Posts Tagged ‘autism genetics’

By Dr. Paul El-Fishawy

Researchers at Yale and the University of California San Diego have discovered a new, likely rare, recessively inherited form of classic autism with epilepsy.  Simultaneous errors in the genetic code of both the maternally and paternally inherited copies of a single gene, BCKDK, cause the disorder.  The protein created by BCKDK acts as a brake on the body’s degradation of 3 amino acids (the branched chain amino acids).  These nutrients, present in dietary protein, cannot be synthesized by the body but must be ingested.  In patients with this form of autism, blood levels of these amino acids are significantly lower than normal, despite normal levels of other amino acids and adequate nutrition.  Mice with the same genetic abnormality have neurological deficits that can be ameliorated by supplementing their diet with branched chain amino acids.  This suggests the possibility that patients with this specific, likely rare disorder could benefit from supplementation and that autism could be potentially be prevented in infants with this disease.

However, it is critical to note that so far cases of this disorder have only been found in only three, rare families in the Middle East where the parents are related as first cousins.  To date, no cases of autism in out-bred families in the United States or other Western countries have been shown to be attributable to this genetic defect.  Thus, the discovery should not lead to the immediate alteration of current practices of diagnosis and treatment of patients in countries like the United States where cousin marriages are uncommon.  There is no evidence from this study that supplementing autistic patients without this specific disorder with branched chain amino acids would be of any benefit.

We do not know how low levels of branched chain amino acids are causing autism in the patients.  The importance of the finding is that it reveals a new biological pathway and a new biological marker.  The hope is that further scientific exploration of this pathway could lead to improved diagnosis and treatments not only for patients with this specific disorder but also for other autistic patients.

One hypothesis about how low branched chain amino acids could be causing autism in these patients is that they could be leading to altered levels of neurotransmitters in the brain.  The branched chain amino acids and other amino acids that compete with them for entry from the blood into the brain are key building blocks for the neurotransmitters glutamate, GABA, dopamine, and serotonin.

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By Joseph Buxbaum, PhD

Researchers of the Autism Genome Project Consortium (AGP) announced today that they have identified new autism susceptibility genes that may lead to the development of new treatment approaches.

The study results are based on analysis of copy number variants (CNVs) — rare submicroscopic insertions and deletions — identified in high-density genotyping data collected from 1,000 individuals with autism spectrum disorder (ASD) and 1,300 without ASD. The findings were published today in Nature by the international consortium of researchers who make up AGP.

There are several important results from this study. First, the findings provide further support for an emerging consensus within the scientific community that autism is caused in part by many “rare variants,” or genetic changes found in one percent or less of the population. While each of these variants may only account for a small fraction of the cases, collectively they are starting to account for a greater percentage of individuals with autism.  More importantly, they are also providing insights into possible common pathological mechanisms.

Second, the findings show that CNVs disrupting genes are more common in ASD than in controls. Some of the more compelling findings include CNVs in SHANK2, SYNGAP1, DLGAP2 and the X-linked DDX53–PTCHD1 locus.

Third, the AGP explicitly tested whether genes previously implicated in intellectual disabilities but not in autism represented autism genes. The evidence was quite clear that such genes are also autism genes. The overlap between autism susceptibility genes and genes previously implicated in intellectual disabilities further supports the hypothesis that at least some genetic risk factors are shared by different psychiatric developmental disabilities.

Finally, the AGP carried out pathway analyses and noted that many of the autism genes that were identified belong primarily to synapse-related pathways, while others are involved in cellular proliferation, projection and motility, and intracellular signaling. Identification of these biological pathways points to new avenues of scientific investigation, as well as potential targets for the development of novel treatments.

Therapies specifically targeted to identified genetic causes (“personalized medicine”) are now being tested in several neurodevelopmental syndromes associated with autism, including Fragile X syndrome, tuberous sclerosis, and Rett syndrome. The identification of additional autism genes will expand such approaches and lead to new therapies.

 Joseph D Buxbaum, PhD is Director of the Seaver Autism Center for Research and Treatment at Mount Sinai and serves as Editor-in-chief of the journal Molecular Autism.  Dr. Buxbaum is one of the leading contributors to the design, analysis, and writing of this study and is a lead AGP investigator.

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