosa:
Demographic and Clinical Features in 94 Cases
KATHERINE A. HALMI, MD
A comprehensive chart study was made of numerous clinical and demographic features in 94
patients with anorexia nervosa. Unlike other large series, this survey included the pediatric age
group. A significantly greater maternal and paternal age at time of the patient's birth and a
greater incidence of both low and high birth weights compared with the general population was
found. A relatively high occurrence of premorbid feeding problems was present. Anxiety and
obsessive-compulsive traits were frequent premorbid symptoms. Precipitating events were
identified more frequently in patients with a greater age at onset of illness. Characteristic
behavior noted during the course of this illness is described.




The mothers' age at time of the patients'
birth was significantly greater (p < .001, Kolmogorov-Smirnov goodness fit test) than that for national control mothers (14) or Iowa control mothers2 (Fig. 1). Also, the fathers' age at the time of the patients' birth was significantly greater (p < .05, Kolmogorov-Smirnov goodness-of-fit test) than that of national control fathers (15) (Fig. 2). A significantly higher mothers' age at the time of probands' birth compared to that of Swedish control mothers was also reported by Theander (1). Kay and Leigh (11) did not analyze their data statistically, but nonetheless stated that youthfulness or advanced age of mothers at the patients' birth appeared unimportant. SUMMARY Significant demographic characteristics found in this survey of the hospital records of 94 anorexia patients include a greater maternal and paternal age at time of the probands' birth and a greater incidence of both low and high birth weights than in the general population. Unlike other large series of anorexia nervosa patients, this survey included the pediatric age group. This would explain the relatively high incidence, 8%, of onset of illness prior to age 10. Labels: Anorexia and advanced paternal and maternal age 1: Eur J Pediatr. 1999 May;158(5):362-6. Links Risk factors for type I diabetes mellitus in children in Austria Rami B, Schneider U, Imhof A, Waldhor T, Schober E. University Children's Hospital Vienna, Austria. The aim of this study was to investigate environmental risk factors in the development of type 1 diabetes mellitus in a population-based case-control study. Parents of all patients with manifestation of type 1 diabetes between 1989 and 1994 in Vienna were asked to complete a questionnaire (n = 114). Control children (n = 495), matched for age and sex, were randomly recruited from all schools in Vienna. Fathers of diabetic children were significantly older at the time their children were born than fathers of control children (P = 0.015). Children with diabetes were more likely to be second- or third-born children (P<0.05) p =" 0.007)." p =" 0.038)." p =" 0.015)." p =" 0.015)." p =" 0.13)." p="0.005).">30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. 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.









1979The British Journal of Psychiatry 134: 169-177 (1979)
© 1979 The Royal College of Psychiatrists

Raised parental age in psychiatric patients: evidence for the constitutional hypothesis
EH Hare and PA Moran

In two series of psychiatric patients (numbering about 6,000 and 2,000 respectively), the mean age of the mothers at the time of the patients' birth was found to be very significantly above expectation from the general population, and this was so for each of the major diagnostic groups. In the second series, the age of the fathers was also found to be very significantly above that expected from a sample survey of the general population, and this was so for each diagnostic group. Fathers' age was raised more than mothers', and was highest for schizophrenia. The raised parental age could not be explained in terms of the patient's year of birth or his father's social class. The raised mothers' age could largely be accounted for by regression on the raised fathers' age. The present findings, and those of previous studies, seem best explained on the hypothesis of a constitutional parental trait leading to delayed marriage
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However, we think that approximately one third or one quarter of all schizophrenia cases may be attributable to paternal age. Paternal age is the major source of de novo genetic diseases in the human population, which was first described by Penrose8 in the 1950s. He hypothesized that this was due to copy errors that arose in the male germ line over the many cycles of sperm cell replications. These mutations accumulate as paternal age advances. After the Penrose report, medical researchers identified scores of sporadic diseases in the offspring of older fathers, suggesting that these could occur from gene mutations. Particular attention was paid to conditions in last-born children. In the 1960s, an excess of schizophrenia in last-born children was also reported.


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We sought to investigate whether older paternal age at the time of birth is associated with schizophrenia and other schizophrenia spectrum disorders among the offspring. Several lines of evidence support a relation between older paternal age and schizophrenia spectrum disorders. First, most previous studies that examined this relationship have demonstrated positive associations (1–5), although these studies have been criticized for methodologic limitations. Most recently, Malaspina et al. (1), in a large Israeli birth cohort, demonstrated a robust and "dose-related" effect of paternal age on risk of schizophrenia and related disorders, a finding that was unaltered after adjusting for maternal age.










Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES: Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry 2001; 58:361-367[Abstract/Free Full Text]
Hare EH, Moran PA: Raised paternal age in psychiatric patients: evidence for the constitutional hypothesis. Br J Psychiatry 1979; 134:169-177[Abstract]
Gregory I: An analysis of family data on 1000 patients admitted to a Canadian mental hospital. Acta Genet Stat Med 1959; 9:54-96[Medline]
Johanson E: A study of schizophrenia in the male. Acta Psychiatr Scand Suppl 1958; 125
Kinnell HG: Parental age in schizophrenia (letter). Br J Psychiatry 1983; 142:204[Medline]
Labels: age of the fathers raised very significantly in schizophrenia 1979




Saying autism is not a mental illness
is functionally incorrect. When the
mental illness schizophrenia is now
determined to be developmental - it
appears in late adolescence as the brain and body mature, while autism manifests itself in childhood - when
autism was once termed “childhood
schizophrenia”, when both illnesses
originate in the brain, when both
conditions share many symptoms, when in
any case it is NOT a disgrace to be called “mentally ill”, you are making
a distinction that is not a distinction.

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: Eur Psychiatry. 2007 Jan;22(1):22-6. Epub 2006 Dec 4.Click here to read 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.

PMID: 17142012 [PubMed - indexed for MEDLINE]


Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina
Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the

fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.

Seminal findings
We initially examined the relationship between paternal age and the risk for schizophrenia because it is well established that paternal age is the major source of de novo mutations in the human population, and most schizophrenia cases have no family history of psychosis. In 2001, we demonstrated a monotonic increase in the risk of schizophrenia as paternal age advanced in the rich database of the Jerusalem Perinatal Cohort. Compared with the offspring of fathers aged 20-24 years, in well-controlled analyses, each decade of paternal age multiplied the risk for schizophrenia by 1.4 (95 percent confidence interval: 1.2-1.7), so that the relative risk (RR) for offspring of fathers aged 45+ was 3.0 (1.6-5.5), with 1/46 of these offspring developing schizophrenia. There were no comparable maternal age effects (Malaspina et al., 2001).

Epidemiological evidence
This finding has now been replicated in numerous cohorts from diverse populations (Sipos et al., 2004; El-Saadi et al., 2004; Zammit et al., 2003; Byrne et al., 2003; Dalman and Allenbeck, 2002; Brown et al., 2002; Tsuchiya et al., 2005). By and large, each study shows a tripling of the risk for schizophrenia for the offspring of the oldest group of fathers, in comparison to the risk in a reference group of younger fathers. There is also a "dosage effect" of increasing paternal age; risk is roughly doubled for the offspring of men in their forties and is tripled for paternal age >50 years. These studies are methodologically sound, and most of them have employed prospective exposure data and validated psychiatric diagnoses. Together they demonstrate that the paternal age effect is not explained by other factors, including family history, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, and birth complications. Furthermore, the paternal age effect is specific for schizophrenia versus other adult onset psychiatric disorders. This is not the case for any other known schizophrenia risk factor, including many of the putative susceptibility genes (Craddock et al., 2006).

There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study. The data support the hypothesis that paternal age increases schizophrenia risk through a de novo genetic mechanism. The remarkable uniformity of the results across different cultures lends further coherence to the conclusion that this robust relationship is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, which is independent of regional environmental, infectious, or other routes.

Indeed, the consistency of these data is unparalleled in schizophrenia research, with the exception of the increase in risk to the relatives of schizophrenia probands (i.e., 10 percent for a sibling). Yet, while having an affected first-degree relative confers a relatively higher risk for illness than having a father >50 years (~10 percent versus ~2 percent), paternal age explains a far greater portion of the population attributable risk for schizophrenia. This is because a family history is infrequent among schizophrenia cases, whereas paternal age explained 26.6 percent of the schizophrenia cases in our Jerusalem cohort. If we had only considered the risk in the cases with paternal age >30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. 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.

Biological plausibility
We used several approaches to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, we established a translational animal model using inbred mice. Previously it had been reported that the offspring of aged male rodents had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies (Auroux et al., 1983). Our model carefully compared behavioral performance between the progeny of 18-24-month-old sires with that of 4-month-old sires. We replicated Auroux's findings, demonstrating significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires (Bradley-Moore et al., 2002).

Next, we examined if parental age was related to intelligence in healthy adolescents. We reasoned that if de novo genetic changes can cause schizophrenia, there might be effects of later paternal age on cognitive function, since cognitive problems are intertwined with core aspects of schizophrenia. For this study, we cross-linked data from the Jerusalem birth cohort with the neuropsychological data from the Israeli draft board (Malaspina et al., 2005a). We found that maternal and paternal age had independent effects on IQ scores, each accounting for ~2 percent of the total variance. 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.

Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.
Labels: why doesn't everybody in this country know that up to 1/3 or more of schizphrenia is caused by older paternal age?

]
Link between older age of fatherhood and an increased risk of schizophrenia was detected in 1958. Since then, 10 studies




It isn't that we don't know, it really isn't such a mystery. For Some reason we are not told and we think that science does not know the answer, but it does know where autism and schizophrenia comes from. WHY WE ARE NOT TOLD IS ANOTHER STORY

Here one of 10 studies that all show the same results.

Am J Psychiatry 159:1528-1533, September 2002
© 2002 American Psychiatric Association

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Alan S. Brown, M.D., Catherine A. Schaefer, Ph.D., Richard J. Wyatt, M.D., Melissa D. Begg, Sc.D., Raymond Goetz, Ph.D., Michaeline A. Bresnahan, Ph.D., Jill Harkavy-Friedman, Ph.D., Jack M. Gorman, M.D., Dolores Malaspina, M.D. and Ezra S. Susser, M.D., Dr.P.H. < n =" 465)." n =" 481)" n =" 1313)">/=50 years old and at time of conception than in subjects whose fathers were 21-24 years old. Growth and development in fetal life and childhood are influencing the risk of schizophrenia in adulthood, but the underlying causal pathways are still unknown. De novo mutations in the germ cells of older fathers may play a causal role in the etiology of some cases of schizophrenia.
Labels: advancing paternal age, de novo mutations, mutations in the germ cells of older fathers may play a causal role, neurodevelopmental disorder, schizophrenia


posted by concerned heart @ 7:40 PM 0 comments

"Increasing father's age was associated with increased risk for autism"

BURD 1999 North Dakota


1: J Perinat Med. 1999;27(6):441-50. Links
Prenatal and perinatal risk factors for autism.Burd L, Severud R, Kerbeshian J, Klug MG. University of North Dakota School of Medicine and Health Sciences, North Dakota Fetal Alcohol Syndrome Center, Grand Forks, USA. laburd@mail.med.und.nodak.edu

AIM: To identify pre- and perinatal risk factors for autism. METHOD: Case control study. We matched names of patients from North Dakota who met DSM criteria for autism, a pervasive developmental disorder, and autistic disorder with their birth certificates. Five matched controls were selected for each case. RESULTS: Univariate analysis of the 78 cases and 390 controls identified seven risk factors. Logistic modeling to control for confounding produced a five variable model. The model parameters were chi 2 = 36.6 and p < p="0.0003)." p =" 0.013)." n =" 114)." n =" 495)," p =" 0.015)." p =" 0.007)." p =" 0.038).">50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning.


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Maternal and Paternal Age and Risk of Autism Spectrum Disorders
Lisa A. Croen, PhD; Daniel V. Najjar, MS; Bruce Fireman, MA; Judith K. Grether, PhD
Arch Pediatr Adolesc Med. 2007;161:334-340.

Objective To explore the association between maternal and paternal age and risk of autism spectrum disorders (ASDs) in offspring.






Results Risk of ASDs increased significantly with each 10-year increase in maternal age (adjusted RR, 1.31; 95% confidence interval [CI], 1.07-1.62) and paternal age (RR, 1.28; 95% CI, 1.09-1.51). Adjusted RRs for both maternal and paternal age were elevated for children with autistic disorder (maternal age: RR, 1.18; 95% CI, 0.87-1.60; paternal age: RR, 1.34; 95% CI, 1.06-1.69) and children with Asperger disorder or pervasive developmental disorder not otherwise specified (maternal age: RR, 1.45; 95% CI, 1.09-1.93; paternal age: RR, 1.24; 95% CI, 0.99-1.55). Associations with parental age were somewhat stronger for girls than for boys, although sex differences were not statistically significant.

Conclusion Advanced maternal and paternal ages are independently associated with ASD risk.
Labels: advancing paternal age, autism, Oprah, paternal and maternal age




Tuesday, April 03, 2007
DE NOVO GERMLINE MUTATIONS AND AUTISM

This is the abstract of the groundbreaking research showing germline copy number variations in some people who are autistic.


1: Science. 2007 Mar 15; [Epub ahead of print] Links
Strong Association of De Novo Copy Number Mutations with Autism.Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M.
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.

We tested the hypothesis that de novo copy number variation (CNV) is associated with autism spectrum disorders (ASDs). We performed comparative genomic hybridization (CGH) on the genomic DNA of patients and unaffected subjects to detect copy number variants not present in their respective parents. Candidate genomic regions were validated by higher-resolution CGH, paternity testing, cytogenetics, fluorescence in situ hybridization, and microsatellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (2%) of patients with an affected first-degree relative, and in 2 out of 196 (1.0%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes. These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
Labels: de novo copy number variations in some autistic children, germline mutations



Low Birthweight and Advancing Paternal Age

Research and Practice
Paternal Age as a Risk Factor for Low Birthweight
Nancy E. Reichman 1* Julien O. Teitler 2


AJPH First Look, published online ahead of print March 29, 2006


©
American Journal of Public Health, 10.2105/AJPH.2005.066324


1 Robert Wood Johnson Medical School
2 Columbia University


Objectives. We examined associations between paternal age and low birthweight in the US urban population.

Methods. Using a population-based sample of 4621 births, we used multiple logistic regression analysis to estimate associations between paternal age and low birthweight, controlling for maternal age, other demographic factors, and the child's gender.

Results. When the child’s gender and the mother's race/ethnicity, birthplace, parity, marital status, and health insurance type were controlled, teenaged fathers were 20% less likely and fathers older than 34 years were 90% more likely than fathers aged 20 to 34 years to have low-birthweight babies. The associations were significant when maternal age was also controlled. No racial/ethnic differences in associations between paternal age and low birthweight were found.

Conclusions. We identified paternal age as an independent risk factor for low birthweight in the US urban population, suggesting that more attention needs to be paid to paternal influences on birth outcomes and to the interactive effects of urban environments and individual risk factors on health.

Key Words: Birth Outcomes, Socioeconomic Factors
Labels: advancing paternal age, autism, low birth weight, schizophrenia




Paternal Age A Major Path To Autism

PRENATAL AND PERINATAL RISK FACTORS FOR AUTISM

A REVIEW and INTEGRATION OF FINDINGS

Alexander Kolevzon, MD; Raz Gross, MD, MPH; Abraham Reichenberg, PhD


Arch Pediatr Adolesc Med. 2007;161:326-333.

Objective To review the evidence for the presence of prenatal and perinatal factors that affect the risk of autism and autism spectrum disorders.

Data Sources Relevant articles were identified by searching MEDLINE, screening reference lists of original studies, and searching major journals likely to publish epidemiological studies on the topic.

.............................
Main Exposures Parental characteristics and obstetric complications.

Main Outcome Measures Rates of autism and autism spectrum disorders.

Results Seven epidemiological studies were identified that fulfilled inclusion criteria. The parental characteristics associated with an increased risk of autism and autism spectrum disorders included advanced maternal age, advanced paternal age, and maternal place of birth outside Europe or North America. The obstetric conditions that emerged as significant fell into 2 categories: (1) birth weight and duration of gestation and (2) intrapartum hypoxia.

Conclusions Evidence to suggest that parental age and obstetric conditions are associated with an increased risk of autism and autism spectrum disorders is accumulating. Although not proven as independent risk factors for autism, these variables should be examined in future studies that use large, population-based birth cohorts with precise assessments of exposures and potential confounders.


Author Affiliations: Department of Psychiatry, Mount Sinai School of Medicine (Drs Kolevzon and Reichenberg), Department of Epidemiology, Mailman School of Public Health, Columbia University (Dr Gross), and Department of Psychiatry, College of Physicians and Surgeons, Columbia University (Dr Gross), New York, NY; Unit of Mental Health Epidemiology, The Gertner Institute of Epidemiology and Health Policy Research, Tel Hashomer, Israel (Dr Gross); and Department of Psychological Medicine, Institute of Psychiatry, King's College, London, England (Dr Reichenberg).



This study does not differeniate between familial and non-familial autism.

Low Birthweight and advancing paternal age have been found to go together.
Labels: advancing paternal age, birth weight, maternal age


posted by concerned heart @ 10:10 AM 0 comments

Monday, April 02, 2007
KAISER PERMANENTE STUDY AUTISM RISES WITH ADVANCED MATERNAL AND PATERNAL AGE

Risk of Autism Rises With Age of Moms, Dads



Kaiser Permanente study of more than 132,000 children suggests link between
chronic, life-long condition and advanced maternal and paternal age

OAKLAND, Calif., April 2 /PRNewswire/ -- Men and women who wait to have
babies later in life may increase their children's risk for autism,
according to a Kaiser Permanente study featured in the April issue of
Archives of Pediatrics & Adolescent Medicine, one of the JAMA/Archives
journals.
The study investigated 132,844 children born at Kaiser Permanente
hospitals in its Northern California region over a five-year period
(1995-1999) and identified 593 children who had been diagnosed with an
autism spectrum disorder (ASD).
Study results show that a mother's and father's risk of delivering a
child with autism steadily increases as they get older. Women ages 40 and
older showed a 30 percent increase in risk for having a child with autism
(1 in 123), when compared to moms between the ages of 25 and 29 (1 in 156).
Men ages 40 and older had up to a 50 percent increased risk of having a
Labels: autism and advanced maternal and paternal age


posted by concerned heart @ 2:24 PM 0 comments

OLDER FATHERS RISK TRANSMITTING GERM-LINE MUTATIONS

1: Hum Reprod. 2007 Jan;22(1):180-7. Epub 2006 Oct 19

The effects of male age on sperm DNA damage in healthy non-smokers.Schmid TE, Eskenazi B, Baumgartner A, Marchetti F, Young S, Weldon R, Anderson D, Wyrobek AJ.
Lawrence Livermore National Laboratory, Livermore, CA, USA.


BACKGROUND: The trend for men to have children at older age raises concerns that advancing age may increase the production of genetically defective sperm, increasing the risks of transmitting germ-line mutations. METHODS: We investigated the associations between male age and sperm DNA damage and the influence of several lifestyle factors in a healthy non-clinical group of 80 non-smokers (mean age: 46.4 years, range: 22-80 years) with no known fertility problems using the sperm Comet analyses. RESULTS: The average percentage of DNA that migrated out of the sperm nucleus under alkaline electrophoresis increased with age (0.18% per year, P = 0.006), but there was no age association for damage measured under neutral conditions (P = 0.7). Men who consumed >3 cups coffee per day had approximately 20% higher percentage tail DNA under neutral but not alkaline conditions compared with men who consumed no caffeine (P = 0.005). CONCLUSIONS: Our findings indicate that (i) older men have increased sperm DNA damage associated with alkali-labile sites or single-strand DNA breaks and (ii) independent of age, men with substantial daily caffeine consumption have increased sperm DNA damage associated with double-strand DNA breaks. DNA damage in sperm can be converted to chromosomal aberrations and gene mutations after fertilization, increasing the risks of developmental defects and genetic diseases among offspring.
Labels: alkali-labile sites, caffeine, coffee, DNA, dna damaged, double-strand breaks in dna, germ-line mutations, older fathers, single-strand breaks in dna, sperm


posted by concerned heart @ 9:31 AM 0 comments

EFFECTS OF MALE AGE ON THE FREQUENCY OF GERMINAL AND HERITABLE CHROMOSOMAL ABNORMALITIES IN HUMANS AND IN RODENTS

: Fertil Steril. 2004 Apr;81(4):925-43. Links
Effects of male age on the frequencies of germinal and heritable chromosomal abnormalities in humans and rodents.Sloter E, Nath J, Eskenazi B, Wyrobek AJ.
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California 94550, USA.
OBJECTIVE: To review evidence regarding the effects of male age on germinal and heritable chromosomal abnormalities using available human and rodent studies and to evaluate possible underlying mechanisms. CONCLUSION(S): The weight of evidence suggests that the increasing trend toward fathering at older ages may have significant effects on the viability and genetic health of human pregnancies and offspring, primarily as a result of structural chromosomal aberrations in sperm.

PMID: 15066442 [PubMed - indexed for MEDLINE]
Labels: genetic health, older fathers, structural chromosomal aberrations in sperm




Sunday, April 01, 2007
Why No Results? More Results Were Due Sept 20?

Older Dads and Autism Survey
Update: Sept 13 2006
The research study by Reichenberg et al (2006) attracted a lot of attention from both the scientific community and the autism community, with many comments supporting and others criticising the results. Such a reaction is important because it helps us to explore new areas of research and to design better studies.
Our Older Dads and Autism Survey is not a rigorous scientific study. BUT we are trying to see whether there is merit in conducting a more in-depth study. This survey taught us many things - the most important of which is that so many families want to participate in research to find answers. Within one hour and 20 minutes of posting, we had 100 responses! By the end of the first day (only 7 hours), we had 300! The word has spread and you helped make that happen - Thank you. We had more than 1000 responses in only 5 days! We are sharing some of those findings with you now, and the analysis of our results will be posted early next week. Please continue to invite others to participate and we hope that you will come back to participate in other surveys.

If you have not already completed this survey, click here.
Labels: What happened to the results?





Minding Your Mind

New Key to Autism
September 25, 2006
By Michael Craig Miller, M.D.Harvard Medical School
Convincing Evidence
What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older.
What Is Autism?
Autism is a profoundly disabling disorder that starts in early childhood. The key features are:
Abnormal social development – little or no eye contact, prefers to be alone
Difficulty communicating – impaired language ability, uses gestures or pointing rather than words
Unusual behavior – spins objects, doesn't like being cuddled
Evidence of strong abilities sometimes in non-verbal areas, such as math or music
Older people with autism may have some ability to interact with people, but about two-thirds are mentally retarded and most cannot live on their own
Unfortunately, the incidence of this illness appears to be on the rise. Some experts think autism is diagnosed more often simply because more people are aware of it. But that's probably not the whole explanation.
Genetic factors almost certainly play a big role. So autism researchers are eager to discover anything that might increase a person's genetic vulnerability, such as delaying parenthood until age 40 or beyond.
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
The Archives study took advantage of the extraordinarily complete health records of over 300,000 Israeli men and women who underwent a complete health assessment when they were 17-year olds — draft age. This gave researchers a good way to determine the incidence of autism in the population. The researchers had access to intellectual, medical and psychiatric evaluations of almost all Israeli boys and three-quarters of girls. (Their identities were kept secret, however.) For most individuals, the father’s age at birth was known.
Although boys were more likely to develop autism than girls, the risk for girls also increased as fathers got older. When fathers were young, about 1 in 6 children with autism were girls. After fathers passed the 40 year-old mark, the proportion of girls with autism rose to about 1 in 3. This suggests that the genetic factors in play for offspring of older fathers are different from those for offspring of younger fathers.
Back to top
What Causes These Genetic Errors?
All children inherit genetic material in equal amounts from both parents. In the case of autism, scientists think that the genetic material in the sperm of these older fathers has somehow become altered in harmful ways. These flaws make the child more vulnerable to developing the disease.
According to one theory, mutations (changes) are more likely to develop as men get older. Germ cells give rise to sperm throughout a man's life. These cells make copies of themselves and after several decades, the germ cells are copies of copies of copies. A second theory suggests that the offending genes passed down by older men are not properly marked or "imprinted." Accurate marking — which establishes whether a gene is from the father or the mother — determines if it will be active or not. If there is an error, the gene may function abnormally.
Back to top
Should Older Men Stop Fathering Babies?
It's true that medical technology and general improvements in health have made life much more enjoyable for people in middle to late life. Maybe 50 is the new 30 when it comes to some aspects of aging. But a healthy and active lifestyle does not make 50-year-old sperm the new 30-year-old sperm.
The increased risk of passing on any genetic vulnerability to a child is significant when you are older. When it comes to autism, however, the numbers are sobering. A man younger than 30 has no more than a 1 in 1,000 chance of fathering a child with autism. But the risk bumps up to approximately 3 in 1,000 for a man in his 40s and 5 in 1,000 above age 50. If a father in his fifties has a son, the risk of autism may approach 1 in 100.


Table II. Long-term effects of paternal ageing on offspring from table on page 2373 of Long –term effects of delayed parenthood by J.J. Tarin, J. Brines, and A. Cano


Dominant disorders


Wilms tumour, thanatophoric dysplasia, retinitis pigmentosa, osteogenisis imperfecta type IIA, acrodysostosis, achondroplasia, Apert’s disease, fibrodysplasia ossificans progressiva, aniridia, bilateral retinoblastoma, multiple exostoses, Marfan’s, Lesch-Nyan’s, Pfeiffer’s, Wardenburg’s, Treacher-Collins, Soto’s, and Crouzon’s syndromes, basel cell nevus, cleidocranial dysostosis, polyposis coli, oculodentodigital syndrome, Costello syndrome , progeria, Recklinghausen’s neurofibromatosis, tuberous sclerosis and renal polycystic kidney disease.


X-linked recessive diseasesHaemophilia A and Duchenne’s muscular dystrophy



Non-cytogenetic congential defectsCongential cataracts, reduction defects of the upper limb, nasal aplasia, pulmonic and urethtal stenosis, perauricular cyst, cleft palate,1 neural tube defects


Athetoid /dystonic cerebral palsy and congenital hemiplegiaPsychotic disorders Decreased learning capacity and/or mental retardation

......This could be because ART couples are generally older .....

Reported July 27, 2007
Assisted Reproduction Creates More Risks of Complications


Researchers analyzed data on in-vitro fertilization (IVF) and intracytoplasmic sperm injection published between 1980 and 2005. They mainly focused on ART single births.

Besides a risk of multiple births, the authors report couples interested in ART should also be aware of other possible problems. For example, the rates of miscarriage are between 20-percent and 34-percent higher for ART couples than for those conceiving naturally. This could be because ART couples are generally older and more likely to have conditions like endocrine disorders.

The review also shows ART increases the risk of preeclampsia by 55 percent, raises the chances of stillbirth by 155 percent and very low birth weight by 170 percent to 200 percent. Other findings include a 30-percent higher risk of major malformations in babies born to ART couples and a higher risk of cerebral palsy.

Risk of Alzheimer's Rises with Age of Father At Birth But They Forget to Tell the Public About That

They've known that offspring of older fathers have a higher rate of Alzheimer's for at least 8 years and they have known about about cognitive disorders in offspring of older fathers since 1958 or of even before that.



Source: Mayo Clinic
Date: July 26, 2007
More on: Alzheimer's, Alzheimer's Research, Dementia, Healthy Aging, Diseases and Conditions, Elder Care

A New Century Of Alzheimer's Disease Research

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


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."
Labels: I am not talking about a specific mutation, the complexity of the myelination process make it more vulnerable to mutations

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.


http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=10732803&query_hl=8&itool=pubmed_DocSum

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]

New Theory about Autism Roots
It appears that some boys have as much as a 50 percent risk of developing the mysterious disorder
By Nikhil Swaminathan


: Mol Psychiatry. 2007 May;12(5):419-421.Paternal age and autism are associated in a family-based sample.Cantor RM, Yoon JL, Furr J, Lajonchere CM.
[1] 1Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA [2] 2Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA [3] 3AGRE Consortium, Los Angeles, CA, USA.

PMID: 17453057 [PubMed - as supplied by publisher]


The paternal age distribution of the AGRE fathers, whose first child is autistic differs significantly from that of the 'control' sample (P=0.005). A 2 goodness-of-fit test with 2 degrees of freedom was conducted using percents in the 'control' group age categories to calculate the expected values in the AGRE sample. The shift toward higher paternal ages in those with an affected first-born is seen most dramatically in the group of AGRE fathers who are 30–39 years inclusive, which is 54.7% of the distribution compared with the 41.9 % that is expected. We interpret this shifted age distribution to provide support for the recently reported finding by Reichenberg and co-workers that autism risk is associated with advancing paternal age.





A hedge-fund titan stirs up research into autism
Thursday, December 15, 2005By Antonio Regalado, The Wall Street Journal
When their daughter Audrey was just a few months old, Jim and Marilyn Simons noticed that she wasn't making eye contact. It wasn't until the girl was 6 years old that she was diagnosed with autism. Ms. Simons scoured records from her pregnancy. Had something gone wrong? What caused her condition?
In their quest for answers, the Simonses aren't just another family seeking comfort. Audrey's father, top mathematician James H. Simons, runs Renaissance Technologies Corp., one of the world's most successful hedge funds. With little notice, the family's charitable foundation has committed $38 million to find the causes of autism. The money manager says he and his wife will spend $100 million more in what is rapidly becoming the largest private investment in the field.
The Simonses' philanthropy is stirring up the small community of autism researchers and advocates. Using his scientific background, Mr. Simons, 67, personally reviews grant applications. When the Massachusetts Institute of Technology asked him for money for brain research, he demanded that the project focus on autism and include scientists he liked. He has provided his family's DNA for study, pitched in to help solve research problems and is pushing scientists to probe a genetically based explanation for the disease.

It is also apparent that DNA damage in spermatozoa is associated with adverse impacts on the health and wellbeing of children.

Soc Reprod Fertil Suppl. 2007;65:81-92.Value of DNA integrity assays for fertility evaluation.Aitken RJ, De Luliis GN.
ARC Centre of Excellence in Biotechnology and Development and Discipline of Biological Sciences, University of Newcastle, NSW 2308, Australia. jaitken@mail.newcastle.edu.au
DNA damage in the male germ line is associated with failed fertilisation, impaired preimplantation development and poor pregnancy outcomes, whether the insemination is natural or artificial. It is also apparent that DNA damage in spermatozoa is associated with adverse impacts on the health and wellbeing of children. This may be particularly important in the case of conceptions involving intracytoplasmic sperm injection. With this technique DNA damaged spermatozoa that would, under physiological circumstances, be excluded from the conception process are able to initiate pregnancies. Although the oocyte actively repairs the DNA damage brought into the zygote by the fertilising spermatozoon, errors in this repair process would generate mutations that might in turn be linked to the increased incidence of dominant genetic disease and childhood cancer seen in the offspring of fathers possessing DNA damaged spermatozoa. Significantly, the incidence of such mutations is so low that it might be several generations before the full consequences of using DNA damaged spermatozoa in assisted conception cycles are realised. The factors modulating DNA damage in the male germ line are complex and largely unresolved. They involve advanced paternal age, exposure to xenobiotics and male genital tract infection. The types of damage being measured by the assays used in most laboratories (SCSA, Comet and TUNEL) are also uncertain. Molecular characterization of this DNA damage might provide insights into the underlying aetiologies, facilitate the development of optimised diagnostic methods for its detection and suggest logical avenues to pursue for its correction and ultimate prevention.

PMID: 17644956 [PubMed - in process]

Related LinksDNA damage to spermatozoa has impacts on fertilization and pregnancy. [Cell Tissue Res. 2005]Pregnancy outcomes after assisted reproductive technology. [J Obstet Gynaecol Can. 2006]The effect of sperm DNA damage on assisted reproduction outcomes. A review. [Minerva Ginecol. 2004]Late, but not early, paternal effect on human embryo development is related to sperm DNA fragmentation. [Hum Reprod. 2004]Founders' Lecture. Human spermatozoa: fruits of creation, seeds of doubt. [Reprod Fertil Dev. 2004]See all Related Articles...

The Fertility and Andrology Industry is Corrupt and Does Everything To Hide, Deny The Known Paternal Age Issue Men Have A Biological Clock!

Rebecca Sokol, M.D. et al. will deny that schizophrenia, autism, mental retardation, prostate cancers, diabetes, Alzheimer's, hemophilia, Duchennes, progeria and on and on have been proven to be caused de novo by older fathers till the cows come home.


And many men maintain their fertility, said Dr. Rebecca Sokol, president of the Society of Male Reproduction and Urology. "If you look at males over 50 or 40, yes, there is a decline in the number of sperm being produced, and there may be a decline in the amount of testosterone," Sokol said. But by and large, she added, "the sperm can still do their job."


Sure do their job!

Monday, July 23, 2007
Thousands of human eggs may be missing
Bankrupt egg-donor registry says fertility doctors may have transferred eggs without permission.
By TERI SFORZA
The Orange County Register

More than 100 fertility doctors in dozens of states may have brokered unauthorized transfers of human eggs, according to the bankruptcy court filing of a local company and its former records supervisor.

Options National Fertility Registry was forced out of business in

Damaged Sperm or the Mother's Damaged Genes from Her Father Are Factors in some Autism, Diabetes, Schizophrenia, etc. What Else Could Be Involved?

Viera Scheibner, PhD - "Ever since mass vaccination of infants began, reports of serious brain, cardiovascular, metabolic and other injuries started filling pages of medical journals." In fact, pertussis vaccine has been used to induce encephalomyelitis, which is characterized by brain swelling and hemorrhaging"


Bart Classen, a Maryland physician, published data showing that diabetes rates rose significantly in New Zealand following a massive hepatitis B vaccine campaign in young children, and that diabetes rates also went up sharply in Finland after three new childhood vaccines were introduced.

The FDA admits that the 12,000 reports it receives annually on pharmacologic

Daughters of Older Fathers Die Younger

Are they more prone to autism, cancer, schizophrenia, diabetes, obesity, Alzheimer's and other "auto-immune" and other genetic disorders?

Young Fathers

7/20/2007
Young fathers
She came to me...
Months ago.
I told her to wait.
A story that she would not tell.
But darkness in her heart.
And pain of a lifetime
The story of children,
And fathers-
Older than nature meant them to be.
And autism.
Or other problems...
that science has not found the cause for.

I looked it up.
The links she supplied.
The research backs her up.
But even though maternal age and child's birth is known...
Nobody thinks of the age of the father.
It matters.
It matters a lot.

Think about it.
Be careful.
If you are still young.

Thoughts and Dreams of Devilbluedress

Mercury, Autism and the Global Vaccine Agenda

An important video on Mercury in Vaccines and autism

What are vaccines for?

While the FDA questioned thimerosal's safety in the 80s, noting that it was "not safe for 'over-the-counter' topical use because of its potential for cell damage", and while it was removed from animal vaccines for the same reason, the government regulatory committees did nothing to question its use in childhood vaccines.

It's too dangerous for cats and dogs but the government is happy for our babies to be pumped full of the stuff on a regular basis.

Dr Haley has also pointed out that it is also well known by any good biochemist that thimerosal and aluminum react dangerously when combined together. Given that Aluminum is a compound added to many vaccines as a catalyst you would think the government would have heeded this warning, yet it has still done nothing.

Despite the continued reports doubting the link between Thimerosal and autism, more studies have continued to verify the link. As reported in the Capitol Times recently:

A study done at the University of Washington in 2006 showed that baby primates exposed to injected thimerosal (50 percent mercury), at a rate equal to the 1990s childhood vaccine schedule, retained twice as much inorganic mercury in their brains as primates exposed to equal amounts of ingested methylmercury. We know from autometallographic determination that inorganic mercury present in the brain, following the dealkylation of organic mercury, is the toxic agent responsible for changes in the microglial population and leads to neuroinflammation.
In other words thimerosal, inorganic mercury, leads to neuroinflammatory disease which is proven to be the underlying medical condition of autism.


Safe Minds also point out that according to the EPA, one in every six women of childbearing age already has blood levels of mercury high enough to cause neurological damage to their unborn children due to environmental exposures alone.

"Injecting even more mercury into the bodies of pregnant women, infants and children when it is not a necessary component of vaccines is just bad medicine," said Lyn Redwood, president of Safe Minds and parent of a mercury-injured child. "It defies logic that a flu vaccine must be disposed of as a hazardous waste if it is not used, but somehow injecting the same mercury-containing vaccine into a baby is safe."
Yes it defies logic to someone who believes in the unabated progression of the entirety of the human race, however, to an elite devoid of all morality and interested only in the endgame pursuit of their own biological, spiritual and financial monopoly over the whole planet, it makes perfect sense

How to prevent non-familial autism, diabetes, schizophrenia, Alzheimer's, cancers, MS, etc.

In order to prevent autism one needs to pass the word to all teenagers and couples that there is a male biological clock. The mid 20s to 31 is the best age range to father babies. The media will not inform the public, the government will not inform the public (look at what the Surgeon General is allowed to say), the pharmaceutical research scientists and academic researchers won't inform the public, the psychiatrists won't inform the public, the genome institutes won't inform the public but the research is there and the evidence is overwhelming. It is not profitable to have healthy citizens.


The average age of fatherhood is increasing in the US and in Western Europe. Research shows that offspring of 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 genetic disease.

Ginger is Awesome!

Julie Gerberding is Doing an Awsome Job

.. or not.

So we are to trust the CDC to tell us the truth about their vaccine schedule injuring our children when they can't be trusted not to steal stuff from their own offices?

Seriously?


Feds probe missing CDC gear Theft suspected in some cases
By CRAIG SCHNEIDER
The Atlanta Journal-Constitution
Published on: 07/12/07

Federal investigators will look into the disappearance of $22 million worth of scientific equipment, computers and other items from the Centers for Disease Control and Prevention.

An audit of procedures and an investigation into allegations of theft at the Atlanta-based agency will be conducted by the Inspector General's office of the U.S. Department of Health and Human Services.

The inquiry was requested by a congressional oversight committee as a consequence of its "troubling" findings last month.

"A thorough audit will help stop the bleeding of taxpayer-owned property at CDC," said U.S. Rep. Joe Barton (R-Texas) in a prepared statement Wednesday. "In cases of theft, it will also tell us what happened to the thieves."

CDC officials said they have accounted for about $9 million of the $22 million in missing goods in recent weeks as a result of efforts to track down lost items and improve accountability.

The House Committee on Energy and Commerce specifically raised concerns about a suspected "insider" burglary of $500,000 in new computers, and millions of dollars worth of other items missing or unaccounted for since the last audit of the agency in 1995.

"The scope of property mismanagement and outright theft at CDC is both astonishing and baffling," said Barton, the ranking Republican on the committee.

Inspector General Daniel Levinson wrote Barton on June 25, "As requested, we will audit CDC's controls over property, such as laptops and scientific equipment, and determine whether CDC has adequately implemented the recommendations in the prior report. We will separately investigate the allegations [you] identified."

The inspector general's office declined to comment further on the inquiries.

Between fiscal 2004 and 2006, there were 61 investigations into the theft or disappearance of agency property. No arrests or disciplinary action resulted from those investigations, said CDC spokesman Tom Skinner on Wednesday. He said several investigations are ongoing........