Movement disorders : official journal of the Movement Disorder Society · 2025
RAB32-Linked Parkinson's Disease: Deep Phenotyping, MDSGene Literature Review, and Application of SynNeurGe Criteria.
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Kleinz Teresa, Cavallieri Francesco, Borsche Max, Toschi Giulia, Valzania Franco, Fioravanti Valentina, Valente Enza Maria, Mitrotti Pierfrancesco, Avenali Micol, Zittel Simone, Born Rommi, Matarazzo Michele, Di Fonzo Alessio, Monfrini Edoardo, Radefeldt Mandy, Santinelli Letizia, Griebner Norman, Shambetova Cholpon, Brand Max, Gabbert Carolin, Blauwendraat Cornelis, Trinh Joanne, Lohmann Katja, Beetz Christian, Bauer Peter, Brüggemann Norbert, Global Parkinson's Genetics Program (GP2), Klein Christine
Аннотация
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.
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.