Objective: To describe the clinical features, family structure of two families identified to have the recently described pathogenic variant RAB32 c.213C>G (p.Ser71Arg).

Background: Genetic mutations are known to cause monogenic Parkinson’s Disease (PD) in approximately 5-10% depending on population. A novel rare variant, RAB32 c.213C>G (p.Ser71Arg), has been identified to be causative for PD with incomplete penetrance. Pathogenicity of this variant results from hyperactivation of the LRRK2 pathway in a manner similar to pathogenic gain-of-function variants in LRRK2, and VPS35 p.Asp620Asn in mice. In vitro studies demonstrate hyperactivation of the LRRK2 pathway through an elevated pRab10:Rab10.

Method: A search for participants with parkinsonism carrying the this variant in the Genomics England 100K Genomes project was performed. Data on demographics, clinical phenotype, investigations and family structure were reviewed. Blood, skin and urine samples were collected. Unaffected relatives were recruited for genotyping where possible. Activation of the LRRK2 pathway in index cases was assessed through measurement of phosphothreonine-Rab10:Rab10 in neutrophils and monocytes.

Results: Both participants were female. Participant UK1 had an age of onset of 58 years. There were three affected family members. The average age of onset in this family was 65 years. The clinical picture was of gradually progressive typical tremor-predominant PD  with mirror movements. Participant UK2 had an age of onset of 49 years. Symptom onset was with dystonic tremor of the upper limbs at 12-13 years old. She also a hereditary demyelinating neuropathy found to be due to a FIG4 variant. Her brother has also been diagnosed with early onset PD. Both participants shared the ancestral haplotype identified in other p.Ser71Arg heterozygotes.

Conclusion: The discovery of the novel RAB32 p.Ser71Arg variant explains parkinsonism in 2 UK families who were identified through exploration of the Genomics England 100K genomes project. The haplotype suggests that these participants originated from a single ancestral founder. Further individuals with this variant are likely to be identified in the future, allowing better characterisation of the clinical phenotype, and providing a clinical diagnosis for previously unsolved cases. Characterisation of non-manifesting carriers within the families is underway to estimate penetrance.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/rab32-c-213cg-p-ser71arg-explains-parkinsons-disease-in-two-uk-families-description-of-the-clinical-and-biochemical-features/