An Autopsy Series of Seven Cases of VPS13A Disease (Chorea‐Acanthocytosis)

Abstract

AbstractBackgroundVacuolar protein sorting 13 homolog A (VPS13A) disease, historically known as chorea‐acanthocytosis, is a rare neurodegenerative disorder caused by biallelic mutations in VPS13A, usually resulting in reduced or absent levels of its protein product, VPS13A. VPS13A localizes to contact sites between subcellular organelles, consistent with its recently identified role in lipid transfer between membranes. Mutations are associated with neuronal loss in the striatum, most prominently in the caudate nucleus, and associated marked astrogliosis. There are no other known disease‐specific cellular changes (eg, protein aggregation), but autopsy reports to date have been limited, often lacking genetic or biochemical diagnostic confirmation.ObjectiveThe goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea‐acanthocytosis).MethodsIn this study, we collected brain tissues and clinical data from seven cases of VPS13A for neuropathological analysis. The clinical diagnosis was confirmed by the presence of VPS13A mutations and/or immunoblot showing the loss or reduction of VPS13A protein. Tissues underwent routine, special, and immunohistochemical staining focused on neurodegeneration. Electron microscopy was performed in one case.ResultsGross examination showed severe striatal atrophy. Microscopically, there was neuronal loss and astrogliosis in affected regions. Luxol fast blue staining showed variable lipid accumulation with diverse morphology, which was further characterized by electron microscopy. In some cases, rare degenerating p62‐ and ubiquitin‐positive cells were present in affected regions. Calcifications were present in four cases, being extensive in one.ConclusionsWe present the largest autopsy series of biochemically and genetically confirmed VPS13A disease and identify novel histopathological findings implicating abnormal lipid accumulation. © 2023 International Parkinson and Movement Disorder Society.