PHILADELPHIA—A team of researchers at the Children’s Hospital of Philadelphia (CHOP) has demonstrated that autism spectrum disorder (ASD) could be caused by defects in the mitochondria of brain cells. The research findings have been published online in Proceedings of the National Academy of Sciences.
Multiple studies have revealed hundreds of mutations associated with autism spectrum disorder, but as yet there is no consensus on how these genetic changes cause the condition. Biochemical and physiological analyses have suggested that mitochondrial deficiencies could be a potential cause, and recent studies have shown that variants of mitochondrial DNA (mtDNA) are associated with autism spectrum disorder.
“Autism spectrum disorder is highly genetically heterogeneous, and many of the previously identified copy number and loss of function variants could have an impact on the mitochondria,” said Dr. Douglas C. Wallace, director of the Center for Mitochondrial and Epigenomic Medicine and the Michael and Charles Barnett Endowed Chair in Pediatric Mitochondrial Medicine and Metabolic Diseases at CHOP, who is co-senior author of the study.
The team hypothesized that if defects in the mitochondria do predispose patients to ASD, then a mouse model in which relevant mtDNA mutations have been introduced should present with autism endophenotypes. In this model, the traits related to autism included behavioral, neurophysiological, and biochemical features.
The researchers — including co-first authors Dr. Tal Yardeni and Dr. Ana G. Cristancho, as well as co-senior author Dr. Eric D. Marsh, attending pediatric neurologist in the Division of Child Neurology at CHOP — introduced a mild missense mutation in the mtDNA ND6 gene into a mouse strain. The resulting mouse exhibited impaired social interactions, increased repetitive behaviors, and anxiety. These behavioral features are commonly associated with autism spectrum disorder.
The team also noted aberrations in electroencephalograms, more seizures, and brain-region specific defects of mitochondrial function in the mouse model. But despite these observations, the researchers found no obvious changes in the brain’s anatomy. These findings suggest that mitochondrial energetic defects appear to be sufficient as a cause for autism.
“Our study shows that mild systemic mitochondrial defects can result in autism spectrum disorder without causing apparent neuroanatomical defects,” Wallace added. “These mutations appear to cause tissue-specific brain defects. While our findings warrant further study, there is reason to believe that this could lead to better diagnosis of autism, and potentially treatments directed toward mitochondrial function."