VPS13A – Chorea-acanthocytosis

Chorea-acanthocytosis (ChAc) is a rare, adult-onset, autosomal recessive neurodegenerative disorder characterized by hyperkinetic movements, orofacial dyskinesia, seizures and the presence of acanthocytes on peripheral blood smears. The disease is caused by biallelic loss-of-function variants in VPS13A, encoding chorein, and presents with neuropsychiatric changes, cognitive decline, and progressive motor disability. Diagnosis requires genetic testing or chorein protein assays, as phenotypic overlap with Huntington disease and atypical motor neuron disease can delay recognition.

Genetic evidence for VPS13A–ChAc includes a mutational spectrum of 57 distinct variants identified in 43 unrelated probands, predominantly nonsense, frameshift and splice-site changes predicted to abolish chorein expression (PMID:12404112). Segregation of a novel homozygous truncating variant c.4326T>A (p.Tyr1442Ter) in three affected siblings confirmed autosomal recessive inheritance, with two additional relatives carrying the variant in a consanguineous Turkish pedigree (PMID:30687222). Over 20 case reports describe compound heterozygous and founder mutations across diverse populations, including a Moroccan nonsense founder p.Gln113Ter and a French–Canadian 37 kb deletion of exons 70–73.

Functional studies demonstrate that chorein interacts with β-adducin and β-actin in erythrocyte membranes and in HEK293 cells, implicating disrupted membrane cytoskeletal dynamics in pathogenesis (PMID:24129186). Brain-specific VPS13A transcript variants identified in a gene-targeted mouse model further support tissue-restricted vulnerability in ChAc (PMID:17196930). An autopsy series of seven genetically and biochemically confirmed cases revealed severe caudate and putamen atrophy with neuronal loss, astrogliosis, variable lipid accumulation and occasional calcifications, mirroring clinical MRI findings of striatal degeneration (PMID:37670483).

No conflicting reports challenge the association between VPS13A and ChAc. Experimental and clinical data consistently support a mechanism of chorein haploinsufficiency leading to impaired lipid transfer at organellar contact sites and cytoskeletal disorganization, resulting in neurodegeneration and acanthocytosis. Additional deep brain stimulation case studies indicate that pallidal GPi-DBS can ameliorate hyperkinetic movements and dysarthria in ChAc.

Key take-home: VPS13A loss-of-function variants cause chorea-acanthocytosis via autosomal recessive inheritance, with high clinical validity (Strong) and concordant functional evidence (Moderate), justifying genetic testing for definitive diagnosis and guiding symptomatic therapies including GPi-DBS.

References

• European Journal of Human Genetics • 2002 • Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis PMID:12404112
• Frontiers in Neurology • 2018 • Chorea-Acanthocytosis Presenting as Autosomal Recessive Epilepsy in a Family With a Novel VPS13A Mutation PMID:30687222
• Biochemical and Biophysical Research Communications • 2013 • Chorein, the protein responsible for chorea-acanthocytosis, interacts with β-adducin and β-actin PMID:24129186
• Biochemical and Biophysical Research Communications • 2007 • Brain-specific transcript variants of 5' and 3' ends of mouse VPS13A and VPS13C PMID:17196930
• Movement Disorders • 2023 • An Autopsy Series of Seven Cases of VPS13A Disease (Chorea-Acanthocytosis) PMID:37670483

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