This study aimed to investigate whether heteroplasmy in the MT-ATP6 gene is associated with the age of onset and clinical features of ataxia in an affected family.

The variant m.9035 T>C in MT-ATP6 was detected in all affected individuals. Specifically, the age of onset of ataxia, ranging from early childhood to the 8th decade, was inversely correlated with heteroplasmy levels. We also identified two additional clinical features associated with the mtDNA mutation: male infertility (azoospermia) and decreased intellectual ability in individuals with ataxia. Male infertility appeared to segregate with the mitochondrial mutation. Detailed neuropsychological evaluations demonstrated mild intellectual disability to low average range intellectual ability for those with onset of ataxia before 40 years of age. Cognitive and motor function in the ataxia group inversely correlated with heteroplasmy percentages.

In summary, this study expands the known phenotype of MT-ATP6-related diseases. We report a large multigenerational family with a constellation of neurologic, cognitive, and reproductive phenotypes due to a known pathogenic mtDNA variant in MT-ATP6 (m.9035T>C). Notably, we also observed an apparent association between the MT-ATP6 m.9035T>C variant and male infertility. It remains to be determined whether the male infertility is specific to the m.9035T>C variant or might be observed more broadly across other pathogenic MT-ATP6 mutations.