Abstract
BackgroundVPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission. Recently, VPS13D biallelic pathogenic variants have been reported in patients displaying variable neurological phenotypes, with an autosomic recessive inheritance.The objectives of the study were to determine the genetic etiology of a patient with early onset sporadic progressive spastic ataxia, and to investigate the pathogenicity of VPS13D variants through functional studies on patient’s skin fibroblasts.Case presentationWe report the case of a 51-year-old patient with spastic ataxia, with an acute onset of the disease at age 7. Walking difficulties slowly worsened over time, with the use of a wheelchair since age 26. We have used trio-based whole-exome sequencing (WES) to identify genes associated with spastic ataxia. The impact of the identified variants on mitochondrial function was assessed in patient’s fibroblasts by imaging mitochondrial network and measuring level of individual OXPHOS complex subunits. Compound heterozygous variants were identified in VPS13D: c.946C > T, p.Arg316* and c.12416C > T, p.(Ala4139Val). Primary fibroblasts obtained from this patient revealed an altered mitochondrial morphology, and a decrease in levels of proteins from complex I, III and IV.ConclusionsOur findings confirmed implication of VPS13D in spastic ataxia and provided further support for mitochondrial defects in patient’s skin fibroblasts with VPS13D variants. This report of long-term follow up showed a slowly progressive course of the spastic paraplegia with cerebellar features. Furthermore, the performed functional studies could be used as biomarker helping diagnosis of VPS13D-related neurological disorders when molecular results are uneasy to interpret.
Highlights
VPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission
VPS13D pathogenic variants have been successively reported in patients displaying variable neurological phenotypes generally dominated by movement disorders including chorea, dystonia, tremor, ataxia, spastic paraplegia, spastic ataxia and seizures with highly variable age at onset [8,9,10,11,12]
We confirmed that spastic ataxia may be related to VPS13D pathogenic variants and we showed abnormal mitochondrial morphology and reduced mitochondrial Oxidative phosphorylation (OXPHOS) complexes in skin fibroblasts suggesting altered mitochondrial function
Summary
VPS13D is a large ubiquitin-binding protein playing an essential role in mitophagy by regulating mitochondrial fission. The objectives of the study were to determine the genetic etiology of a patient with early onset sporadic progressive spastic ataxia, and to investigate the pathogenicity of VPS13D variants through functional studies on patient’s skin fibroblasts. Vps13D is localized at different membrane contact sites and may regulate mitochondria_endoplasmic reticulum contacts, as well as peroxisome biogenesis [4,5,6,7] This localization could be largely determined by competition between specific protein adaptors, all of them binding to VAB (VPS13 adaptor binding domain) [6]. VPS13D pathogenic variants have been successively reported in patients displaying variable neurological phenotypes generally dominated by movement disorders including chorea, dystonia, tremor, ataxia, spastic paraplegia, spastic ataxia and seizures with highly variable age at onset [8,9,10,11,12]. Progressive spastic ataxia constitutes a genetically heterogeneous group of disorders characterized by simultaneous cerebellar ataxia and limb spasticity, possibly associated with other severe neurological complications [13].
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