# The Diverse Neuromuscular Spectrum of VPS13A Disease

## TL;DR

This study explores the neuromuscular symptoms of VPS13A disease, revealing a wider range of severity than previously recognized.

## Contribution

The study highlights the underrecognized neuromuscular spectrum in VPS13A disease and identifies a novel copy-neutral inversion variant.

## Key findings

- Neuromuscular signs in VPS13A disease range from hyporeflexia to severe muscle wasting.
- Electromyography showed chronic neurogenic changes in all patients.
- Muscle MRI revealed fatty atrophy, particularly in the calves.

## Abstract

VPS13A disease (chorea‐acanthocytosis) is a rare neurodegenerative disorder caused by biallelic variants in VPS13A, typically presenting with hyperkinetic movement disorders, while neuromuscular signs are often mild. The aim of the project was to investigate the frequency and severity of neuromuscular impairment in VPS13A disease.

We systematically assessed the neuromuscular involvement in six patients with VPS13A disease. Our evaluation included genetic and clinical data, blood tests, electrophysiological studies, muscle MRI, and tissue samples from muscle and nerve.

Age at clinical onset was 14 to 38 years (median: 37.5). Age at onset of paresis was 27 to 29 years (median: 29). Initial symptoms included seizures (5/6), hyperkinesia (2/6), and muscle weakness (1/6). Neuromuscular signs ranged from hyporeflexia (5/6) to progressive muscle wasting (3/6). Nine VPS13A variants were detected, including a novel copy‐neutral inversion. Phosphocreatine kinase was elevated in all cases (498–12,420 U/L; median of highest values: 2230 U/L). Nerve conduction studies revealed sensorimotor axonal neuropathy. Electromyography showed chronic neurogenic changes with high amplitudes, polyphasic potentials, and reduced interference patterns (6/6). Muscle MRI displayed fatty atrophy, most prominently in the calves (5/5). Muscle histology indicated neurogenic and myopathic changes. Electron microscopy of mitochondria and respiratory chain analysis showed no specific pathological findings.

Our findings emphasize the underrecognized neuromuscular spectrum in VPS13A disease, ranging from subclinical signs to severe paresis and sometimes preceding the hyperkinesia that gave rise to the historical term of chorea‐acanthocytosis. A comprehensive understanding of the phenotype is crucial for early diagnosis and appropriate management of VPS13A disease.