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

Abstract

Background Alterations of vacuolar protein sorting‐associated protein 13 (VPS13) family members including VPS13A, VPS13B, and VPS13C lead to chorea acanthocytosis, Cohen syndrome, and parkinsonism, respectively. Recently, VPS13D mutations were identified as a cause of VPS13D‐related movement disorders, which show several phenotypes including chorea, dystonia, spastic ataxia, and spastic paraplegia. Methods We applied whole‐exome analysis for a patient with a complicated form of hereditary spastic paraplegia (HSP) and her unaffected parents. Then, we screened the candidate genes in 664 Japanese families with HSP in Japan. Results We first found a compound heterozygote VPS13D mutation and a heterozygote ABHD4 variation in a sporadic patient with spastic paraplegia. Then, we found three patients with VPS13D mutations in two Japanese HSP families. The three patients with homozygous mutations (p.Thr1118Met/p.Thr1118Met and p.Thr2945Ala/p.Thr2945Ala) in the VPS13D showed an adult onset pure form of HSP. Meanwhile, the patient with a compound heterozygous mutation (p.Ser405Arg/p.Arg3141Ter) in the VPS13D showed a childhood onset complicated form of HSP associated with cerebellar ataxia, cervical dystonia, cataracts, and chorioretinal dystrophy. Conclusion In the present study, we found four patients in three Japanese families with novel VPS13D mutations, which may broaden the clinical and genetic findings for VPS13D‐related disorders.

Mitochondrial fission, integrity and completion of mitophagy require separable functions of Vps13D inDrosophilaneurons

“…In 2018 our collaborators and others identified VPS13D as a cause of familial ataxia (Seong et al 2018), developmental movement disorders (Seong et al 2018;Gauthier et al 2018) and spastic paraplegia (Koh et al 2020). We found that Vps13D depleted neurons accumulate severely enlarged mitochondria which fail to be trafficked to distal axons (Seong et al 2018).…”

“…In conclusion, we have shown that Vps13D is essential for two processes that are critical to general mitochondrial health: mitochondrial fission and mitophagy ( Figure 6A). This knowledge now establishes a framework for future work to determine whether patient mutations in VPS13D differentially affect one or both of these processes, which should lead to a better understanding of disease pathogenesis in patients with mutations in this gene (Seong et al 2018;Gauthier et al 2018;Koh et al 2020).…”

“…However, scenarios that both induce mitochondrial damage and impair clearance lead to strong lethality. Impairments in Vps13D function can lead to dual defects in damage and defective clearance, providing an attractive explanation for the accelerated neurological pathophysiology associated with patients harboring mutations in this gene (Seong et al 2018;Gauthier et al 2018;Koh et al 2020).…”

Challenges and Controversies in the Genetic Diagnosis of Hereditary Spastic Paraplegia

“…Mutations in SACS cause autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a disorder characterised by the triad of cerebellar ataxia, peripheral neuropathy, and spasticity; however not all features of the triad may be present and there is a phenotypic overlap with the AR HSP with a thin corpus callosum (AR-HSP-TCC) [ 29 ]. VPS13D mutations cause a recessive ataxia-spasticity spectrum movement disorder [ 30 ] but have also been reported to cause a pure or complicated form of HSP (Table 1 ) [ 31 ]. Additionally, HSP-like phenotypes can also be caused by expansions in triplet-repeat ataxia loci [ 32 ] and thus, may not be detected on a sequencing panel.…”

Flavonoids as Potential Drugs for VPS13-Dependent Rare Neurodegenerative Diseases

“…ChAc is caused by mutations in VPS13A gene [ 6 , 7 ], one of the four VPS13 homologs present in the human genome [ 8 ]; about 90% of these cause a lack of the VPS13A (or chorein) protein [ 9 ]. Mutations in other VPS13 ( B – D ) genes have also been linked to different diseases with neurological defects [ 10 , 11 , 12 , 13 , 14 ]. Currently, there is no cure for VPS13 -associated diseases, only symptomatic treatment is offered.…”