Objective: Clinical and genetic characterization of a multigenerational family with spinocerebellar ataxia type 10 (SCA10) and parkinsonism.

Background: Pentanucleotide repeat expansions of ATTCT in intron 9 of the ATXN10 gene typically cause a distinct clinical phenotype of progressive spinocerebellar ataxia with or without seizures and present neuropathologically with Purkinje cell loss resulting in symmetrical cerebellar atrophy.

Methods: We clinically characterized several affected and unaffected family members of a large 4-generation Mexican kindred with 28 affected family members with ATXN10 expansions using standardized clinical assessment tools. Furthermore, to fully understand the genetic architecture of the ATXN10 repeat expansion, we used a novel technology combining single molecule real time (SMRT) sequencing and CRISPR/Cas9-based capture method, and sequenced the entire span of ~5.1kb-6.5kb repeat expansions as one continuous fragment.

Results: Four of the affected family members examined showed clinical features of progressive ataxia and seizures with cognitive and psychological changes including dementia. However, one affected individual presented with early-onset L-Dopa responsive parkinsonism and no signs of ataxia, and one sibling was clinically unaffected indicating reduced penetrance or delayed onset for this allele. Interestingly, no repeat interruptions were detected in the patient presenting with Parkinson’s disease and his sister with reduced or delayed penetrance. However, in the siblings with typical ataxia, we found ATXN10 repeat interruptions which have not been associated with seizures previously.

Conclusions: This is the first reported case with clinically typical L-dopa responsive parkinsonism and an ATXN10 repeat expansion. We propose that the absence of repeat interruptions is responsible for the clinical presentation of Parkinson’s disease. It will be important to understand the underlying genetic and molecular differences that lead to the changes in the neurodegenerative process in this family with different clinical and presumably neuropathological phenotypes.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/pure-atxn10-repeat-expansion-causes-parkinsons-disease/