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. 2025 Oct 17.
doi: 10.1002/mds.70037. Online ahead of print.

RAB32-Linked Parkinson's Disease: Deep Phenotyping, MDSGene Literature Review, and Application of SynNeurGe Criteria

Teresa Kleinz  1   2 , Francesco Cavallieri  3 , Max Borsche  1   2 , Giulia Toschi  3 , Franco Valzania  3 , Valentina Fioravanti  3 , Enza Maria Valente  4   5 , Pierfrancesco Mitrotti  4   6 , Micol Avenali  4   6 , Simone Zittel  7 , Rommi Born  8 , Michele Matarazzo  9 , Alessio Di Fonzo  10 , Edoardo Monfrini  10 , Mandy Radefeldt  11 , Letizia Santinelli  1 , Norman Griebner  2 , Cholpon Shambetova  1 , Max Brand  1 , Carolin Gabbert  1 , Cornelis Blauwendraat  12   13 , Joanne Trinh  1 , Katja Lohmann  1 , Christian Beetz  11 , Peter Bauer  11 , Norbert Brüggemann  1   2 ; Global Parkinson's Genetics Program (GP2); Christine Klein  1   2
Affiliations

RAB32-Linked Parkinson's Disease: Deep Phenotyping, MDSGene Literature Review, and Application of SynNeurGe Criteria

Teresa Kleinz et al. Mov Disord. .

Abstract

Background: The RAB32 p.Ser71Arg variant is a novel cause of monogenic Parkinson's disease (PD), for which detailed phenotypic information is currently scarce.

Objectives: Our aim was to clinically and biologically characterize individuals with PARK-RAB32 to gain insights into genotype-phenotype relationships, disease severity, and underlying pathology.

Methods: We conducted a literature review following the MDSGene protocol, alongside detailed phenotyping of 11 PARK-RAB32 patients and one prodromal individual from the Rostock International PD (ROPAD) study. In addition to comprehensive scale-based assessments, including olfactory testing, we obtained neuroimaging data and various biomaterials, and performed α-synuclein seeding assays (SAA) in cerebrospinal fluid in a subset.

Results: 83 patients (72 from the literature) were included in the analysis. The median age at onset was 54 (IQR: 46-61) years. Typical parkinsonism with a favorable dopaminergic response was observed in all patients. In our cohort, after a median disease duration of 11 years (IQR: 7-19.5), the mean Movement Disorders Society Modified Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III score was 38.5 ± 21.8 points. Targeted testing revealed autonomic symptoms were present in all individuals, and 10 of 11 patients had hyposmia. Misfolded α-synuclein was identified in 2 of 2 patients, but not in the prodromal individual. 123I-FP-CIT imaging was available for eight patients, revealing neurodegeneration in all of them.

Conclusion: While PARK-RAB32 is clinically and likely pathologically similar to idiopathic PD, our study underscores the importance of carefully assessing non-motor symptoms in this newly described form of PD. According to SynNeurGe criteria, PARK-RAB32 is classified as S+ (evidence of synucleinopathy), N+ (neurodegeneration supported by imaging data), and GP + (presence of a genetic variant). © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; RAB32; SynNeurGe criteria; genotype–phenotype relationship; monogenic PD; seed amplification assay (SAA).

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References

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    1. Hop PJ, Lai D, Keagle PJ, et al. Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease. Nat Genet 2024;56(7):1371–1376.
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