Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects

• Published in: Annals of neurology 2018-06, Vol.83 (6), p.1075-1088
• Main Authors: Seong, Eunju, Insolera, Ryan, Dulovic, Marija, Kamsteeg, Erik‐Jan, Trinh, Joanne, Brüggemann, Norbert, Sandford, Erin, Li, Sheng, Ozel, Ayse Bilge, Li, Jun Z., Jewett, Tamison, Kievit, Anneke J. A., Münchau, Alexander, Shakkottai, Vikram, Klein, Christine, Collins, Catherine A., Lohmann, Katja, Warrenburg, Bart P., Burmeister, Margit
• Format: Article
• Language: English
• Subjects: Adult; Ataxia; Axons; Cerebellar Ataxia - genetics; Chromosome 1; Disorders; Drosophila; Female; Fibroblasts; Genetic Linkage; Humans; Insects; Intellectual Disability - genetics; International cooperation; Male; Middle Aged; Missense mutation; Mitochondria; Mitochondria - genetics; Mitochondrial DNA; Morphology; Movement disorders; Muscle Spasticity - genetics; Mutation; Mutation - genetics; Neurological diseases; Optic Atrophy - genetics; Paralysis; Patients; Pedigree; Proteins - genetics; Sequences; Spastic paraplegia; Spastic Paraplegia, Hereditary - genetics; Spasticity; Spinocerebellar ataxia; Spinocerebellar Ataxias - genetics
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.25220

Objective To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia. Methods In an international collaboration, we independently performed exome sequencing in 7 families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knockout model and investigated mitochondrial function in patient‐derived fibroblast cultures. Results Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all 7 families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4 (SCAR4). Linkage to chromosome 1p36 was found in this family with a logarithm of odds score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but 2 patients carried a loss‐of‐function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knockdown or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production. Interpretation Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia–spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. Ann Neurol 2018