Autism is a physical condition linked to abnormal biology and chemistry in the brain. The exact cause of this developmental disorder remains unknown, but is an active area of research, especially in the area of genetics where researchers are honing in on the gene mutations linked to autism which one day could lead to improved diagnosis and potentially a medical cure.
A recent report released by the Centers for Disease Control and Prevention (CDC) suggests that autism and related disorders is more common than previously thought. About one in 88 children in the United States are diagnosed with an autism spectrum disorder (ASD).
Researchers are fairly certain that autism has genetic roots, as the condition appears to run in families. However, genetic causes found so far have been so varied that it is hard to find enough people with a given mutation to establish a clear pattern.
One study conducted by researchers at Boston Children’s Hospital and published in the journal Neuron have found evidence for several inherited mutations using whole-exome sequencing to study large Middle Eastern families with autism. There is some evidence of the same mutations in US families as well, however American families aren’t usually the best for studies as they aer typically much smaller.
Tim Yu MD PhD and colleagues began by looking at three Middle Eastern families that had two or more children with an ASD. In all three families, the parents were first cousins, a common tradition in the Middle East. The researchers used genetic mapping techniques to narrow the search for specific chromosomal locations, and then proceeded to sequence the genes in those areas.
The team found recessive mutations in three genes not previously known to be involved in autism, but rather in severe genetic syndromes:
• Mutations in AMT, a gene classically associated with a severe metabolic syndrome known as nonketotic hyperglycinemia, marked by severe seizures and death during infancy.
• Mutations in PEX7. Typical PEX7 mutations cause rhizomelic chondrodysplasia punctata, a severe syndrome causing metabolic and bone abnormalities, cataracts, severe epilepsy and early death.
• Mutations in SYNE1, a gene associated with brain malformation, severe motor and muscle problems, and possibly bipolar psychiatric disease.
"This is the first time these genes have been associated with autism," says Dr. Maria Chahrour PhD who shares first authorship of the study with Yu. "The AMT and PEX7 mutations weren't picked up by standard tests for metabolic disorders, but when you're able to sequence the entire exome, you can find them."
These findings inspired the team to look further for other genetic syndromes affecting cognition and behavior. They screened 163 additional Middle Eastern families with autism for mutations in 70 known genes associated with the disorder. This approach revealed even more genetic abnormalities, including:
• Two families with recessive mutations in VPS13B (known to cause Cohen syndrome, which includes intellectual disability, obesity, vision and joint problems, and small head size)
• A family with a recessive mutation in POMGNT1 (known to cause muscle-eye-brain disease, marked by brain malformation, intellectual disability, muscle and vision problems)
• A family with an X-linked mutation in MECP2 in two boys (MECP2 mutations are known to cause Rett syndrome in girls, but are typically lethal in boys)
"It's not clear yet how many U.S. families have these recessive mutations," says Yu. "Further studies could begin to estimate what fraction of autism cases might fall under this model."
This study is only one among the many searching for a genetic cause for autism. Genetic scientists from the Children’s Hospital of Philadelphia and the University of Utah, together with Lineagen Inc (a biotech company) have identified 25 additional genetic variants that occur in some people with autism. These are described as “individually rare” but of “high impact” – meaning that each one has a strong effect in increasing a person’s risk for autism.
Scientists from the Seaver Autism Center at Icahn School of Medicine at Mount Sinai suggest that there are potentially hundreds of mutated genes linked to ASDs.
Researchers with the George Washington University have found that another genetic defect associated not only with autism, but also with other conditions of interrupted brain development could be due to a disruption at the cellular level. The team found that one type of cortical neuron, the projection neuron, is not generated in appropriate numbers during development in a mouse model of 22q11 Deletion Syndrome causing autistic symptoms.
"This gives us two pieces of the puzzle for this genetic developmental disorder," said Anthony Samuel LaMantia PhD, professor of pharmacology and physiology. "These two pieces tell us that in very early development, those with 22q11.2 deletion syndrome do not make enough cells in one case, and do not put the other cells in the right place. This occurs not because of some degenerative change, but because the mechanisms that make these cells and put them in the right place during the first step of development have gone awry due to mutation."
So what does this mean for parents who already have a child diagnosed with autism?
Several things come to mind. For one, even before thinking about a more accurate diagnostic test or a cure, if a family has additional children, screening for autism could begin sooner so that interventions could begin sooner – increasing the likelihood for improved behavioral outcomes. It also should provide comfort to those families who feel to blame for their child’s autism. It reinforces the fact that no two cases of autism are exactly alike, so interventions should be modified to each child’s individual needs. And it proves once in for all that autism is a medical disorder for which treatment deserves to be included under medical insurance.
1. Timothy W. Yu, et al. Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. Neuron, 2013; 77 (2): 259 DOI: 10.1016/j.neuron.2012.11.002
2. Hakon Hakonarson . " Identification of Rare Recurrent Copy Number Variants in High-Risk Autism Families and Their Prevalence in a Large ASD Population". PLOS ONE 8(1): e52239. doi:10.1371/journal.pone.0052239
3. T. M. Maynard, G. T. Haskell, A. Z. Peters, L. Sikich, J. A. Lieberman, and A.-S. LaMantia. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proceedings of the National Academy of Sciences, 2003; 100 (24): 14433 DOI:10.1073/pnas.2235651100