Cornell researchers have confirmed a genetic link between mitochondrial DNA (mtDNA), which is passed on from the mother, and some forms of autism spectrum disorder (ASD).

Previous research suggested a link between mitochondrial functional defects and ASD, but those studies included small sample sizes and could not verify whether the cause was genetic or environmental.

The current study, published online Oct. 28 in the journal PLOS Genetics, analyzed mtDNA in 903 families, where the researchers compared the mtDNA of an affected child and an unaffected sibling and their mother. They found that in instances when the children had both mutant and normal mtDNA in a single cell, called heteroplasmy, all the children showed similar numbers of mutant mtDNA, but the autistic children had more than twice as many harmful mtDNA mutations compared to their non-autistic siblings.

“When we compared the inheritance between the mother and the children, we confirmed this particular pattern, which is the child with autism inherited more bad mutations than their siblings during the process of passing mitochondrial DNA from mother to children,” said Zhenglong Gu, associate professor of nutritional sciences and the paper’s senior author.

“We show not only that mitochondrial DNA heteroplasmy is associated with autism, but also, among autistic kids, these pathogenic mitochondrial DNA mutations are significantly associated with intellectual disability, and other neurological and developmental defects,” said Yiqin Wang, a graduate student in Gu’s lab and the paper’s first author.

The current findings may lead to better diagnosis and treatment of children with a sub-type of autism caused by pathogenic mtDNA mutations. Analyzing mtDNA could help diagnose some forms of autism in the future. Interventions restoring mitochondrial function might also be useful for treatment, Gu said. These findings also have relevance for other childhood neurodevelopmental disorders, which may be caused by disease-causing mtDNA mutations and is a subject for future work, he said.

Most human cells carry two copies of nuclear DNA, one copy from each parent, and hundreds of copies of mtDNA, which exist in an organelle called the mitochondrion, where most of a cell’s energy is created. Aside from the nuclear genome that resides in the cell’s nucleus, the mitochondrion is the only organelle that contains DNA. Compared to nuclear DNA, mtDNA is known to mutate rapidly, which has prompted Gu to look for age-related diseases and pediatric diseases linked to these mutations.

During egg production, there is a dramatic reduction in the numbers of copies of mtDNA, as a way of eliminating bad mutations passed from mother to child. But some bad mutations still pass to the next generation, and the number of pathogenic mtDNA in children may be affected by the mother’s environment or physiology, Gu said.

“Does the mother have inflammation or diabetes, or is she obese?” Gu said. “These things could make the process of cleaning up mutations less efficient. This could give us some insight into why autism is rising,” and will be a subject for future studies, Gu said.

Future work will also include looking into the effects of environment, diet and the mother’s health on mtDNA in children, Gu said. The group is also developing better tools for efficient and cost-effective mtDNA sequencing, he said.

Martin Picard, an assistant professor of behavioral medicine at Columbia University, is a co-author on the paper.

The study was funded by Cornell University, the National Science Foundation, the National Institutes of Health, and the ENN Science and Technology Development Co.