Recessive mutations in VPS13D cause childhood onset movement disorders

Abstract

VPS13 protein family members VPS13A through VPS13C have been associated with various recessive movement disorders. We describe the first disease association of rare recessive VPS13D variants including frameshift, missense, and partial duplication mutations with a novel complex, hyperkinetic neurological disorder. The clinical features include developmental delay, a childhood onset movement disorder (chorea, dystonia, or tremor), and progressive spastic ataxia or paraparesis. Characteristic brain magnetic resonance imaging shows basal ganglia or diffuse white matter T2 hyperintensities as seen in Leigh syndrome and choreoacanthocytosis. Muscle biopsy in 1 case showed mitochondrial aggregates and lipidosis, suggesting mitochondrial dysfunction. These findings underline the importance of the VPS13 complex in neurological diseases and a possible role in mitochondrial function. Ann Neurol 2018;83:1089-1095.

VPS13D‐related disorders presenting as a pure and complicated form of hereditary spastic paraplegia

“…To date, HSP has been reported in only one patient (Gautheir et al, ). According to earlier reports (Gautheir et al, ; Seong et al, ), 19 patients exhibited cerebellar ataxia (79%; 15/19), movement disorders (dystonia, chorea, and tremor) (37%; 7/19), cognitive impairment (42%; 8/19), and spastic paraplegia (0.5%; 1/19). Our four patients exhibited spastic paraplegia (100%; 4/4), cerebellar ataxia (25%; 1/4), movement disorders (25%; 1/4), and no cognitive impairment.…”

“…Only the CADD score, which was 22, indicated disease causing. To date, 23 mutations in the VPS13D have been described (Gautheir et al, ; Seong et al, ). Earlier studies showed 11 compound heterozygous mutations and one homozygous mutation (Gautheir et al, ; Seong et al, ).…”

Collaborative science unites researchers and a novel spastic ataxia gene

“…Separately, in this same issue, Gauthier et al report a family with 2 patients with spastic ataxia, chorea, and dystonia also harboring variants in VPS13D . Another 5 cases from 4 additional families were located at collaborative sites, also utilizing contributions from GeneMatcher . In this cohort, all patients showed early onset before age 12 years, developmental delay, intellectual disability, axial hypotonia, and chorea, eventually progressing to spastic ataxia and dystonia in adulthood .…”

“…Further complicating the phenotypic spectrum, 1 family presented with early tremor progressing to dystonia, spasticity, and mild ataxia as adults. MRI of the brains of the cohort showed T2/fluid‐attenuated inversion recovery hyperintensities either in a pattern restricted to the putamen and caudate, or more diffusely involving the white matter, reminiscent of patterns described in Leigh syndrome …”

“…VPS13D is now the final member of the VPS13 family to be associated with human neurological disease. The gene is highly intolerant to missense variation and even more so to loss of function variants . VPS13D has recently been shown to be essential for mitochondrial metabolism in Drosophila , including viability, autophagy, and clearance .…”