Objective: To describe clinical and demographic features of Parkinson’s Disease (PD) patients, found to be carriers of heterozygous pathogenic/likely pathogenic ATP7B variants.

Background: Biallelic ATP7B pathogenic mutations are classically associated with Wilson disease; however, emerging evidence suggests that heterozygous ATP7B variants may be implicated in parkinsonian phenotypes, potentially via copper dysregulation and related mechanisms (including altered ceruloplasmin biology and copper‑linked neurotoxicity). The contribution of such variants to Parkinson’s disease remains poorly understood (1–3).

Method: We report a case series of six patients clinically diagnosed with idiopathic Parkinson’s disease who underwent genetic testing through the PDGeneration study, and were found to carry heterozygous pathogenic/likely pathogenic ATP7B mutations.

Results: The ATP7B-positive cohort comprised four women and two men; four were Japanese and two White. Age at onset ranged 56–79 years; disease duration 1–12 years. Three reported a family history of PD. All met clinical PD criteria with typical motor features and levodopa responsiveness. None fulfilled clinical criteria for Wilson disease. Variants included recurrent intronic c.1543+40G>A (n=4), a missense p.Ala1018Val (n=1), and a frameshift p.Met769Hisfs26* (n=1). Interestingly, the c.1543+40G>A variant was found in all four Japanese patients only. The c.1543+40G>A variant has functional evidence of splicing impact in ATP7B, supporting pathogenicity in Wilson disease, though penetrance for overt WD is variable (4–6).

Conclusion: Our series adds to accumulating observations that heterozygous ATP7B variants can co‑occur with PD and may act as susceptibility factors rather than monogenic causes. Prior literature includes early‑onset PD in ATP7B heterozygotes with biochemical copper disturbances and functional modeling of deleterious substitutions(1,7), small series/abstracts describing levodopa‑responsive parkinsonism in ATP7B carriers, and imaging evidence that heterozygotes can show basal ganglia hyperechogenicity suggestive of copper effects(8). Larger, ancestry‑diverse studies integrating deep ATP7B sequencing (including noncoding regions), copper biomarkers, and dopaminergic imaging are needed to test whether ATP7B heterozygosity modifies PD risk or phenotype and to clarify mechanisms linking copper homeostasis to nigrostriatal degeneration.

References: 1. Ilyechova EY, Miliukhina IV, Karpenko MN, et al. Case of Early-Onset Parkinson’s Disease in a Heterozygous Mutation Carrier of the ATP7B Gene. J Pers Med 2019;9(3):41. https://doi.org/10.3390/jpm9030041
2. Karpenko MN, Muruzheva ZM, Ilyechova EY, Babich PS, Puchkova LV. Abnormalities in Copper Status Associated with an Elevated Risk of Parkinson’s Phenotype Development. Antioxidants (Basel) 2023;12(9):1654. https://doi.org/10.3390/antiox12091654
3. Zhang H, Nagai J, Hao L, Jiang X. Identification of Key Genes and Immunological Features Associated with Copper Metabolism in Parkinson’s Disease by Bioinformatics Analysis. Mol Neurobiol 2024;61(2):799–811. https://doi.org/10.1007/s12035-023-03565-8
4. Wallace DF, Dooley JS. ATP7B variant penetrance explains differences between genetic and clinical prevalence estimates for Wilson disease. Hum Genet 2020;139(8):1065–1075. https://doi.org/10.1007/s00439-020-02161-3
5. Xu W-Q, Wang R-M, Dong Y, Wu Z-Y. Pathogenicity of Intronic and Synonymous Variants of ATP7B in Wilson Disease. J Mol Diagn 2023;25(1):57–67. https://doi.org/10.1016/j.jmoldx.2022.10.002
6. Huang C, Fang M, Xiao X, et al. Genetic studies discover novel coding and non‐coding mutations in patients with Wilson’s disease in China. Clinical Laboratory Analysis 2022;36(6):e24459. https://doi.org/10.1002/jcla.24459
7. Johnson S. Is Parkinson’s disease the heterozygote form of Wilson’s disease: PD = 1/2 WD? Med Hypotheses 2001;56(2):171–173. https://doi.org/10.1054/mehy.2000.1134
8. Skowronska M, Litwin T, Kurkowska-Jastrzębska I, Członkowska A. Transcranial sonography changes in heterozygotic carriers of the ATP7B gene. Neurol Sci 2020;41(9):2605–2612. https://doi.org/10.1007/s10072-020-04378-6

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MDS Abstracts - https://www.mdsabstracts.org/abstract/detection-of-heterozygous-atp7b-variants-in-hawaiis-parkinsons-disease-cohort-a-case-series-of-six-patients/