Objective: To describe a retrospective case series of thirteen cases carriers of heterozygous variants of the ATP7B gene manifesting with specific cases of parkinsonism.

Background: Parkinsonism as a phenotype in patients with homozygous variants in the ATP7B gene corresponding to clinical Wilson’s disease has been well described. However, very few cases of parkinsonism have been reported in the heterozygous carriers of variants of the ATP7B gene. We report the clinical features of thirteen patients with heterozygous variants of unknown significance (VUS) of the ATP7B gene with clinical phenotypes of parkinsonism.

Method: We included all patients with a heterozygous ATP7B VUS and a diagnosis of parkinsonism that were evaluated at Mayo Clinic Rochester from 1998 to 2024. Clinical features, genetic testing, neuroimaging, medication trials, and responses were obtained from chart review of identified patients. All patients had genetic tests to detect single exon level deletions, additions, and pathogenic variants.

Results: Thirteen patients met the inclusion criteria. All patients exhibited clinical parkinsonism and underwent evaluation by a movement disorders neurologist, MRI imaging, and genetic testing for commonly inherited variants for parkinsonism. Of the thirteen patients, twelve showed clinically significant motor improvement to levodopa therapy. Six patients underwent serum testing for copper or ceruloplasmin and one showed abnormalities of low copper. Eleven patients were also found to have other VUS in genes known to cause parkinsonism.

Conclusion: Certain variants in the ATP7B gene contribute to the complex genetic architecture of parkinsonism possibly secondary to its role in copper metabolism, synergism from other genetic variants, and environmental influences. Genetic testing, especially in patients with young onset parkinsonism, could hold important implications for future therapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/heterozygous-atp7b-variants-in-patients-with-parkinsonism/