RAB32-linked Parkinson's disease: Deep phenotyping, MDSGene literature review, and application of SynNeurGe criteria

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The discovery of the autosomal-dominant p.Ser71Arg pathogenic variant in the RAB32 gene represents a novel monogenic form of Parkinson’s disease (PD). Functionally, this variant leads to overactivation of LRRK2, a mechanism shared with another well-established monogenic PD gene, thereby linking PARK-RAB32 to a known disease-relevant molecular pathway.

Our work combines a systematic MDSGene-based literature review with deep clinical and biological phenotyping of 11 patients and one prodromal individual with PARK-RAB32, providing the most comprehensive characterization of this genetic form to date.

Across a total of 83 individuals (including 72 previously reported patients), PARK-RAB32 manifests as clinically typical parkinsonism with a good response to dopaminergic treatment. The median age at onset was 54 years (IQR 46-61), with a wide range from 31 to 82 years, while 26% of patients reported a negative family history, indicating variable expressivity and reduced penetrance.

Genetically characterized individuals shared a common founder haplotype, predominantly of (Southern) European or North African ancestry.

Within the deeply phenotyped cohort, disease severity at a median disease duration of 11 years was reflected by a mean MDS-UPDRS III score of 38.5 ± 21.8 points. Notably, this study reveals a significant burden of non-motor symptoms through targeted testing, underscoring the importance of systematic assessment. Autonomic dysfunction was present in all patients; hyposmia in 10/11; depression in 8/11; and sleep disorders in 10/11 individuals.

Cognitive impairment affected approximately one-third of all reported PARK-RAB32 patients (mean MoCA score: 23.2 points), a rate comparable to that observed in other autosomal-dominant PD genes.

Biologically, this study provides the first evidence for misfolded α-synuclein pathology in PARK-RAB32 through cerebrospinal fluid-based seed amplification assays (SAA), which were positive in 2 of 2 PD patients but negative in the prodromal individual without hyposmia. Together with abnormal DaTSCAN imaging (available for seven patients) and the presence of a pathogenic genetic variant, PARK-RAB32 can be classified according to the biological SynNeurGe criteria, as S⁺ (evidence of synucleinopathy), N⁺ (neurodegeneration based on imaging), G_P⁺ (strong genetic predisposition), and C⁺ (clinical picture consistent with PD).

Collectively, these findings highlight PARK-RAB32 as a clinically typical form of PD with a lower age at onset, underscore the importance of systematic deep phenotyping and reporting in monogenic PD, and may open the door to future LRRK2-pathway-targeted therapeutic strategies.

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