Objective: To report a rare case of young-onset Parkinson’s disease (PD) with a positive family history in which the patient was found to harbor double pathogenic variants in GBA1 and ATXN3, and to describe the detailed clinical phenotype associated with this unusual genetic coexistence

Background: Variants in GBA1 represent the most common genetic risk factor for PD, while spinocerebellar ataxia type 3 (SCA3), caused by CAG repeat expansion in ATXN3, may occasionally manifest with parkinsonism. The coexistence of a pathogenic GBA1 variant and ATXN3 repeat expansion has not been described, and the potential interaction between these two genetic risk factors remains unknown.

Method: A case report

Results: A 39-year-old woman developed leg limping and arm tremor on her left side and was diagnosed with PD. Prodromal symptoms included REM sleep behavior disorder, constipation, and hyposmia, and family history was notable for parkinsonism in her father in his seventies. Over the disease course, the patient showed a sustained response to levodopa but gradually developed motor fluctuations, dyskinesia, off-state dystonia, and freezing of gait. Non-motor features included urinary urgency, depression, visual hallucinations, and dyspnea temporally related to medication-off state. Cognitive function remained largely preserved, with MMSE 27 and MoCA 26 at age 59. Considering the young-onset PD and positive family history, genetic testing was performed, including repeat expansion testing for SCA2, SCA3, and SCA17, along with a next-generation sequencing panel for PD-related genes. Genetic analysis identified a heterozygous pathogenic GBA1 variant (c.475C>T, p.Arg159Trp) and an expanded ATXN3 allele with 55 CAG repeats consistent with SCA3. Despite the ATXN3 expansion, the clinical presentation remained dominated by a levodopa-responsive parkinsonian phenotype without prominent cerebellar ataxia.

Conclusion: In this case, lysosomal dysfunction related to glucocerebrosidase and polyglutamine-mediated proteotoxicity raises the possibility of a “double-hit” mechanism contributing to early disease onset and clinical phenotype. This case highlights the need to consider broader genetic testing in early-onset parkinsonism and suggests potential interactions between lysosomal and polyglutamine-related neurodegenerative pathways.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/young-onset-parkinsons-disease-with-coexisting-gba1-mutation-and-atxn3-repeat-expansion-a-double-hit/