Objective: To evaluate patients with PD and unaffected carriers of the pathogenic variant RAB32 p.Ser71Arg using a multimodal approach to gain insight into genotype-phenotype relationships and to characterize disease progression, symptom severity, penetrance, presence of α-synuclein pathology, and structural brain abnormalities.

Background: RAB32 (Ser71Arg) was recently reported as a novel monogenic cause of autosomal dominantly inherited PD[1,2]. This variant leads to overactivity of LRRK2, pathogenic variants of which cause a related form of monogenic PD. Deep clinical phenotyping has currently only been carried out in a small number of patients.

Method: We characterized a series of 11 PARK-RAB32 patients from 10 families from the Rostock International PD Study (ROPAD)[3] as part of a larger multimodal phenotyping effort, comprising clinical and scale-based (i.e., MDS-UPDRS, MoCA, UPSIT, GDS, and SCOPA-AUT) examination, structural brain MRI, and biomaterial collection, including CSF and skin biopsies. The systematic literature search utilized the MDSGene Database protocol[4].

Results: Clinical data was compiled from 74 patients with PARK-RAB32, 11 of whom underwent deep phenotyping (RAB32 cohort). The other 63 were published in 5 publications to date[1, 2, 5–7]. The median age at onset was 54 years (IQR 14), 55.4% were female, and in 64.8% of the patients, a positive family history was reported, suggesting reduced penetrance of this variant, as also confirmed in 8/10 families from the RAB32 cohort.

Classic parkinsonism [figure1A] with an overall good dopaminergic response was observed in all patients in the literature where mentioned. The mean MDS-UPDRS III was 37.6±21points with a disease duration of 12.2±7 years. Several non-motor symptoms were first reported in our deeply phenotyped patients [figure1B], where hyposmia and autonomic dysfunction were found in all patients. Structural MRI imaging was unremarkable.

Conclusion: i) The significant amount of missing clinical data even for a novel monogenic form of PD calls for systematic future reporting of phenotype-genotype relationships.

ii) The literature review and deep phenotyping of our cohort suggest PARK-RAB32 to be classical form of PD.

iii) Like PARK-LRRK2, PARK-RAB32 features reduced penetrance. In contrast to iPD, females appear to be more frequently affected with PARK-RAB32 than men.

(A) Motor symptoms in RAB32-PD

(B) Non-motor symptoms in RAB32-PD

References: [1] Gustavsson EK, Follett J, Trinh J, Barodia SK, Real R, Liu Z, Grant-Peters M, Fox JD, Appel-Cresswell S, Stoessl AJ, Rajput A, Rajput AH, et al. (2024) RAB32 Ser71Arg in autosomal dominant Parkinson’s disease: linkage, association, and functional analyses. The Lancet Neurology; 23: 603–614.
[2] Hop PJ, Lai D, Keagle PJ, Baron DM, Kenna BJ, Kooyman M, Shankaracharya, Halter C, Straniero L, Asselta R, Bonvegna S, Soto-Beasley AI, et al. (2024) Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson’s disease. Nat Genet; 56: 1371–1376.
[3] Beetz C, Radefeldt M, Tripolszki K, Kandaswamy KK, Bauer P. (2024) RAB32 mutation in Parkinson’s disease. The Lancet Neurology; 23: 961.
[4] Klein C, Hattori N, Marras C. (2018) MDSGene: Closing Data Gaps in Genotype-Phenotype Correlations of Monogenic Parkinson’s Disease. Journal of Parkinson’s Disease; 8: S25–S30.
[5] Monfrini E, Minardi R, Valzania F, Calandra-Buonaura G, Mandich P, Di Fonzo A, Carelli V, Gaudio A, Fant A, Palmieri I, Fioravanti V, Cavallieri F, et al. (2024) RAB32 mutation in Parkinson’s disease. The Lancet Neurology; 23: 961–962.
[6] Magistrelli L, Brumana M, Rimoldi V, Poggi‐Longostrevi S, Contaldi E, Pezzoli G, Straniero L, Isaias IU, Asselta R. (2024) The RAB32 p.Ser71Arg Variant in Parkinsonisms: Insights from a Large Italian Cohort. Movement Disorders; mds.30103.
[7] Cogan G, Tesson C, Brefel‐Courbon C, Lanore A, Kodjovi GC, Welment L, Clot F, Lesage S, Brice A. (2025) Confirmation of RAB32 SER71ARG Involvement in Parkinson’s Disease. Movement Disorders; 40: 174–175.

« Back to 2025 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/deep-phenotyping-of-parkinsons-disease-patients-with-the-rab32-ser71arg-pathogenic-variant-and-mdsgene-literature-review/