Scientists reveal dangers of older fathers--

Scientists reveal dangers of older fathers
By Laura Donnelly, Health Correspondent
Last Updated: 10:18PM BST 31/05/2008
Children are almost twice as likely to die before adulthood if they have a father over 45, research has shown.
A mass study found that deaths of children fathered by over-45s occurred at almost twice the rate of those fathered by men aged between 25 and 30.

Scientists believe that children of older fathers are more likely to suffer particular congenital defects as well as autism, schizophrenia and epilepsy. The study was the first of its kind of such magnitude in the West, and researchers believe the findings are linked to the declining quality of sperm as men age.

A total of 100,000 children born between 1980 and 1996 were examined, of whom 830 have so far died before they reached 18, the majority when they were less than a year old.

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The deaths of many of the children of the older fathers were related to congenital defects such as problems of the heart and spine, which increase the risk of infant mortality. But there were also higher rates of accidental death, which the researchers believe might be explained by the increased likelihood of suffering from autism, epilepsy or schizophrenia.

Most research into older parents has, until now, focused on the risks passed on by older mothers. But the new study, published in the European Journal of Epidemiology, was adjusted to take account of maternal age and socio-economic differences.

The research also found higher death rates among children of the youngest fathers, especially those below the age of 19. However, the study said these differences were explained by the risks of teenage motherhood and poorer diet and lifestyle.

Previous research using the same data found that older men were four times as likely to father a child with Down's syndrome, while other studies have found that the genetic quality of sperm deteriorates as men age.

More than 75,000 babies in Britain are born to fathers aged 40 and over each year, or more than one in 10 of all births. This includes more than 6,000 born to fathers aged 50 or over. The average age of fathering a child in this country is 32.

Dr Allan Pacey, senior lecturer in andrology – the medical specialty dealing with male reproduction – at the University of Sheffield, said: "A lot of people know that there are risks for the child that come from having an older mother, but children of older fathers also carry an increased risk. These sorts of results provide another good reason to have children early, when possible."

Dr Pacey, who is secretary of the British Fertility Society, said scientists were unsure exactly what impact the ageing process had on the quality of sperm, making it impossible to detect defects before conception.

Dr Jin Liang Zhu, from the Danish Epidemiology Science Centre, which carried out the research, said: "The risks of older fatherhood can be very profound, and it is not something that people are always aware of."

The mother's age still has the bigger impact on child health, however. About one in 900 babies born to women under 30 have Down's syndrome – a figure which reaches one in 100 by the age of 40. The number of over-40s giving birth in Britain each year has doubled in the past decade to 16,000. The risk of miscarriage rises sharply with age.

Mothers with epilepsy, mothers with epilepsy taking valproate and autism a clue? Low birth weight and paternal age

May 2006, Vol 96, No. 5 | American Journal of Public Health 862-866
© 2006 American Public Health Association
DOI: 10.2105/AJPH.2005.066324 --------------------------------------------------------------------------------

RESEARCH AND PRACTICE
Paternal Age as a Risk Factor for Low Birthweight
Nancy E. Reichman, PhD and Julien O. Teitler, PhD

Nancy E. Reichman is with the Department of Pediatrics, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick. Julien O. Teitler is with the School of Social Work, Columbia University, New York, NY.

Correspondence: Requests for reprints should be sent to Nancy E. Reichman, PhD, Department of Pediatrics, Robert Wood Johnson Medical School, 97 Paterson St, Room 435, New Brunswick, NJ 08903 (e-mail: nancy.reichman@umdnj.edu).



Objectives. We examined associations between paternal age and low birth-weight 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.








Local stem cell firm gets fed grant
Chief scientist cited in Forbes magazine

The Capital Times — 5/31/2008 12:14 pm

Madison-based stem cell company Stemina Biomarkers Discovery Inc. has learned it will receive a $150,000 Phase I grant from the National Cancer Institute through the federal government's Small Business Innovation Research grant program, the Wisconsin Technology Council said in a news release Friday.

Stemina, founded in late 2006 by chief executive officer Beth Donley and UW-Madison stem cell scientist Gabriella Cezar, is aiming to use human embryonic stem cells to help determine whether new drug candidates will cause birth defects in humans. So-called "biomarker" research can also test drug toxicity in other ways.

The SBIR grant awarded this week will be used for research to develop a test that could combine stem cell research and metabolomics, which is the systematic study of biomarkers that specific cellular processes leave behind. The goal is to develop a test to determine whether cancer-fighting drugs actually kill the cancerous stem cells, which otherwise can regenerate.

Cezar and fellow UW-Madison scientist and stem cell pioneer James Thomson are featured as part of a group of 12 "stem cell revolutionaries" in the latest issue of Forbes magazine. The story notes that Cezar "is using stem cells to get to the roots of autism. Autism appears in a tenth of the children born to mothers who take the epilepsy drug valproate."Stemina also has raised $1.5 million from angel investors and received a $1 million start-up grant from the state.



The Capital Times — 5/31/2008 12:14 pm



Low Birth weight also link to older father and schizophrenia in girls.

Low Birth Weight May Increase Autism Risk in Girls (Update1)
By Elizabeth Lopatto
June 2 (Bloomberg) -- Autism strikes low birth weight baby girls at a higher rate than similar-sized boys when the infants are compared with larger children, according to a study that suggests risk factors for the disorder vary by sex.
Baby girls weighing less than 2.5 kilograms, or about 5.5 pounds, had 3.5 times increased risk of autism and baby girls born more than seven weeks early had a 5.4 times increased risk. Boys born small or early didn't have a significant difference in their risk of being autistic, the according to a report in the journal Pediatrics.
Doctors aren't sure what causes autism, though genetics and the environment probably both play roles, according to the National Institutes of Health. This research indicates that boys and girls have different risk factors for the disorder, said study author Diana Schendel.
``This suggests there may be sex differences in genetic factors leading to autism,'' said Schendel, a researcher for the Centers for Disease Control and Prevention, in a May 30 telephone interview. ``Girls may need an additional insult'' before birth that could include reduced growth or premature birth.
Autism and related disorders, some of them less severe, affect about 1 in 150 U.S. children. There is no cure for the malady, in which children may refuse to engage with other people, echo words and phrases, or repeat actions many times. Risk factors include older fathers and environmental toxins.
About 1 in 13 babies in the U.S. has low birth weight, according to the March of Dimes. Babies may weigh less than 5 pounds 8 ounces because they're premature, because the mother has heart problems, because of infections or because of cigarette, drug, or alcohol use.
`Biggest Risk Factors'
``We know that low birth weight and pre-term birth are among the biggest risk factors for developmental disabilities,'' Schendel said. ``The higher prevalence of autism supports monitoring these children carefully for behavioral problems.''
Babies born with low birth weights are likelier to have bleeding in the brain, lungs that are more likely to collapse, heart problems, and vision loss.
The study was of children born from 1981 to 1993 in Atlanta, who lived to 3 years of age, and were still living in Atlanta at ages 3 to 10. Over 550 children with autism were paired to normal children born in the same year.
To contact the reporter on this story: Elizabeth Lopatto in New York at elopatto@bloomberg.net.

7thSpace is the source of this article IS PATERNAL AGE RESPONSIBLE FOR THESE CNVs?

Researchers pinpoint gene mutations responsible for 10 percent of schizophrenia


NEW YORK – Scans of the genome of patients with schizophrenia have revealed rare spontaneous copy number mutations that account for at least 10 percent of the non-familial cases of the disease. Researchers describe specific genetic mutations present in individuals who have schizophrenia, but not present in their biological parents who do not have the disease. These individuals were eight times more likely to have these mutations than unaffected individuals. This new data, reported in the May 30 on-line issue of Nature Genetics, will help researchers account for the persistence of schizophrenia in the population despite low birth rates among people with the disease.

Researchers at Columbia University Medical Center scanned the genome of 1,077 people which included 152 individuals with schizophrenia, 159 individuals without schizophrenia, and both of their biological parents for copy number mutations. They found mutations, either a gain or loss of genes, in 15 individuals diagnosed with schizophrenia that were not present in the chromosomes of either biological unaffected parent. Only two of such mutations were found in those without schizophrenia. Study subjects were from the European-origin Afrikaner population in South Africa, a genetically homogenous population that is ideal for genetic evaluation.

“We now know the cause of around 10 percent of the cases of sporadic schizophrenia,” said Maria Karayiorgou, M.D., professor of psychiatry, Columbia University Medical Center, the senior author on the study. “Schizophrenia is not as much of a ‘big black box’ as it used to be. The identification of these genes lets us know what brain development pathways are involved in disease onset, so that in the future we can look at better ways of treating this devastating disease.”

Schizophrenia affects approximately 1 percent of the population worldwide. About 40 percent of the disease is thought to be inherited, with the other 60 percent sporadically showing up in people whose family history does not include the disease.

One of the new or de novo mutations researchers found in more than one affected individual in this study was a deletion of a region of chromosome 22. Dr. Karayiorgou had previously provided evidence that loss of genes in this region, 22q11.2, was responsible for introducing “new” or sporadic cases of schizophrenia in the population. This confirms 22q11.2 as the only known recurrent such mutation linked to schizophrenia.

“We have already demonstrated 22q11.2 to be involved in sporadic schizophrenia and we have made considerable progress in understanding the underlying biological mechanisms,” said Dr. Gogos. “Now, we have a new set of mutations that we can investigate. The more information we have about the biological basis for this disease, the more information we can provide to those who suffer from it and their families.”

“Such abnormal deletions or duplications of genetic material are increasingly being implicated in schizophrenia and autism,” explains National Institute of Mental Health Director Thomas R. Insel, M.D. “Now we have a dramatic demonstration that genetic vulnerabilities for these illnesses may stem from both hereditary and non-hereditary processes. This line of research holds promise for improved treatments – and perhaps someday even prevention – of developmental brain disorders.”

Karayiorgou and co-senior author Joseph A. Gogos, M.D., Ph.D., associate professor of physiology and neuroscience at Columbia University Medical Center, agree that the goal is for psychiatrists to be able to inform patients that they have a mutation that is causing their disease and ultimately to be able to tailor treatments to individual patients based on their specific mutation. This tailored treatment is a ways off, according to Dr. Karayiorgou, but she says patients and their families are relieved to know that there is a biological cause of their illness.

The researchers plan to extend their screen for additional de novo mutations by using increased resolution scans to study additional families. They also plan to scrutinize further genes affected by the identified mutations through human genetics and animal model approaches.


###

The first author of this study, Bin Xu, is also from CUMC. Co-authors include J. Louw Roos from the Department of Psychiatry and Elizabeth J. van Rensburg from the Department of Genetics at the University of Pretoria in Pretoria in South Africa, and Shawn Levy from the Microarray Shared Resource at Vanderbilt University in Nashville, Tenn.

This study was supported by the National Institutes of Health’s (NIH) National Institute of Mental Health (NIMH) and the Lieber Center for Schizophrenia Research at Columbia University Medical Center.


Columbia University Medical Center provides international leadership in basic, pre-clinical and clinical research, in medical and health sciences education, and in patient care. The medical center trains future health care leaders at the College of Physicians & Surgeons, the Mailman School of Public Health, the College of Dental Medicine, the School of Nursing, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. Established in 1767, Columbia’s College of Physicians & Surgeons was the first in the country to grant the M.D. degree. CUMC is home to the largest medical research enterprise in New York state and one of the largest in the United States. Visit www.cumc.columbia.edu.

Columbia Psychiatry is ranked among the best departments and psychiatric research facilities in the nation and has contributed greatly to the understanding of and current treatment for psychiatric disorders including depression, suicide, schizophrenia, bipolar and anxiety disorders, and childhood psychiatric disorders. Located at the New York State Psychiatric Institute on the NewYork-Presbyterian Hospital/Columbia University Medical Center campus in the Washington Heights community of Upper Manhattan, the department enjoys a collaborative relationship with physicians in various disciplines at Columbia University’s College of Physician and Surgeons. Visit http://columbiapsychiatry.org/.


Susan Craig
sc2756@columbia.edu
212-305-9746
Columbia University Medical Center


Published on: 2008-05-31


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"Worst Vaccine Bill Ever" Seeks Compulsory Shots For All Children

"Worst Vaccine Bill Ever" Seeks Compulsory Shots For All Children
Activist group calls for defense of right to exemption in New York State


Steve Watson
Infowars.net
Friday, May 30, 2008







A pending New York State Assembly Bill dubbed, the "worst vaccine bill ever" by one activist group, would see all vaccines recommended by the Centers for Disease Control and Prevention (CDC) made mandatory for all children, including infants and toddlers.
Assembly Bill 10942, introduced at the request of Richard Daines, the Commissioner of the New York State Department of Health, calls for changes to the law in order to make recommended inoculation compulsory in order for children to attend school.

The bill would also permit the administration of vaccines for sexually transmitted infections to minors without parental consent.

Separate sections of the bill would come into effect next year with others becoming law in 2010.

A-CHAMP, a national, non-partisan political action organization formed by parents in support of children with neurodevelopmental and communication disorders, has called for rejection of the bill and is demanding the passage of A5468/S3031, a bill that would give individuals a right to a philosophical exemption from vaccine mandates.

The group's press release highlights the key points in the bill:

Our elected New York representatives would no longer determine the mandatory schedule of vaccines to attend school; decisions made by the federal Advisory Committee on Immunization Practices would automatically become mandatory.


All children, infants and toddlers included, in New York would be required to get all vaccines recommended by the ACIP according to the ACIP schedule


All children in New York up to age 18 would be required to get annual flu shots.


All girls in New York would be required to get a human papilloma virus shot.


All junior high school children and college students would be required to get meningococcal shots.


Doctors would be required to issue certificates for every shot given and parents would be required to maintain the records and provide them to school and other authorities.


The rules committee claims that the new laws would have no fiscal impact on the state despite the necessity of the state to spend tens of millions on purchasing new vaccines, a vast increase in mandatory record keeping and enforcement for schools, and a huge increase that could be expected in the number of cases of neurological damage, Guillian Barré syndrome and other vaccine-caused injuries.




Call Today to Stop Worst Vaccine Bill Ever in New York
ALL FEDERAL SHOTS WILL BECOME MANDATORY


Act now to stop the worst vaccine law ever proposed in New York since the invention of the mandatory schedule. Assembly Bill 10942 would make all vaccines recommended by the CDC mandatory for all children to attend school and, and for the first time vaccines would become mandatory for infants and toddlers.


The bill was introduced in Rules Committee at the request of Richard Daines, the Commissioner of the New York State Department of Health. The Rules Committee in the personal committee of the Assembly Speaker Sheldon Silver (D-Manhattan).


A-CHAMP is calling for rejection of this bill and is demanding the passage of A5468/S3031, a bill that would give individuals a right to a philosophical exemption from vaccine mandates. This is no time to transfer vaccine decisions away from individuals and elected officials answerable to the voters and give it to obscure bureaucrats with financial ties to the vaccine industry.


Here are a few features of the proposed bill:


· Our elected New York representatives would no longer determine the mandatory schedule of vaccines to attend school; decisions made by the federal Advisory Committee on Immunization Practices would automatically become mandatory.


· All children, infants and toddlers included, in New York would be required to get all vaccines recommended by the ACIP according to the ACIP schedule


· All children in New York up to age 18 would be required to get annual flu shots.


· All girls in New York would be required to get a human papilloma virus shot.


· All junior high school children and college students would be required to get meningococcal shots.


· Doctors would be required to issue certificates for every shot given and parents would be required to maintain the records and provide them to school and other authorities.


· The rules committee claims that the new laws would have no fiscal impact on the state despite the necessity of the state to spend tens of millions on purchasing new vaccines, a vast increase in mandatory record keeping and enforcement for schools, and a huge increase that could be expected in the number of cases of neurological damage, Guillian Barré syndrome and other vaccine-caused injuries.


We only have a few weeks to defeat this bill. Let your Assemblymember and State Senator know immediately that a vote for this bill guarantees that you will do everything you can to get them un-elected. In addition to emailing and calling your local representatives, please call Speaker Sheldon Silver and let his staff know, politely, that this is a disastrous idea. While you are at it please call Governor David Paterson and let his staff know, politely, that this is a horrible law.


Governor David Paterson (518) 474-8390

Speaker Sheldon Silver (518) 455-3791

Insane NY Bill Makes All Federal Vaccines Mandatory

WOW!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Insane NY Bill Makes All
Federal Vaccines Mandatory
5-29-8

Act now to stop the worst vaccine law ever proposed in New York since the invention of the mandatory schedule. Assembly Bill 10942 would make all vaccines recommended by the CDC mandatory for all children to attend school and, and for the first time vaccines would become mandatory for infants and toddlers.


The bill was introduced in Rules Committee at the request of Richard Daines, the Commissioner of the New York State Department of Health. The Rules Committee in the personal committee of the Assembly Speaker Sheldon Silver (D-Manhattan).


A-CHAMP is calling for rejection of this bill and is demanding the passage of A5468/S3031, a bill that would give individuals a right to a philosophical exemption from vaccine mandates. This is no time to transfer vaccine decisions away from individuals and elected officials answerable to the voters and give it to obscure bureaucrats with financial ties to the vaccine industry.


Here are a few features of the proposed bill:


* Our elected New York representatives would no longer determine the mandatory schedule of vaccines to attend school; decisions made by the federal Advisory Committee on Immunization Practices would automatically become mandatory.


* All children, infants and toddlers included, in New York would be required to get all vaccines recommended by the ACIP according to the ACIP schedule


* All children in New York up to age 18 would be required to get annual flu shots.


* All girls in New York would be required to get a human papilloma virus shot.


* All junior high school children and college students would be required to get meningococcal shots.


* Doctors would be required to issue certificates for every shot given and parents would be required to maintain the records and provide them to school and other authorities.


* The rules committee claims that the new laws would have no fiscal impact on the state despite the necessity of the state to spend tens of millions on purchasing new vaccines, a vast increase in mandatory record keeping and enforcement for schools, and a huge increase that could be expected in the number of cases of neurological damage, Guillian Barré syndrome and other vaccine-caused injuries.


We only have a few weeks to defeat this bill. Let your Assemblymember and State Senator know immediately that a vote for this bill guarantees that you will do everything you can to get them un- elected. In addition to emailing and calling your local representatives, please call Speaker Sheldon Silver and let his staff know, politely, that this is a disastrous idea. While you are at it please call Governor David Paterson and let his staff know, politely, that this is a horrible law.


Governor David Paterson (518) 474-8390

Speaker Sheldon Silver (518) 455-3791

Rett syndrome gene found to be full of surprises

Rett syndrome gene found to be full of surprises

Published: Thursday, 29-May-2008



Medical Research News


A study funded by the National Institutes of Health (NIH) has transformed scientists' understanding of Rett syndrome, a genetic disorder that causes autistic behavior and other disabling symptoms. Until now, scientists thought that the gene behind Rett syndrome was an "off" switch, or repressor, for other genes. But the new study, published today in Science, shows that it is an "on" switch for a startlingly large number of genes.
Rett syndrome is caused by a deficiency of the MECP2 gene. It occurs almost exclusively in girls, robbing them of language, cognitive and fine motor skills around the time they are learning to walk. Having extra copies of MECP2 can also cause Rett-like symptoms.

By manipulating the number of copies of the MECP2 gene in mice, the authors of the new study found that it controls thousands of other genes, suppressing some, but activating most. The research was funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), both part of NIH.

"This study simultaneously upends prevailing ideas about the disease process in MECP2-related disorders, and hints at new therapeutic strategies," says NIH Director Elias Zerhouni, M.D.

Rett syndrome occurs predominantly in girls because the MECP2 gene is located on the X chromosome. In boys, who have only one X compared to girls' two, a deficiency of MECP2 tends to cause death during infancy. Girls with Rett syndrome tend to develop normally until about one year of age, and then regress in their language, cognitive and motor skills. They lose the words they have learned, as well as their skilled hand movements, which become replaced by repetitive wringing and clapping. Other common features include seizures, stunted growth and small brain size, mood disturbances, and sleep problems.

Duplications of MECP2 have been linked to another syndrome, which can cause Rett-like symptoms, and sometimes severe mental retardation, in boys.

MECP2's dual roles in gene repression and activation were "a total surprise," says the lead author of the new study, Huda Zoghbi, M.D., a professor at Baylor College of Medicine in Houston and an investigator of the Howard Hughes Medical Institute. Dr. Zoghbi led the team that first linked MECP2 deficiencies to Rett syndrome in 1999, also an NIH-funded effort. Many lines of evidence pointed to the MeCP2 protein as a gene repressor, and that is how experts in the field, including Dr. Zoghbi, have defined its function for the past 10 years.

Dr. Zoghbi did not intend to question that definition. She was interested in comparing Rett syndrome and MECP2 duplication syndrome, and in adding to the list of the few genes known to be regulated by MECP2.

Toward that end, she and her team analyzed gene activity patterns in the brains of mice with a MECP2 deficiency and in mice with a MECP2 duplication (MECP2+). Previous studies had revealed only subtle differences between the brains of normal and MECP2-mutant mice, but those studies measured gene activity throughout the brain. Dr. Zoghbi's group focused on a brain region called the hypothalamus, which is known to produce hormones that influence growth, mood, and the sleep-wake cycle - all of which typically become derailed in Rett syndrome.

Their analysis revealed nearly 2600 genes that are misregulated in both mouse models, with opposite patterns. The activity of about 2200 genes dropped in MECP2-deficient mice and spiked in MECP2+ mice, indicating that MECP2 is an activator for those genes. About 400 genes showed the reverse pattern, indicating that MECP2 is a repressor for those genes.

In other experiments, the researchers confirmed that the MeCP2 protein binds directly to several of the target genes. They also found evidence that MeCP2 collaborates with another protein known to serve as a gene activator. Among the genes activated by MeCP2, the researchers found many that encode neuropeptides, proteins that are secreted by nerve cells.

All of these results raise a number of challenges and opportunities for future research, Dr. Zoghbi says. Researchers could design effective therapies for Rett syndrome and MECP2 duplication syndrome by aiming at MeCP2's target genes, but first they would have to know which target genes are most relevant to neurological function. Also, given that the two disorders have opposite gene activity profiles, they might not respond to the same therapies.

The ideal therapy would aim closer to MECP2 itself, Dr. Zoghbi says.

"We know that the MeCP2 protein is important for orchestrating gene expression in neurons," Dr Zoghbi says. "To treat the disease, we may need to find a way to re-orchestrate gene expression. The challenge is to identify the immediate lieutenants of MeCP2, and co-opt them to take over when MeCP2 is not working."

NINDS (http://www.ninds.nih.gov) is the nation?s primary supporter of biomedical research on the brain and nervous system. NICHD (http://www.nichd.nih.gov/) sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information on Rett syndrome, visit http://www.ninds.nih.gov/disorders/rett/rett.htm or http://www.nichd.nih.gov/health/topics/Rett_Syndrome.cfm

The National Institutes of Health (NIH) - The Nation's Medical Research Agency - includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases.

http://www.nih.gov.

"If I were to do it over again," Poling said, "I'd just be extremely cautious, space the vaccines out, ...................

Posted on Thu, May. 29, 2008


Autism theory gains support
Conceding a rare vaccine tie.
By Marie McCullough

Inquirer Staff Writer

For a decade, the government, public- health experts and medical groups have said there is no credible scientific evidence - none - that vaccines cause autism.

Then came Hannah Poling, a 9-year-old from Athens, Ga. A federal program created to compensate vaccine-injury victims conceded that her autism is linked, albeit indirectly, to immunizations she received as a toddler.

Hannah's case, made public by her parents in March, is unusual and circumstantial, yet it is building mainstream support for a notion long considered dangerously misguided: There may be subgroups of children who should not be vaccinated - or at least, they should get fewer shots over a longer period.

Bernadine Healy, former director of the National Institutes of Health, risked "incurring the wrath of some of my dearest colleagues" to express that opinion in U.S. News & World Report.

"Yes, vaccines are extraordinarily safe and bring huge public health benefit," she wrote last month. "But vaccine experts tend to look at the population as a whole. . . . And population studies are not granular enough to detect individual metabolic, genetic, or immunological variation that might make some children under certain circumstances susceptible to neurological complications after vaccination."

Geraldine Dawson, chief scientific officer of the advocacy group Autism Speaks, declared that the Poling case "shines a spotlight" on the issue of unusual sensitivities.

"We need to conduct research to better understand and identify subgroups of children who may respond poorly to vaccines," said the former University of Washington developmental-psychology professor.

Hannah's case is complex because of an abnormality involving her mitochondria.

Called the "powerhouses of the cell," mitochondria are microscopic structures that convert oxygen and nutrients into energy. When they malfunction, the cell may be so starved for energy that it is damaged, or even dies.

Defects in mitochondria - first linked to disease only 20 years ago - are now known to cause a long list of problems, including seizures, migraines, strokes and digestive abnormalities. Depending on the extent of mitochondrial dysfunction, the stress of "even a simple flu or cold virus" can worsen symptoms, says the United Mitochondrial Disease Foundation, an advocacy group.

Mitochondrial defects occur in about one in 10,000 people, but their role in autism is unclear. The few studies that exist suggest at least 7 percent of autistic children have these abnormalities.

Hannah is one of them.

Her father, neurologist Jon Poling, and mother, Terry, a registered nurse and lawyer, believe a battery of nine vaccinations Hannah received when she was 19 months old contributed to her transformation from an alert, verbal toddler to one with autism. She stopped communicating, wouldn't make eye contact, and fixated on lights.

The Polings spent a year seeking a medical explanation for her developmental regression before tests of her blood and muscle samples revealed abnormalities of mitochondrial function.

The parents turned to the federal Vaccine Injury Compensation Program, created in 1986 to offer an efficient, "no-fault" alternative to lawsuits that were driving vaccine companies out of the business. Claimants need to prove only that a vaccine caused injury, without placing blame.

Medical personnel at the compensation program reviewed Hannah's file but did not hold a hearing. They conceded the immunizations "significantly aggravated" her underlying cellular disorder, causing neurological damage with features of autism.

Hannah's case is not representative of the backlog of 4,900 petitions filed by other families. Those parents argue that the measles-mumps-rubella shot, a mercury-containing vaccine preservative called thimerosal, or the combination, caused their children's autism. (Most vaccines no longer use thimerosal.)

The compensation program is now hearing nine "test" cases that represent these three causation theories. Decisions are not expected before next year.

The program, supported with an excise tax on each vaccine dose, has so far awarded about $890 million to compensate 2,140 claims, but Hannah's is the only one known to involve autism. The fund still has $2.7 billion.

Despite the concession in Hannah's case, experts say the idea that a cellular energy deficit could be aggravated by stimulating the immune system with vaccines is speculative.

Columbia University neurologist Salvatore DiMauro, an expert in disorders of cellular energy metabolism, said: "I like to say we're dealing with three dots. Two dots have been reasonably connected - autism and mitochondrial disease. The third dot - vaccines - has not been connected in any evidence-based way to autism or mitochondrial disease."

Says the mitochondrial-disease foundation: "There are no scientific studies documenting that . . . vaccinations cause mitochondrial diseases or worsen . . . symptoms."

Public-health officials also point out that for anyone with mitochondrial dysfunction, the theoretical danger of vaccines is far less than the real danger of diseases they prevent.

But that suggests, incorrectly, that the Polings are urging parents not to vaccinate their offspring at all.

"I really don't want that to happen," Jon Poling said in a phone interview.

What the Polings advocate is research into the possible role of mitochondrial disease and vaccines in autism.

That, they hope, would lead to screening tests to identify children who could benefit from customizing the standard vaccination schedule, which has grown from 10 shots against seven diseases in 1980 to the current 28 shots against 14 diseases, not including the annual flu shot. (Vaccine experts counter that the total number of immune-stimulating proteins in the shots is lower than ever.)

Hannah had missed the vaccinations usually given at ages 12 months and 15 months because of recurring illnesses, so when she was 19 months old, her pediatrician followed guidelines to catch her up: He gave five shots against nine diseases all at once.

"If I were to do it over again," Poling said, "I'd just be extremely cautious, space the vaccines out, make sure her nutritional status was good and that she was very healthy."

The American Academy of Pediatrics says "it is not advisable to skip or delay vaccines." But many doctors are becoming less dogmatic as parents ask about the persistent vaccine-autism controversy.

Atlanta pediatrician Jennifer Shu, a spokeswoman for the pediatricians' group, said that in deference to parents, she has spread shots out over weeks. She also ordered a blood test that showed a 5-year-old autistic child had enough immunity to postpone the measles-mumps-rubella booster; now 11, he is being retested to see if he needs it.

"If it's something the parents feel strongly about, I try to work with them to find a way to protect the child," she said.

Whatever the cause of autism, federal data show it has become common. One child in 150 is now diagnosed with some form of the disorder, compared with one in 2,000 in the early 1980s. Recognizing that the most severely affected need lifelong therapy and support, Gov. Rendell announced last week that Pennsylvania is extending Medicaid-funded autism services to a few hundred people over age 21, the first state to do so.

Poling won't discuss how much compensation his family will receive, because part of the award is undecided. Equally important, Poling said, Hannah's case "has raised many intelligent discussions and questions."

"What happened to my daughter won't be in vain if it leads to a safer vaccine program," he said.



--------------------------------------------------------------------------------
Contact staff writer Marie McCullough at 215-854-2720 or mmccullough@phillynews.com.

Every Honest Autism Researcher Finds a Paternal Age Effect in non-familial autism

It is universal, older paternal age past 32, getting worse with age, causes some non-familial autism. If one has autoimmune diseases in the family the risk is higher. Past the age of 40 the risk is higher and get higher at 50, 60, 70.

If you want to prevent de novo autism, father your babies by your early 30s. Doing this will also prevent your children from paternal age related cancers, Alzheimer's, autoimmune disorders and many other genetic diseases and disorders.

Why the repercussions of the male biological clock aren't universally known is outrageous. For fifty years or more, researchers have been warning about the paternal age effects.

If you are interested in the research on this subject, take the time and search my blogs.


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



By Martin Holt


So there I was, 49 years old, after a first failed marriage, with no children, and sure that parenting was a closed book for me. And then-- "Guess what you are getting for your 50th birthday"-- said the love of my life.

"By the look in your eyes, it is something really special," I replied.

"Yes, you are going to be a father."

I was thrilled by the idea. But being an only child myself, what did I know about babies?

During the next nine months I learned a lot. I read all the books including Childbirth for Men. I went to the pre-natal class and puffed and pushed down with the rest of the class. As the due date got closer, I rented a crib, a wicker basket on wheels, and set it up in our bedroom. For the first time I realized that a new being was coming into my life. My mother-in-law arrived from abroad, full of knowledge and endless stories of near tragedies and melodramas concerning newly born babies and their ignorant parents - mainly fathers.

The birth itself was exactly as emotional and wonderful as it was supposed to be. I was right there; I was amazed; I was terrified; I was completely overwhelmed. Two days later they let us out of the hospital with a brand new baby.

Suddenly, we were three instead of two. What on earth was I supposed to do? Well, I could certainly prepare bottles. I set aside the top shelf of the refrigerator and in a corner of the kitchen created a "sterile area" that NASA would have been proud of. No one was allowed near. No ungloved hands touched the bottles. Everything was handled with sterile tongs. My mother-in-law, still present, laughed non-stop at most of this.

More Patience, More Understanding

I will never forget the first time that I picked him up for my first night feed . Fifty years of life experience, a participating father, but still I was anxious about picking up this tiny, fragile, little human. I held him at arm's length away from me as if he was a priceless crystal vase that might break at any moment. A warm sleepy voice came from the depths of the bed: "Not like that, hold him close, take him in your arms, look into his eyes." So I did, and from that moment on I have always held him close, even though now he is 13 years old and as tall as me.


I feel that the years under my gray hair have given me that pause between thought and action, between temper and lashing out, so that I never get close to physical punishment.

What does it mean, being a father 50 years older than his first born? It means that I have much more patience and understanding than I had when I was 25. It means that I can use the wisdom that I have accumulated. It means that I don't try to reduce the age gap by pretending to be a young father but instead I try and give the message that there are advantages to being an older father.

My maturity has helped when it comes to setting limits and dealing with situations that demand discipline. In my house there was always the physical fear of what was called "a good hiding ." It was always "hit first and then listen." I swore that this would never happen with my children. I feel that the years under my gray hair have given me that pause between thought and action, between temper and lashing out, so that I never get close to physical punishment.

I have heard my son say: "My dad does such-and-such well." But I have never heard him say "My Dad's too old for stuff like that ". I have heard him say plenty of other things, some of which have made me cringe but the KO that I had feared, never came. There were moments in the eye-to-eye confrontations that are bound to happen in any parent-child relationship when he called me everything else under the sun - and under the earth too, but not ever, "You old whatever... ."

Less Running, More Ingenuity

That's not to say there aren't problems. But there are ways of getting around them. For example, when my son was younger and learning to ride a bike, I couldn't run after him holding the saddle of his bicycle. I solved the problem by standing at the top of a not-too-steep hill near our house and getting him to coast down it with his feet touching the ground. Clever old Dad had taken off the pedals. I shouted encouragement all the way and jumped up and down.

There is, of course, a down side as the years slip by. The summer holidays are still eternity for him, whereas for me they are frighteningly swift. There is no way that I cannot make the inevitable calculations. When I will be eighty, he will be thirty. Will I ever see him married, will I ever have grandchildren? Will I be a burden while he is still a young man making his way?

And now that I am the proud father of a daughter born seven years after my son, the situation has grown more poignant. I have quickly learned that everything that they say about fathers and their daughters is true. She really can twist me around her little finger with one look of her huge, infinitely blue eyes. But what about her? Will she be able to tell me of her first loves or will I be too gaga by then to understand - or not there at all?

I can't predict the future. I only know that I have lived and am living the most wonderful experience of my life. Every day is for itself. Every look, every time a little hand comes out of nowhere to hold mine, I know that the age difference means nothing at all. Every time I see my kids standing on their own two feet and looking the world in the eye, I give thanks.

I just hope they won't want me to go skateboarding with them.




Martin Holt is an internationally renowned artist whose drawings appear throughout WholeFamily



So there I was, 49 years old, after a first failed marriage, with no children, and sure that parenting was a closed book for me. And then-- "Guess what you are getting for your 50th birthday"-- said the love of my life.

"By the look in your eyes, it is something really special," I replied.

"Yes, you are going to be a father."

I was thrilled by the idea. But being an only child myself, what did I know about babies?

During the next nine months I learned a lot. I read all the books including Childbirth for Men. I went to the pre-natal class and puffed and pushed down with the rest of the class. As the due date got closer, I rented a crib, a wicker basket on wheels, and set it up in our bedroom. For the first time I realized that a new being was coming into my life. My mother-in-law arrived from abroad, full of knowledge and endless stories of near tragedies and melodramas concerning newly born babies and their ignorant parents - mainly fathers.

The birth itself was exactly as emotional and wonderful as it was supposed to be. I was right there; I was amazed; I was terrified; I was completely overwhelmed. Two days later they let us out of the hospital with a brand new baby.

Suddenly, we were three instead of two. What on earth was I supposed to do? Well, I could certainly prepare bottles. I set aside the top shelf of the refrigerator and in a corner of the kitchen created a "sterile area" that NASA would have been proud of. No one was allowed near. No ungloved hands touched the bottles. Everything was handled with sterile tongs. My mother-in-law, still present, laughed non-stop at most of this.

More Patience, More Understanding

I will never forget the first time that I picked him up for my first night feed . Fifty years of life experience, a participating father, but still I was anxious about picking up this tiny, fragile, little human. I held him at arm's length away from me as if he was a priceless crystal vase that might break at any moment. A warm sleepy voice came from the depths of the bed: "Not like that, hold him close, take him in your arms, look into his eyes." So I did, and from that moment on I have always held him close, even though now he is 13 years old and as tall as me.


I feel that the years under my gray hair have given me that pause between thought and action, between temper and lashing out, so that I never get close to physical punishment.

What does it mean, being a father 50 years older than his first born? It means that I have much more patience and understanding than I had when I was 25. It means that I can use the wisdom that I have accumulated. It means that I don't try to reduce the age gap by pretending to be a young father but instead I try and give the message that there are advantages to being an older father.

My maturity has helped when it comes to setting limits and dealing with situations that demand discipline. In my house there was always the physical fear of what was called "a good hiding ." It was always "hit first and then listen." I swore that this would never happen with my children. I feel that the years under my gray hair have given me that pause between thought and action, between temper and lashing out, so that I never get close to physical punishment.

I have heard my son say: "My dad does such-and-such well." But I have never heard him say "My Dad's too old for stuff like that ". I have heard him say plenty of other things, some of which have made me cringe but the KO that I had feared, never came. There were moments in the eye-to-eye confrontations that are bound to happen in any parent-child relationship when he called me everything else under the sun - and under the earth too, but not ever, "You old whatever... ."

Less Running, More Ingenuity

That's not to say there aren't problems. But there are ways of getting around them. For example, when my son was younger and learning to ride a bike, I couldn't run after him holding the saddle of his bicycle. I solved the problem by standing at the top of a not-too-steep hill near our house and getting him to coast down it with his feet touching the ground. Clever old Dad had taken off the pedals. I shouted encouragement all the way and jumped up and down.

There is, of course, a down side as the years slip by. The summer holidays are still eternity for him, whereas for me they are frighteningly swift. There is no way that I cannot make the inevitable calculations. When I will be eighty, he will be thirty. Will I ever see him married, will I ever have grandchildren? Will I be a burden while he is still a young man making his way?

And now that I am the proud father of a daughter born seven years after my son, the situation has grown more poignant. I have quickly learned that everything that they say about fathers and their daughters is true. She really can twist me around her little finger with one look of her huge, infinitely blue eyes. But what about her? Will she be able to tell me of her first loves or will I be too gaga by then to understand - or not there at all?

I can't predict the future. I only know that I have lived and am living the most wonderful experience of my life. Every day is for itself. Every look, every time a little hand comes out of nowhere to hold mine, I know that the age difference means nothing at all. Every time I see my kids standing on their own two feet and looking the world in the eye, I give thanks.

I just hope they won't want me to go skateboarding with them.




Martin Holt is an internationally renowned artist whose drawings appear throughout WholeFamily

Identical Twins Aren't Identical

#links

Autism and Mitochondrial Disorders

Features
Children with Autism




Some children with autism may have a genetic defect that affects the muscles, according to research presented at the American Academy of Neurology 60th Anniversary Annual Meeting in Chicago, in April.

The study looked at 37 children with autism spectrum disorders who were evaluated for mitochondrial disease, which causes muscle weakness and prevents a child from being able to participate in physical activities and sports. Mitochondrial disease occurs when genetic mutations affect the mitochondria, or the part of the cell that releases energy.

A total of 24 of the children, or 65 percent, had defects in the process by which cells produce and synthesize energy in the muscles, or oxidative phosphorylation defects in the skeletal muscles.

"Most children with autism spectrum disorders do not have recognizable abnormalities when you look at genetic tests, imaging, and metabolic tests," said study author John Shoffner, MD, owner of Medical Neurogenetics, LLC in Atlanta, GA. "But a subset of these children does have significant defects in this area. Identifying this defect is important for understanding how genes that produce autism spectrum disorders impact the function of the mitochondria."

The study was supported by Medical Neurogenetics, which conducted the testing.

The parents of Jonathan Carey accuse a state agency of a cover-up in the death of their 13-year-old autistic son.

Alleged Cover-Up in Autistic Teen's Death
Updated: May 28, 2008 08:20 AM PDT




The parents of Jonathan Carey accuse a state agency of a cover-up in the death of their 13-year-old autistic son.

Jonathan died in February of last year after being improperly restrained by Edwin Tirado, a caregiver from O.D. Heck. Under a law passed in Jonathan's name, his parents were able to obtain all the paperwork regarding the alleged abuses and the investigation into Jonathan's death. But the Carey's say the agency that conducted the investigation - the Commission on Quality of Care - is covering up for O.D. Heck. They outline a series of documented problems with Tirado, including one where Jonathan had bruising on his eyes and nose.

"If this was properly investigated earlier, Ed Tirado, it's a good chance (he) might have been removed and prosecuted earlier," Jonathan's father, Michael Carey says. "But he wasn't removed, he was left in his job and he ended up killing my son."

And today, the State Legislature is announcing a new initiative for a statewide autism research effort. We will bring you that story tonight, on NEWS10 starting @ 5 o'clock.

Dr. Bernadine Healy Time to Investigate Vaccines CBS News

http://adventuresinautism.blogspot.com/search?q=bernadine+healy

Adventures in Autism: Former Head Of NIH Says Time to Investigate Vaccines and Autism#links#links#links#links

MMR: The debate that won't go away

MMR: The debate that won't go away
Last Updated: 12:01am BST 26/05/2008
Page 1 of 3
"It seemed the MMR controversy had been resolved, but does new research point to another possible connection between autism and vaccinations? Cassandra Jardine reports
Four years ago, it seemed as if the agonising over autism and the measles, mumps and rubella (MMR) triple vaccine had finally been consigned to history. Several large-scale epidemiological studies concluded there was no evidence of a link between the two.

By the age of three, 90 per cent of children have had the MMR vaccine
Taking just one of these studies - involving 4,500 children in Denmark - Sir David King, chief scientific adviser to the Government until the end of 2007, said: "If anything, there was more autism found among the children who weren't vaccinated."
Parents who had claimed that their children had regressed mentally and physically following the MMR vaccination were told it was probably a coincidence. Meanwhile, Dr Andrew Wakefield, the gastroenterologist whose research had triggered the scare, with a study in 1998 of 12 such cases, is currently defending himself in front of the General Medical Council against charges of gross professional misconduct.
So how is it now that the debate has been reignited in the US, with growing concern that an apparent increase in the number of children with autism may have an environmental cause (including MMR and other childhood vaccinations)?
All three presidential candidates have referred to what Republican Senator John McCain calls the "autism epidemic", pledging substantial sums of money for research.
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Then, earlier this month, Dr Bernardine Healy, former head of the National Institutes of Health, America's medical research agency, told CBS News: "I think that the public health officials have been too quick to dismiss the [autism link to vaccination] hypothesis as irrational." She called for detailed studies of children whose parents believe they have been affected. "I have not seen major studies that focus on 300 kids who got autistic symptoms within a period of a few weeks of the vaccines," she said.
Healy's comments are significant because she's the first figure from the mainstream medical establishment not to dismiss the link.
Next month David Kirby, author of the award-winning book Evidence of Harm, will be in London giving a public lecture and addressing the House of Lords about the causes of regressive autism (as opposed to classic autism, which does not involve a sudden loss of speech and other functions).
The focus of his attention is not MMR but thiomersal, a preservative containing mercury (a known neurotoxin) that is used in some vaccines, including those for flu. (The Department of Health is keen to stress that no children's vaccine in this country has contained thiomersal for the past four years, and when it was formerly used in childhood vaccines it was at levels that were lower than those in the US.)
"A convergence of events," Kirby says, "has highlighted the importance of research, treatment and identifying the minority of children who may be susceptible to vaccine damage."
Chief among these convergent events is the case of Hannah Poling, the nine-year-old daughter of neurologist Jon Poling, from Georgia. In July 2000, aged 19 months, she received five different vaccinations, against a total of nine diseases, in one day. Her mother Terry says that when she entered the surgery, she was a bright - even precocious - child. Within 48 hours, she had stopped eating, ceased to respond to speech and become prone to episodes of screaming and fever.
Hannah Poling's case is part of the Omnibus Autism Proceeding - 5,000 cases of regressive autism being looked at by the US Vaccines Court, a body funded by a 75 cent levy on every vaccine given in the US. In February, the US government agreed compensation for her disabilities, having conceded, out of court, that her condition had been "significantly aggravated" by vaccination.
Initially, her case didn't appear to be of widespread significance because she was found to have a dysfunction of the mitochondria, the "batteries" in our cells that produce energy essential for normal functioning. This abnormality made her an unsuitable test case in any legal proceedings.
But then the next child under consideration as a test case was found to have a similar weakness, raising the possibility that a small minority of children may, because of a genetic predisposition, be more susceptible to the damaging side-effects of vaccination.
"It now looks as if 20 per cent of children with regressive autism may have this weakness; some are saying 65 per cent," says Kirby. "The cause of this weakness could be genetic or environmental."
ContinuedMMR: The debate that won't go away
Last Updated: 12:01am BST 26/05/2008
Page 2 of 3
The last point is crucial. Jon Poling, Hannah's father, believes two triggers are needed before a child becomes severely ill: possibly, an early vaccination which might compromise a child's metabolic system, then a later one which results in symptoms. There are various theories why this might be so. According to David Kirby, even trace elements of mercury and aluminium (also used in vaccines) might damage the mitochondria and could be passed from mother to foetus.
The actor Jim Carrey and his wife Jenny McCarthy believe that McCarthy's son, Evan, was "vaccine-damaged" four years ago, aged two. "In the Eighties. children received only 10 vaccines by age five, whereas today they are given 36 immunisations, most of them by age two," says McCarthy. "With billions of pharmaceutical dollars, could it be possible that the vaccine programme is becoming more of a profit engine then a means of prevention?" On June 4 they will be leading a march in Washington DC, waving banners saying "Too many. Too soon."
To date there has been no successful legal challenge to MMR in the UK. There is a Vaccine Damage Payments Unit which was set up in 1979, following concerns that the whooping cough (pertussis) vaccine could cause brain damage (the vaccine has since been changed).
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However, compensation is capped at £120,000 (including legal costs) and disability thresholds are high. Only two out of 53 claims were successful in the year to April 2008 - neither of them for autism.
"Under the US system, a person may receive an award if they can prove the vaccine caused an existing condition to get worse," explains a spokesperson for the Department of Work and Pensions. "This provision doesn't exist in the UK system, where… payments are made when it can be shown that it was more probable than not that someone became severely disabled as a result of vaccination."
In the civil courts, more than 1,000 cases were being prepared for a group MMR action until, in September 2003, legal aid was withdrawn. No reason was given. Following the success of the Poling case in the US, Peter Todd of London solicitors Hodge, Jones & Allen, has 200 clients who want to reapply for legal aid. He believes vaccines could be linked to a whole range of neurological and auto-immune disorders - epilepsy, childhood diabetes, arthritis, and even attention deficit hyperactivity disorder (ADHD).
"Vaccines are designed not to infect but to stimulate the immune system into making a response, so it would not be surprising if they were implicated in auto-immune disorders," Todd says. "Even if the condition was underlying, vaccines may have materially affected its onset."
The vaccine hypothesis was bolstered recently by a five-year study in monkeys who were given the same vaccinations that American children are routinely given. Last week, Dr Laura Hewitson, a specialist in obstetrics, gynaecology and reproductive sciences at the University of Pittsburgh, told the International Meeting for Autism Research in London that in the double-blind placebo-controlled study, 13 vaccinated animals showed increased aggression, impaired cognitive skills and developmental delay. The three unvaccinated animals in the study developed normally.
"There was a significant difference between the two groups," said Hewitson. "The vaccinated group had trouble developing reflexes?… They also became more insular and more aggressive. There was an increase in aggressive behaviour after they had their MMR vaccines, and they stopped exploring their surroundings as much."
Abnormal brain activity was found in the monkeys, and higher sensitivity to a naturally occurring brain chemical linked to sleeplessness, hallucinations, lack of social skills and a high pain threshold - all symptoms found in children on the autistic spectrum. The monkeys also exhibited abnormalities of the amygdala, the part of the brain which regulates emotions.
"We can't conclude that vaccines cause autism from this study," said Hewitson, "What we can conclude is that the vaccinated monkeys showed significant negative behavioural differences before and after the MMR."
Certainly autism appears to have increased dramatically. In the early Nineties prevalence in the UK was put at four or five per 10,000. In 2006, The Lancet put it at one in 86 and, last year, Cambridge University's Autism Research Centre estimated that some 210,000 children - one in 58 - suffer from an autistic spectrum disorder.
Few people believe that vaccination programmes should cease. The vast majority of children benefit from being protected against a range of diseases, but there are concerns that some may be paying a high price for immunity. Already there is a sense of panic coming from Government circles about the future of the immunisation programme.
Continued

Earlier this month Labour MP, Mary Creagh, proposed that children should not be allowed to attend school if they haven't had all their jabs; last week it emerged that doctors in the south-east of England were giving children two doses of MMR in a three-month interval (the usual regime is at 13 months and then aged 3) to prevent a measles outbreak spreading beyond the capital.
Of course further research is needed into the early identification of autism and its causes. However the new evidence from the US suggests that screening children for mitochondrial dysfunction (there are "markers" in the blood of affected children) may also be beneficial.
Delays in vaccinating children who display asthma, eczema, food allergies and other signs of a compromised immune system should also be considered, as well as a ban on "catching up" - children who have missed immunisation being given vaccines in a shorter time period - which could overload a young system.
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Many parents believe that provision of single vaccines on the NHS would allay concern further and that some vaccinations should be scheduled for later in childhood when immune systems are stronger. The alternative may be another panic."
Additional reporting by Sally Beck
David Kirby is giving a free public lecture on Wednesday 4th June, 6.30-10pm at Regent Hall, 275 Oxford Street, London W1

Growth and schizophrenia: aetiology, epidemiology and epigenetics.

Novartis Found Symp. 2008;289:196-203; discussion 203-7, 238-40.
Growth and schizophrenia: aetiology, epidemiology and epigenetics.
Malaspina D, Perrin M, Kleinhaus KR, Opler M, Harlap S.
Department of Psychiatry, New York University School ofMedicine, New York, NY 10016, USA.
There is a strong genetic component for schizophrenia risk, but it is unclear how the illness is maintained in the population given the significantly reduced fertility of those with the disorder. One possibility is that new mutations occur in schizophrenia vulnerability genes. If so, then those with schizophrenia may have older fathers, since advancing paternal age is the major source of new mutations in humans. We found that paternal age at conception is a robust risk factor for schizophrenia, explaining perhaps a quarter of all cases. The predisposing genetic events appear to occur stochastically in proportion to advancing paternal age, and the possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The risk might also be related to paternal 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 germline cause an independent and common variant of schizophrenia and that abnormal methylation of paternally imprinted genes could be the mechanism. These findings suggest exciting new directions for research into the aetiology of schizophrenia.
PMID: 18497104 [PubMed - in process]

Latinos/Latinas have less autism and other diseases. One of the causes is a lower average paternal age for Latinos/Latinas. Genes are in better shape to begin with.

There's a lot said about a woman's ticking biological clock, but male biology doesn't age as gracefully as men might like to think

There's a lot said about a woman's ticking biological clock, but male biology doesn't age as gracefully as men might like to think. By analyzing sperm from men of various ages, scientists from the McKusick-Nathans Institute for Genetic Medicine at Johns Hopkins have discovered that older men's sperm is more likely to contain disease-causing genetic mutations that also seem to increase a sperm's chances of fertilizing an egg. The findings, which appear in the advance online section of the American Journal of Human Genetics, emerged during efforts to explain why a rare genetic disease is more common in children born to older fathers. The disease, Apert syndrome, leads to webbed fingers and early fusion of the skull bones, which must be surgically corrected. The researchers found that mutation rates in sperm increased as men aged, but not enough to fully account for the increased incidence of Apert syndrome in children born to older fathers, leading to the suspicion that the disease-causing mutations confer some benefit to the sperm, despite the mutations' effects on the resulting baby. 'Mutations causing this disease occur more frequently in the sperm of older men, but the mutation rate isn't quite as high as the incidence of Apert syndrome,' says Ethylin Jabs, M.D., director of the Center for Craniofacial Development and Disorders at Johns Hopkins. 'For some reason, a sperm with one of these mutations is more likely to be used to make a baby than normal sperm.' While Apert syndrome itself affects only 1 in 160,000 births, the scientists believe a combination of increased mutation rate and 'mutation advantage' might also be behind some of the 20 or so other genetic conditions linked to older fathers, including achrondroplasia dwarfism. These disorders begin to increase rapidly with the father's age at about the same time as maternal risks increase -- age 33 to 35. Most of the evidence for paternal age effects has come from determining how many children with these conditions are born to fathers of various ages. For the current study, the Hopkins scientists studied sperm from 148 men of various ages and looked for two genetic changes that are responsible for 99 percent of Apert syndrome cases. They found that men over 60 were, on average, three times as likely as men under 30 to have sperm with at least one of these changes. The mutations didn't appear in the men's blood. 'Men over age 52 are six times more likely than a 27-year-old to have a child with Apert syndrome, so the mutation rate alone can't account for the condition's link to paternal age,' says first author Rivka Glaser, a graduate student in the human genetics and molecular biology program at Johns Hopkins. 'Literally hundreds of millions of sperm are made in each batch, so in most cases there are still many normal sperm available,' adds Jabs, also a professor of pediatrics. 'Because the few mutated sperm are more likely to be used to make a baby than would be expected, the mutation must provide them some competitive advantage over their normal counterparts.' The two genetic mutations that cause most cases of Apert syndrome affect a protein called fibroblast growth-factor receptor-2 (FGFR2). The mutated versions of FGFR-2 don't bind to its usual targets with the same affinity, perhaps contributing to the sperm's likelihood of fertilizing an egg, the researchers suggest. The scientists looked for the two FGFR2 mutations in sperm from two groups of men who did not have children with Apert syndrome. These controls -- 57 from a Johns Hopkins study and 76 from an ongoing study at Lawrence Livermore National Laboratory -- were asked to provide sperm and blood samples and to complete a health survey. They also analyzed sperm from 15 fathers of children with Apert syndrome.

Some things we know about autism

People with Asperger's are more likely to have autistic children. People with schizophrenia are more likely to have autistic children. Older fathers(34+) are more likely to have autistic/schizophrenic children. People with autoimmune disorders such as type 1 diabetes, MS, Lupus are more likely to have autistic offspring.

Paternal Factors and Schizophrenia Risk: De Novo Mutations and Imprinting

This article has reviewed data that support an association
between schizophrenia risk and advancing paternal age.
As such, schizophrenia may be one of a number of neurodevelopmental
disorders caused by de novo mutations
in the male germ line. This mutation mechanism may contribute
a significant proportion of schizophrenia risk
within a population in proportion to the demographics of
paternal childbearing age. Furthermore, this risk may
have implications for public health and for the primary
prevention of schizophrenia.






The PDF of the paper is available for free.


Schizophrenia Bulletin 2001 27(3):379-393;
© 2001 by Oxford University Press and the Maryland Psychiatric Research Center (MPRC)
This Article




© Oxford University Press


Paternal Factors and Schizophrenia Risk: De Novo Mutations and Imprinting
Dolores Malaspina, M.D., M.S.P.H., Associate Professor
Clinical Psychiatry at Columbia University Department of Psychiatry/New York State Psychiatric Institute, New York New York

Send reprint requests to Dr. D. Malaspina, New York State Psychiatric Institute, 1051 Riverside Drive, New York, NY 10032; e-mail: dm9@Columbia.edu

There is a strong genetic component for schizophrenia risk, but it is unclear how the illness is maintained in the population given the significantly reduced fertility of those with the disorder. One possibility is that new mutations occur in schizophrenia vulnerability genes. If so, then those with schizophrenia may have older fathers, because advancing paternal age is the major source of new mutations in humans. This review describes several neurodevelopmental disorders that have been associated with de novo mutations in the paternal germ line and reviews data linking increased schizophrenia risk with older fathers. Several genetic mechanisms that could explain this association are proposed, including paternal germ line mutations, trinucleotide repeat expansions, and alterations in genetic imprinting in one or several genes involved in neurodevelopment. Animal models may be useful in exploring these and other explanations for the paternal age effect and they may provide a novel approach for gene identification. Finally, it is proposed that environmental exposures of the father, as well as those of the mother and developing fetus, may be relevant to the etiology of schizophrenia.

From the body of the paper:
Mutations May Occur in Any One of a Number of
Genes Involved in Neurodevelopment. Thousands of
genes are estimated to play a role in neurodevelopment;
therefore, it is possible that mutations in many genes
could cause schizophrenia as a final common phenotype.
Mutations arising in the male germ line would be
amplified in clones of spermatozoa over the repeated
cell divisions that occur with paternal aging. Although a
full discussion of the agents that augment mutations in
spermatogenesis is beyond the scope of this article, it is
worth mentioning that they are, by and large, the same
ones that induce mutations in somatic cells, including
DNA repair enzyme insufficiency, free radicals, oxidative
damage, radiation, nutritional deficiency,
chemotherapy, and high temperature (Cummins et al.
1994; Robbins 1996; see Cohen 1986). Cigarette smoking
has also been linked to genetic damage in spermatozoa,
and free radical-induced mutations are theorized to
be a common cause of male infertility; both of these
exposures have been implicated in the etiology of childhood
cancer (Aitken 1999; Shen and Ong 2000; Zenzes
2000).
Despite the high fidelity of DNA replication, a
small number of new mutations are generated at every
cell division and are fixed by repair enzymes. The
amount of new mutations tolerated by an organism is a
trade-off between the cellular energy expenditures by
DNA proofreading and repair and the loss of offspring
viability from mutations. Because most mutations
decrease fitness, evolution will sustain genomes with
efficient DNA repair enzymes. However, there has
likely been little evolutionary pressure to maintain high
DNA replication accuracy in older men (Drake et al.
1998). Of note, the offspring of very young fathers also
have an elevated risk for de novo genetic disorders,
which may result from the immaturity of spermatids or
from low activity of DNA repair or antioxidant
enzymes. This leads to a "U-shaped curve" for paternal
age and the offspring's risk for several genetic conditions,
including type 1 diabetes mellitus (Tai et al.
1998), cardiac ventricular and atrial septal deficits
(Olshan et al. 1994), and neural tube defects (Mclntosh

From Something Beginning with A

Something Beginning with A
This about the treatment of Autism in London UK . we do not need awareness or advocacy. we need Educational Action and Medical Help. Hannah poling case

Friday, 23 May 2008
DAVID KIRBY AT UK PARLIAMENT TO SPEAK ABOUT AUTISM

BESTSELLING AMERICAN AUTHOR

DAVID KIRBY TO SPEAK AT HOUSES OF PARLIAMENT


Briefing by Journalist Who Covers Vaccine-Autism Debate is Sponsored

By Lord Robin Granville Hodgson, Baron Hodgson of Shropshire


U.S. Journalist David Kirby, author of the award winning book “Evidence of Harm, Mercury in Vaccines and the Autism Epidemic – A Medical Controversy,” will give a special briefing on this debate at the Houses of Parliament in London, on Wednesday, 4 June.


Mr. Kirby will speak about recent legal, political and scientific developments in the United States in the ongoing vaccine-autism controversy. The briefing is open to Peers in the House of Lords, Members of Parliament, their Staff, members of the Media, and Invited Guests. It is sponsored by His Lordship Robin Hodgson, Baron Hodgson of Astley Abbotts, Shropshire.


The briefing will take place on Wednesday, 4 June at 3:30PM at the Houses of Parliament, Palace of Westminster, Committee Room 4.


In addition to his Parliament briefing, Mr. Kirby will also give a free public lecture on Wednesday 4th June, 6:30-10PM at Regent Hall, 275 Oxford Street, London.


In addition, Mr. Kirby will attend an informal reading, book signing and Q&A on Friday 6th June, 4:00-7:00PM at Gudrun Jonsson, 2 Napier Road, Kensington, London.


Among the subjects to be addressed by Mr. Kirby are:


1) A recent case in the US Vaccine Court in which the federal government conceded that vaccines induced autism in one little girl – and updates on other cases in the court.

2) Growing evidence of a link between mitochondrial dysfunction and autistic regression, and case studies of several ASD children with mitochondrial issues.

3) State-of-the-art research underway at top universities on the connection between environmental toxins, mitochondrial function, oxidative stress, glutathione depletion, neuro-inflammation and autistic encephalopathy.

4) Declarations by all 3 US Presidential candidates that autism is epidemic and calling for more research into vaccines and mercury as possible causes.

5) Recent studies linking ASD risk with heavy metals and other contaminants in air pollution.


The visit is sponsored by US autism organizations Generation Rescue, Autism Research Institute, National Autism Association, Coalition for SAFE MINDS, and Talk About Curing Autism.


David Kirby is a former contributor to The New York Times and a writer for the popular blog, The Huffington Post. “Evidence of Harm,” debuted on The New York Times bestseller list in 2005, and is still widely read today. It won the Investigative Reporters and Editors Award in 2005 for Best Book. Kirby has appeared on NBC’s Meet the Press, CNN’s Larry King Live, NBC’s The Today Show, MSNBC’s Imus in the Morning, CNN Headline News, Air America, and many others.

We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders

Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina


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.

A variant of schizophrenia
A persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980).

It is possible that the genetic events that occur in the paternal germ line are affecting the same genes that influence the risk in familial cases. However, there is evidence that this is not the case. First, a number of the loci linked to familial schizophrenia are also associated with bipolar disorder (Craddock et al., 2006), whereas advancing paternal age is specific for schizophrenia (Malaspina et al., 2001). Next, a few genetic studies that separately examined familial and sporadic cases found that the "at-risk haplotypes" linked to familial schizophrenia were unassociated with sporadic cases, including dystrobrevin-binding protein (Van Den Bogaert et al., 2003) and neuregulin (Williams et al., 2003). Segregating sporadic cases from the analyses actually strengthened the magnitude of the genetic association in the familial cases, consistent with etiological heterogeneity between familial and sporadic groups.

Finally, the phenotype of cases with no family history and later paternal age are distinct from familial cases in many studies. For example, only sporadic cases showed a significant improvement in negative symptoms between a "medication-free" and an "antipsychotic treatment" condition (Malaspina et al., 2000), and sporadic cases have significantly more disruptions in their smooth pursuit eye movement quality than familial cases (Malaspina et al., 1998). A recent study also showed differences between the groups in resting regional cerebral blood flow (rCBF) patterns, in comparison with healthy subjects. The sporadic group of cases had greater hypofrontality, with increased medial temporal lobe activity (frontotemporal imbalance), while the familial group evidenced left lateralized temperoparietal hypoperfusion along with widespread rCBF changes in cortico-striato-thalamo-cortical regions (Malaspina et al., 2005b). Other data linking paternal age with frontal pathology in schizophrenia include a proton magnetic resonance spectroscopy study that demonstrated a significant association between prefrontal cortex neuronal integrity (NAA) and paternal age in sporadic cases only, with no significant NAA decrement in the familial schizophrenia group (Kegeles et al., 2005). These findings support the hypothesis that schizophrenia subgroups may have distinct neural underpinnings and that the important changes in some sporadic (paternal germ line) cases may particularly impact on prefrontal cortical functioning.

Genetic mechanism
Several genetic mechanisms might explain the relationship between paternal age and the risk for schizophrenia (see Malaspina, 2001). It could be due to de novo point mutations arising in one or several schizophrenia susceptibility loci. Paternal age is known to be the principal source of new mutations in mammals, likely explained by the constant cell replication cycles that occur in spermatogenesis (James Crow, 2000). Following puberty, spermatogonia undergo some 23 divisions per year. At ages 20 and 40, a man's germ cell precursors will have undergone about 200 and 660 such divisions, respectively. During a man's life, the spermatogonia are vulnerable to DNA damage, and mutations may accumulate in clones of spermatogonia as men age. In contrast, the numbers of such divisions in female germ cells is usually 24, all but the last occurring during fetal life.

Trinucleotide repeat expansions could also underlie the paternal age effect. Repeat expansions have been demonstrated in several neuropsychiatric disorders, including myotonic dystrophy, fragile X syndrome, spinocerebellar ataxias, and Huntington disease. The sex of the transmitting parent is frequently a major factor influencing anticipation, with many disorders showing greater trinucleotide repeat expansion with paternal inheritance (Lindblad and Schalling, 1999; Schols et al., 2004; Duyao et al., 1993). Larger numbers of repeat expansions could be related to chance molecular events during the many cell divisions that occur during spermatogenesis.

Later paternal age might confer a risk for schizophrenia if it was associated with errors in the "imprinting" patterns of paternally inherited alleles. Imprinting is a form of gene regulation in which gene expression in the offspring depends on whether the allele was inherited from the male or female parent. Imprinted genes that are only expressed if paternally inherited alleles are reciprocally silenced at the maternal allele, and vice versa. Imprinting occurs during gametogenesis after the methylation patterns from the previous generation are "erased" and new parent of origin specific methylation patterns are established. Errors in erasure or reestablishment of these imprint patterns may lead to defective gene expression profiles in the offspring. The enzymes responsible for methylating DNA are the DNA methyltransferases, or DNMTs. These enzymes methylate cytosine residues in CpG dinucleotides, usually in the promoter region of genes, typically to reduce the expression of the mRNA. The methylation may become inefficient for a variety of reasons; one possibility is reduced DNA methylation activity in spermatogenesis, since DNMT levels diminish as paternal age increases (Benoit and Trasler, 1994; La Salle et al., 2004). Another possible mechanism is that this declining DNMT activity could be epigenetically transmitted to the offspring of older fathers. There are a number of different DNMTs that differ in whether they initiate or sustain methylation, and which are active at different ages and in different tissues.

Human imprinted genes have a critical role in the growth of the placenta, fetus, and central nervous system, in behavioral development, and in adult body size. It is an appealing hypothesis that loss of normal imprinting of genes critical to neurodevelopment may play a role in schizophrenia. Indeed, one of the most consistently identified molecular abnormalities in schizophrenia has been theorized to result from abnormal epigenetic mechanisms (Veldic et al., 2004), that is, the reduced GABA and reelin expression in prefrontal GABAergic interneurons. An overexpression of DNMT in these GABAergic interneurons, hypermethylating the reelin and GAD67 promoter regions, might be responsible for reducing their mRNA transcripts and expression levels. These decrements could functionally impair the role of GABAergic interneurons in regulating the activity and firing of pyramidal neurons, thereby causing cognitive dysfunction. Later paternal age could be related to the abnormal regulation or expression of DNMT activity in specific cells.

Conclusion
These findings suggest exciting new directions for research into the etiology of schizophrenia. If there is a unitary etiopathology for paternal age-related schizophrenia, then it is likely to be the most common form of the condition in the population and in treatment settings, since genetic linkage and association studies indicate that familial cases are likely to demonstrate significant allelic heterogeneity and varying epistatic effects. Schizophrenia is commonly considered to result from the interplay between genetic susceptibility and environmental exposures, particularly those that occur during fetal development and in adolescence. The data linking paternal age to the risk for schizophrenia indicate that we should expand this event horizon to consider the effects of environmental exposures over the lifespan of the father. The mutational stigmata of an exposure may remain in a spermatogonial cell, and be manifest in the clones of spermatozoa that it will subsequently generate over a man's reproductive life.

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