Ataxia and Azoospermia Caused by an MT-ATP6 Mutation with Apparent Anticipation due to Heteroplasmy in a Large Extended Kindred
David Zhu1, Changrui Xiao2, Jon Pryor3, Sally Frutiger4, Brent Clark5, Hannah Casey1, Matthew Bower5, Guoyun Yu6, Xiaofei Du1, Camilo Toro7, Christopher Gomez1
1Department of Neurology, University of Chicago, 2Department of Neurology, UC Irvine, 3Department of Urology, 4Department of Neurology, 5Department of Lab Medicine and Pathology, University of Minnesota, 6National Human Genome Research Institute, 7NIH
Objective:

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.

Background:
Mutations in mitochondrial-encoded genes, particularly MT-ATP6, have been implicated in neurodegenerative disorders, including certain forms of progressive ataxia. In addition to allelic variation, repeat expansion instability, and modifier genes, variations in heteroplasmy may also be related to phenotypic variability in cerebellar ataxias.
Design/Methods:
We analyzed mitochondrial DNA samples from 48 members of a five-generation kindred exhibiting features of progressive ataxia and cognitive impairment, for which testing for repeat expansions associated with the SCAs was negative. Genotyping was compared alongside cognitive profiles, fertility evaluations, and clinical data.
Results:

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.

Conclusions:

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.

10.1212/WNL.0000000000215179
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