A recent study published in the Journal of the American Medical Association, however, sheds new light on physiological roots — though not causes — of autism [2], and in so doing rules out the potential for any link between vaccination and development of the disease. In the study, researchers examined the size and number of neurons in the prefrontal cortex of young deceased males with autism, and compared the data to that obtained from young deceased non-autistic males.

With data adjusted for age, compared to the control brains (brains of children without autism), brains of autistic children had 67% more neurons in a region called the prefrontal cortex, which is associated with cognitive development, communication, and social and emotional function. The brains of the autistic children were also significantly heavier (by an average of 17.6%) than those of the non-autistic children, despite the fact that brain weight didn’t vary significantly among non-autistic children (average variation of 0.2%).

While this was a preliminary study involving only 13 children, the data nevertheless reveal significant differences between the brains of autistic and non-autistic children. Total neuron number and brain weight aside, there was another difference between the autistic and non-autistic brains: those of non-autistic children showed better correlation between neuron number and brain weight. That is to say, while both neuron number and brain weight were greater in autistic children than in non-autistic children, the increased weight of the brain was less than expected based upon the greatly increased number of neurons. This suggests a neural pathology, rather than simply a “larger than normal” brain.

Cortical neurons, such as those in the prefrontal cortex, proliferate between about 10 and 20 weeks of gestation — that is to say, prenatally — and no longer proliferate once a baby has been born. As such, the study authors point out, the tremendously increased neuron count suggests that autism has its roots in prenatal development, as opposed to being caused by exposure to some causative agent (including vaccinations) during infancy or toddlerhood.

The study did not attempt to determine the ultimate cause of autism, nor did the authors speculate as to whether the neural pathology was due to over-proliferation of neurons prenatally, failure of normal apoptosis, or both.

It’s not unreasonable to hypothesize, however, that — particularly as the brain changes associated with autism appear to happen prenatally — a combination of factors could be involved. Animal studies show that gene dysregulation can result in neuronal overabundance [3], and the emerging field of epigenetics has demonstrated the potential of environmental factors to turn genes off and on.

Autism researchers still have much to learn about the mechanisms by which children become susceptible to and develop autism — and more importantly, about what might be done to prevent it. Still, by revealing that autism is, in all likelihood, determined prenatally, medical researchers can help parents to focus their concerns and make more accurate risk-to-benefit judgements regarding early childhood health decisions, such as vaccination schedules. As the number of vaccinations has risen over the years, parents and physicians often discuss alternative vaccination schedules.

References

1. Poland GA. MMR Vaccine and Autism: Vaccine Nihilism and Postmodern Science. Mayo Clin Proc. 2011 Sep;86(9):869-71.
   View abstract
2. Courchesne et al. Neuron number and size in prefrontal cortex of children with autism. JAMA. 2011 Nov 9;306(18):2001-10.
   View abstract
3. Chenn and Walsh. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. 2002 Jul 19;297(5580):365-9.
   View abstract

The study, supported by the National Institutes of Health, found that shared environmental factors — experiences and exposures common to both twin individuals — accounted for 55% of strict autism and 58% of more broadly defined autism spectrum disorders (ASD). Genetic heritability accounted for 37% of autism and 38% of ASD. Random environmental factors not shared among twins play a much smaller role.

Earlier twin studies had estimated the genetic heritability of autism to be as high as 90%, due to much lower estimates of concordance — both members of a twin pair having the disorder — in fraternal twins. The new study found such concordance to be four to five times higher.

Joachim Hallmayer, M.D., of Stanford University, Palo Alto, California and a grantee of the NIH’s National Institute of Mental Health, explained:

High fraternal twin concordance relative to identical twin concordance underscores the importance of both the environment and moderate genetic heritability in predisposing for autism. Both types of twin pairs are more often concordant than what would be expected from the frequency of autism in the general population. However, the high concordance among individuals who share only half their genes relative to those who share all of their genes implies a bigger role for shared environmental factors.

Hallmayer, senior co-investigator Neil Risch, Ph.D., of the University of California, San Francisco, and colleagues report on findings of the California Autism Twins Study (CATS) in the July 2011 issue of the Archives of General Psychiatry [1].

NIMH director Thomas R. Insel, M.D. said:

These new findings are in line with other recent observations supporting both environmental and genetic contributions to ASD, with the environmental factors likely prenatal and the genetic factors highly complex and sometimes not inherited.

Studies are under way to determine if autism may be traceable, in part, to environmental exposures early during pregnancy.

The new study is the first to analyze a large sample of twins drawn from the general population; previous twin studies have been based on more limited samples, such as patients in treatment. It is also the first to employ the latest standard in diagnosing autism, which requires structured clinical assessments based on interviews with the parents as well as direct observation of the child.

Drawing upon state records, the researchers initially identified 1,156 twin pairs, with at least one member affected by an ASD, born to California mothers between 1987 and 2004. The children were all at least 4 years old, an age when autism can be reliably diagnosed. Ultimately, this group was winnowed to 192 twin pairs — 54 identical and 138 fraternal — for genetic analysis. Since autism disproportionately affects males, males outnumbered females by four to five times, with 80 of the pairs including both sexes.

Concordance for ASD was 77% among identical male pairs, and 31% among fraternal male pairs. In females, concordance for ASD was more closely spaced — 50% for identical and 36% for fraternal pairs. By contrast, previous studies had found concordance rates for fraternal twins that were much lower, ranging only in the single digits.

Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, noted:

Spectrum disorders traditionally thought to have less genetic loading turn out to stem from a similar mix of environmental and genetic heritability as narrowly defined autism.

Yet, there can also be genetic influences that are not inherited from parents. New evidence emerged last month that rare, spontaneous mutations occur at abnormally high rates in autism [2]. Risch explained:

Such non-inherited genetic changes were proposed as a major mechanism of autism susceptibility, based on the very low concordance among fraternal twins found in earlier studies and evidence of increased risk associated with older parental age. In light of the high fraternal twin concordance observed in our study, such new mutations may play a more limited role, since they would primarily occur in only one member of a fraternal pair, which would not lead to concordance.

Also participating in the research were investigators at: Autism Genetic Resource Exchange; California Department of Public Health; Kaiser Permanente; University of California, Davis. The research was also funded by Autism Speaks.

References

1. Hallmayer et al. Genetic Heritability and Shared Environmental Factors Among Twin Pairs With Autism. Arch Gen Psychiatry. 2011 Jul 4. [Epub ahead of print]
   View abstract
2. Sanders et al. Multiple Recurrent De Novo CNVs, Including Duplications of the 7q11.23 Williams Syndrome Region, Are Strongly Associated with Autism. Neuron. 2011 Jun 9;70(5):863-85.
   View abstract

Source: NIH News

Researchers supported through the NIH Autism Centers of Excellence were the first to contribute data to NDAR in 2008. Since then, NDAR staff has been working to define, standardize and transfer data into NDAR from earlier NIH programs, such as the Collaborative Programs of Excellence in Autism (CPEA) and Studies to Advance Autism Research and Treatment (STAART).

Data from the majority of ASD grants that were recently funded under the American Recovery and Reinvestment Act of 2009, as well as data from other ASD studies conducted at NIH, also will be submitted to and shared through NDAR. It is expected that data from newly-initiated NIH-funded autism research will be added to NDAR. Other ASD researchers have also been encouraged to contribute their study data, regardless of funding source.

Two goals were outlined in the Interagency Autism Coordinating Committee 2010 Strategic Plan for ASD Research. The first goal is to create mechanisms to specifically support the contribution of data to NDAR from 90 percent of newly initiated projects by 2012. The second goal is to link NDAR by 2012 with other significant existing data resources including:

• The Autism Genetic Resource Exchange

  The Autism Genetic Resource Exchange is an electronic data repository housing information from more than 1,000 families affected by ASD. It is created by the advocacy group Cure Autism Now and is currently supported by Autism Speaks.

• The Interactive Autism Network

  The Interactive Autism Network is an online project of the Kennedy Krieger Institute with funding from Autism Speaks, which contains data on 30,000 individuals with an ASD diagnosis whose families have voluntarily submitted information of interest to scientists.

• The National Institute of Mental Health’s (NIMH) Genetics Repository

  The NIMH Genetics Repository stores clinical data, biological materials, and genetic analysis data from more than 3,000 individuals with ASD.

• The NIMH Transcriptional Atlas of Human Brain Development

  The NIMH Transcriptional Atlas of Human Brain Development aims to map when and where in the brain genes are transcribed through development.

• The Pediatric MRI Data Repository

  The Pediatric MRI Data Repository receives support from four NIH institutes including the National Institute of Mental Health, and stores data from more than 500 typically developing children, from birth to young adulthood.

NDAR was created through the joint efforts of National Institute of Mental Health, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Environmental Health Sciences, the National Institute of Neurological Disorders and Stroke, and the NIH Center for Information Technology.

The mission of the NIMH is to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery and cure. For more information, visit www.nimh.nih.gov.

Source: NIH News

Today, one in 150 children is diagnosed with autism. In fact, more children will be diagnosed with autism this year than with cancer, diabetes and AIDS combined [3]. Autism is a brain development disorder that impairs a person’s ability to communicate or interact socially. The disorder is associated with restricted and repetitive behavior. While there is no cure for autism, with appropriate treatment and education, many children can learn and develop. The genetics of autism are the focus of much study, as it is unclear whether the disorder is due to rare mutation(s) or multigene interactions.

In 2007, the Autism Genome Project Consortium evaluated 10,000 single nucleotide polymorphisms or SNPs in 1,181 families that had at least two autistic individuals [4]. SNPs (pronounced “snips”) are DNA sequence variations that occur when a single nucleotide — A, T, C or G — in the genome is changed, producing different alleles (meaning sequences that code for the same gene). These small variations in DNA sequence make up almost 90% of all human genetic variation.

The consortium study, using genetic linkage and copy number variation analysis, highlighted a region of chromosome 11 tightly linked to a gene called neurexin 1 (NRXN1), which encodes a cell surface protein found in neurons that contributes to glutamate synapses. Although the result was intriguing, it failed to meet genome-wide significance, scoring just below the threshold (4.03 versus 4.1).

Now, researchers at Johns Hopkins University, the Broad Institute of Harvard and MIT and the Institute for Juvenile Research at the University of Illinois at Chicago, have used more recent SNP technologies to profile 500,000 SNPs in 802 affected sibling pairs; 50x the number of SNPs as the 2007 consortium study. They performed family-based linkage analysis [1] and an association analysis to examine the role of common variants [2].

The scientists identified five genomic loci of significant linkage, three of which have not been previously identified; two at the end of the long arm of chromosome 6 (6q25.2 and 6q27) and one near the centromere (meaning the region of DNA typically found near the middle of a chromosome) of chromosome 17 (17p12).

Image generated from the Ensemble Karyotype Genome Browser

The SNP data set was also combined with a smaller National Institue of Mental Health (NIMH) autism sample to perform familial association mapping in 864 complete families [2]. Utilizing additional SNP microarray follow-up data and genotyping top hits revealed an array SNP on chromosome 5p15 that was transmitted less often than expected from parent to autistic offspring. The researchers argue that the allele likely confers some protection against autism [5]. A likely candidate for the allele is the gene semaphorin 5A (SEMA5A), which is in the genomic region and is involved in axonal (i.e. nerve fiber) guidance during neural development.

The scientists assayed brain slices from 20 autistic individuals (compared to 10 controls) and found reduced SEMA5A expression, further implicating a role in autism [5]. SEMA5A has been suggested by others to be a candidate gene in the etiology of autism. A 2006 gene expression study of six subjects with autistic disorder compared to healthy controls identified SEMA5A downregulation in blood samples [6].

For additional information on autism, visit Autism Speaks, an advocacy group that promotes autism research and improved public awareness about autism.

The familial association mapping study is compelling because it utilized genomic data, focused in on a target gene and validated the difference between autistic and control samples biochemically. Even more striking is the involvement of SEMA5A during neural development. These are the types of studies that will identify the molecular basis for autism and help us to better diagnose and treat the disorder.

References

1. Arking et al. A large-scale high-density linkage study of autism identifies multiple genome-wide significant loci. American Society of Human Genetics. 2008 Nov 15.
2. Weiss et al. Genome-wide association mapping in multiplex autism families. American Society of Human Genetics. 2008 Nov 15.
3. Facts about Autism. Autism Speaks. Accessed 2008 Nov 22.
4. Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007 Mar;39(3):319-28. Epub 2007 Feb 18.
   View abstract
5. New autism loci discovered. The Scientist. 2008 Nov 12.
6. Melin et al. Constitutional downregulation of SEMA5A expression in autism. Neuropsychobiology. 2006;54(1):64-9. Epub 2006 Oct 5.
   View abstract