Autism spectrum disorders (ASD) are characterized by impairments in social interaction, communication, and repetitive or restrictive behavior. Although multiple physiologic and biochemical studies have reported defects in mitochondrial oxidative phosphorylation in patients with ASD, the role of mitochondrial DNA (mtDNA) variation has remained relatively unexplored.
Now, a study by researchers at the Children’s Hospital of Philadelphia (CHOP) has revealed how variations in mitochondrial DNA (mtDNA) originating during ancient human migrations may play an important role in predisposition to ASDs.
“What we discovered is that a very significant proportion of the risk of developing autism correlates with the mitochondrial DNA variants, not the nuclear variants, so that implies then that mitochondrial energetics might be the cause, or a major factor, in the etiology of this disease,” said senior study author Douglas Wallace, “The brain uses 20% of all the energy that our body generates but is only 2% to 3% of our body’s weight; therefore, subtle changes in mitochondrial energy production should have a disproportionate effect on the brain.”
Haplogroups, the ancient mtDNA variants, are genetic variants that arose thousands of years ago when humans migrated from Africa into the rest of the world. The variants altered energy metabolism in subtle ways
, allowing people to adapt and live in new environments, and have since been inherited maternally.The researchers, wanting to determine the relationship between mtDNA haplogroups and ASD, utilised data from 933 families involved in the Autism Genetic Resource Exchange, totalling 1,624 patients and 2,417 healthy parents and siblings.
They analysed single-nucleotide functional variants–base changes in the cohort’s mtDNA that characterize mitochondrial haplogroups. Haplogroups are lineages of associated mtDNA variants that reflect the ancient migration patterns of early human bands that spread out of Africa to the rest of the world during prehistory. Based on his seminal 1980 discovery that the human mtDNA is inherited only through the mother, Wallace’s surveys over the years, covering mtDNA variation among indigenous populations around the world, have permitted the reconstruction of human worldwide migrations and evolution patterns over hundreds of millennia.
Each haplogroup was compared with the most common European haplogroup, HHV. When compared with HHV, European haplogroups I, J, K, O-X, T, and U as well as Asian and Native American haplogroups A and M were associated with ASD, having odds ratios between 1.55 (95% CI, 1.16–2.06) and 2.18 (95% CI, 1.59–3) (adjusted P<0.4).
Wallace and his team also considered the gender imbalance between ASD patients. The striking tendency for ASD to occur more frequently in males than females may reflect another peculiarity of mitochondrial genetics, added Wallace. Males are four times more likely to suffer blindness from a well-known mtDNA disease, Leber hereditary optic neuropathy (LHON). The lower risk of blindness in females may arise from estrogen effects in mitochondria that increase beneficial antioxidant activity.
Wallace said that his team’s finding that subtle changes in mitochondrial energetics are important risk factors in ASD suggests potential alternative approaches for therapy. He added, “There is increasing interest in developing metabolic treatments for known mtDNA diseases such as LHON. If ASD has a similar etiology, then these same therapeutic approaches may prove beneficial for ASD.”
The team is already working on the next steps to exploring mitochondrial dysfunction as the etiology of ASD. They have made mouse lines that have subtle mtDNA mutations and defects.
“We are now screening those animals to see if they have autism-like phenotypes, and that’s ongoing work,” Wallace said. “Once we have animal models, we can then use them for screening drugs that will increase mitochondrial energy production and hopefully ameliorate the symptoms.”
