Objective:

To describe a case of cerebellar ataxia due to a pathogenic variant in RAB3A and the importance of earlier comprehensive genetic testing. 

Background:

Hereditary cerebellar ataxias are phenotypically diverse with a growing number of associated genes. Recently, variants in the RAB3A gene causing a loss-of-function of the Rab3a protein, important for intracellular trafficking of neurotransmitters, were found to be associated with autosomal dominant cerebellar ataxia with mean age of onset at 25 years, and epilepsy, spasticity, tremors, and neurodevelopmental disorders. To our knowledge, less than 20 individuals with this mutation have been described worldwide.

Design/Methods:

N/A

Results:

A 35-year-old female developed bilateral arm tremors and gait imbalance around age 20 years. She later had slow, halting speech, occasional dysphagia, worsened gait requiring occasional use of a cane, and progressive tremors. There was no relevant family history, except her son had concentration issues in early childhood.  Pertinent exam findings included normal tone, moderate intention tremors in bilateral arms, hypermetric saccades, end gaze downbeat nystagmus, 2+ brisk reflexes throughout, dysmetria in upper and lower extremities, wide-based gait with irregular stride, unsteady turning and inability to stand or walk in tandem. MRI brain showed vermian and superior cerebellar atrophy. Initial genetic panel testing was unrevealing. Ultimately, whole exome sequencing noted a variant (of uncertain significance) in the RAB3A gene (c.247C>T; p.R83W). Five months later, with review of published reports, this variant was reclassified as pathogenic.

Conclusions:

Mutations in RAB3A should be considered as a potential etiology of progressive tremors, cerebellar ataxia, and/or spastic paraparesis in young adults. This case highlights the importance of routine re-consideration of variants of uncertain significance in undiagnosed individuals. Furthermore, we illustrate the necessity and potential cost-effectiveness of pursuing whole exome or genome sequencing sooner in individuals without clear family history.