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.
RAB32-Linked Parkinson's Disease: Deep Phenotyping, MDSGene Literature Review, and Application of SynNeurGe Criteria
Valente E. M.;Mitrotti P.;Avenali M.;
2025-01-01
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
