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

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 G_P ⁺ (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).

FIG. 1

Presence of motor (A) and non‐motor symptoms (B) in RAB32‐PD, reported in the literature (dark red or blue parts of the stacked bar diagram) and observed in our PARK‐RAB32 cohort (light red or blue parts of the stacked bar diagram). [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 2

Pedigrees of RAB32 families. The first family, ITA‐I, from Italy (A), comprises three brothers affected by RAB32‐PD. Otherwise, the family history is blank. Both parents died in their late 80s. Two of the brothers were examined in this study (L‐26617 and L‐26618). The second family, GER‐I, originates from Germany (B). The index patient (L‐26631) and both daughters, L‐26638 (RAB32 p.Ser71Arg carrier with subtle signs) and L‐26639 (wt), were examined. The patient's mother and cousin from the maternal side are also affected by PD. PD, Parkinson's disease; M, confirmed mutant; wt, wildtype; AAO, age at onset; y, years. [Color figure can be viewed at wileyonlinelibrary.com]

FIG. 3

Comparison of the median age at onset (and interquartile ranges) for patients with different genetic forms of Parkinson's disease (PD), adapted from Vollstedt et al. (Mov Disord). red, autosomal recessive inherited genes (PRKN, PINK1, PARK7); blue, autosomal dominantly inherited genes (LRRK2, SNCA, VPS35, RAB32); gray, GBA1. [Color figure can be viewed at wileyonlinelibrary.com]