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

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

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 database 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 (74 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, the mean MDS-UPDRS III score was 38.5±21.8 points. Autonomic symptoms were present in all individuals, and 10/11 patients had hyposmia. Several non-motor symptoms were reported for the first time in PARK- RAB32 . Misfolded α-synuclein was identified in 2/2 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 _F ⁺ (presence of a genetic variant).