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

Abstract

Background: Vacuolar 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.

Objective: The goal of this study was to characterize neuropathological findings in the brains of seven patients with VPS13A disease (chorea-acanthocytosis).

Methods: In 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.

Results: Gross 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.

Conclusions: We 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.

Keywords: VPS13A; chorea-acanthocytosis; lipid; neuroacanthocytosis; neuropathology.

FIG. 1

Gross neuropathology and microscopic degenerative findings of VPS13A disease (chorea-acanthocytosis). (A) Coronal hemi-brain section (right) at the level of the amygdala (case 3) showing marked atrophy of the caudate nucleus and putamen with ventricular dilatation. (B) Section at the level of the lateral geniculate shows an unremarkable hippocampal formation with no dilatation of the temporal horn of the lateral ventricle. (C) Higher power image of the striatum highlighting atrophy of the caudate with discoloration and atrophy of the putamen with prominent perivascular spaces. Scale bar, 2 cm (A, B), 0.5 cm (C). (D) Luxol fast blue counterstained hematoxylin & eosin (LH&E) stained sections show neuronal loss of the striatum with (E, F) fibrotic astroglial scarring. (G) Immunohistochemistry staining for glial fibrillary acidic protein (GFAP) highlights astroglial proliferation. (H, I) Rare vacuolated neurons were observed in the substantia nigra. (J, K) Neurons in the putamen (case 5) showed concentric perineuronal mineralization. (L, M) This case also displayed frequent cortical neurons exhibiting perineuronal mineralization. (N) Neuron showing a perivascular calcospherite pattern. (O) Non-neuronal mineralization in the white matter. 10x magnification for D-K; 20x magnification (L-O).

FIG. 2

Immunohistochemistry (IHC) of autophagy and ubiquitin-proteasome protein accumulation in VPS13A disease (chorea-acanthocytosis). Sections show rare p62-positive cytoplasmic structures with variable morphologies, including (A) cytoplasmic staining in the caudate (case 2), (B) granular cytoplasmic staining in the putamen (case 3), and (C) a p62-positive (α-synuclein negative) “Lewy body-like” inclusion in the hippocampus (case 7). Ubiquitin (Ubi) immunopositive structures are seen in the neurons, neuropil, and other cells of the (D) caudate, (E) putamen, and (F) hippocampus. Case 1 displayed mild α-synuclein-positive Lewy bodies in the substantia nigra (G). Case 5 had α-synuclein positivity in a rare ballooned neuron (H) and rare perivascular positivity in the pons (I).

FIG. 3

Examples of lipid accumulation morphologies in VPS13A disease (chorea-acanthocytosis) and transmission electron microscopy. Sections stained with Luxol fast blue (LFB) showed variable patterns of granular lipid accumulation in the striatum (A, B), and amygdala (C). We also observed compact cytoplasmic accumulations shown in the striatum (D) and parietal cortex (E), as well as more diffuse patterns here shown in the amygdala (F). 40x magnification for all images. Images illustrate robust accumulation of electron dense coarse granular material within neurons in the (G) dorsolateral prefrontal cortex and (H) putamen of case 3. Scale bar 50 mm.