Objective: To report two adult-onset cases of slowly progressive Parkinson’s disease (PD) carrying a heterozygous pathogenic ATP13A2 variant.

Background: ATP13A2 (PARK9) encodes a P-type ATPase predominantly localized to late endosomes and lysosomes [1,2]. Biallelic ATP13A2 mutations cause Kufor-Rakeb syndrome, a rapidly progressive juvenile parkinsonism characterized by spasticity and cognitive decline [1]. However, the role of heterozygous variants in adult-onset parkinsonism remains unclear.

Method: We report the clinical features (assessed using MDS-UPDRS), genetic testing, neuroimaging, and treatment responses of two siblings carrying the same heterozygous pathogenic ATP13A2 deletion (c.3057del, p.Tyr1020Thrfs*3).

Results: These cases suggest that heterozygous pathogenic ATP13A2 variants may contribute to slowly progressive, levodopa-responsive PD, beyond their established role in biallelic Kufor-Rakeb syndrome. In vitro studies have shown mitochondrial dysfunction and zinc dyshomeostasis in cells from carriers, whereas ATP13A2-related lysosomal impairment has been associated with enhanced alpha-synuclein aggregation. Multiple clinical studies have also reported sporadic PD cases harboring heterozygous ATP13A2 mutations.Both patients initially exhibited slowly progressive cognitive and behavioral changes and essential tremor, followed several years later by mild-to-moderate parkinsonian motor symptoms. DaTscan imaging was abnormal in both patients, supporting the clinical diagnosis of PD. They showed a suboptimal response to immediate-release carbidopa/levodopa but an excellent response to combined extended- and immediate-release formulations.

Conclusion: This case report suggests heterozygous pathogenic ATP13A2 variants may increase susceptibility to PD, beyond their established role in biallelic Kufor-Rakeb syndrome. In vitro studies have shown mitochondrial dysfunction and zinc dyshomeostasis in fibroblasts from carriers, and ATP13A2-related lysosomal impairment has been associated with enhanced alpha-synuclein aggregation. Furthermore, multiple clinical studies have also reported sporadic PD cases harboring heterozygous ATP13A2 mutations.

[Abstract presented at the 2026 AAN Annual Meeting, Chicago, March 22]

References: [1] Park JS, Koentjoro B, Klein C, Sue CM. Single Heterozygous ATP13A2 Mutations Cause Cellular Dysfunction Associated with Parkinson’s Disease. Mov Disord. 2018 May;33(5):852-854. doi: 10.1002/mds.27327.
[2] Fujii T, Nagamori S, Wiriyasermkul P, Zheng S, Yago A, Shimizu T, Tabuchi Y, Okumura T, Fujii T, Takeshima H, Sakai H. Parkinson’s disease-associated ATP13A2/PARK9 functions as a lysosomal H+,K+-ATPase. Nat Commun. 2023 Apr 20;14(1):2174. doi: 10.1038/s41467-023-37815-z.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/adult-onset-incomplete-kufor-rakeb-syndrome-presenting-with-parkinsonism-a-case-report/