Objective: To identify the genetic cause in two sisters with spastic ataxia and to functionally characterize mitochondrial function in patient-derived cells.

Background: Spastic ataxia is a clinically and genetically highly heterogeneous disease, the genetic basis of which is largely unknown.

Methods: We performed exome sequencing in the two affected sisters and their healthy parents. Detected variants were filtered for rare, protein-changing variants shared by the sisters. The most promising candidate gene, VPS13D, has previously been linked to mitochondrial dysfunction in Drosophila. Therefore, we investigated mitochondrial morphology (form factor) and function (ATP synthesis) in patient-derived fibroblasts. The effect of the nonsense variant on VPS13D transcription was investigated by quantitative PCR, cDNA sequencing, and cycloheximide treatment in patient-derived fibroblast lines.

Results: The disease onset in both sisters was in the third decade of life. The 35-year-old sister presented with oculomotor abnormalities including saccadic pursuit and square wave jerks, appendicular and gait ataxia, spasticity and reduced deep sensory functions. Brain MRI was normal. The 29-year-old sister was wheelchair-bound due to combined spastic ataxia, and additionally presented dysarthria. Exome sequencing revealed compound-heterozygous variants in VPS13D [c.5409C>A [Tyr1803Ter] and c.12629C>T [Ala4210Val]) in both patients. Sanger sequencing of cDNA showed lower expression of the nonsense mutated allele compared to the missense mutated allele, resulting in a ~50% reduction in the total mRNA level of VPS13D in the patient compared to non-mutation carriers. This reduction was caused by nonsense mediated mRNA decay as demonstrated by cycloheximide treatment in cultured cells. Patient´s fibroblast cells showed more roundly mitochondria and disrupted mitochondrial interconnectivity in comparison to controls with elongated organelles and complex network. These structural mitochondrial changes were accompanied by a reduced ATP production rate.

Conclusions: Our study demonstrated that compound-heterozygous variants in VPS13D cause a movement disorder along the ataxia-spasticity spectrum and make VPS13D the fourth VPS13 paralog involved in neurological disorders. Analyses of patient-derived fibroblasts suggest that mutations in this new ataxia/spasticity gene impact on mitochondrial structure and function. Of note, mitochondrial dysfunction has been associated with other ataxias and spastic paraplegias.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/compound-heterozygous-mutations-in-vps13d-are-a-novel-cause-of-spastic-ataxia-and-lead-to-mitochondrial-dysfunction/