Heterozygous VPS13A and PARK2 Mutations in a Patient with Parkinsonism and Seizures

Abstract

Neuroacanthocytosis (NA) is a diverse group of disorders in which nervous system abnormalities co-occur with irregularly shaped red blood cells called acanthocytes. Chorea-acanthocytosis is the most common of these syndromes and is an autosomal recessive disease caused by mutations in the <i>vacuolar protein sorting 13A</i> (VPS13A) gene. We report a case of early onset parkinsonism and seizures in a 43-year-old male with a family history of NA. Neurologic examinations showed cognitive impairment and marked parkinsonian signs. MRI showed bilateral basal ganglia gliosis. He was found to have a novel heterozygous mutation in the VPS13A gene, in addition a heterozygous mutation in the PARK2 gene. His clinical picture was atypical for typical chorea-acanthocytosis (ChAc). The compound heterozygous mutations of VPS13A and PARK2 provide the most plausible explanation for this patient’s clinical symptoms. This case adds to the phenotypic diversity of ChAc. More research is needed to fully understand the roles of epistatic interactions on phenotypic expression of neurodegenerative diseases.

Exome sequencing of choreoacanthocytosis reveals novel mutations in VPS13A and co-mutation in modifier gene(s)

“…Neurodegenerative conditions are multigene disorders that manifest diverse phenotypes among the affected individuals (Roberts et al 2020 ). These can be attributed to mutations that occur in several functionally overlapping genes in similar or distinct pathways (Mitchell et al 2021 ; Park and Neiman 2020 ). VPS13A is classified as a membrane trafficking protein (De et al 2017 ; Kumar et al 2018 ); hence, membrane trafficking proteins in the exome data of the cases were identified and variants in those genes were shortlisted irrespective of being in a homozygous or heterozygous state (Online Resource 3).…”

“…Presence of thorny red blood cells in the peripheral blood smear, neurodegeneration of the basal ganglia, uncontrollable hyperkinetic movements, cognitive impairment, and neuropsychiatric features are the core features of ChAc. However, additional phenotypes such as epilepsy, self-mutilation behavior, bruxism, dysarthria, dysphasia, seizure attacks, parkinsonian symptoms, and diminished or reduced tendon are also observed (Velayos Baeza et al 2019 ; Shen et al 2017 ; Mitchell et al 2021 ). Magnetic resonance imaging (MRI) shows atrophy of the striatum-caudate nuclei, putamen, globus pallidum, and substantia nigra and, occasionally, deposition of iron (Velayos Baeza et al 2019 ; Shen et al 2017 ; Niemelä et al 2020 ).…”