Abstract

Objective
To quantify key disease milestones, particularly loss of ambulation and survival, and to describe the VPS13A variant spectrum and clinical heterogeneity in patients with chorea-acanthocytosis (ChA).
Methods
We conducted a cross-sectional study of 34 ChA patients from 24 unrelated families. Whole-exome sequencing identified VPS13A variants in all probands. Clinical and paraclinical data were collected through neurological evaluations and electronic medical records. Patients were classified as either surviving (ambulatory or non-ambulatory) or deceased.
Results
Twenty-one VPS13A variants were identified, including 12 novel variants. Median current age and disease duration were 38.5 (IQR, 34-43) and 8 (IQR, 4-12.25) years, respectively. Loss of ambulation occurred in 26.5% of patients after a median of 10 years (range, 5-16) from onset. Kaplan–Meier analysis estimated a median time to loss of ambulation of 16.0 years (95% CI, 8.8-23.2), with estimated ambulation probabilities of 87% at 6 years and 38% at 16 years. Seven patients died after a median disease duration of 10 years (range, 3-17). The median survival time was not reached during follow-up; the estimated restricted mean survival time was 16.7 years (95% CI, 14.1-19.3). Compulsions co-occurred with obsessions in all cases and were associated with higher rates of suicidal ideation, while insomnia was more frequent in patients without compulsions. Suicide and sepsis were the leading causes of death.
Conclusions
This study defines the natural history of ChA, providing prognostic data on ambulation and survival. The discovery of novel VPS13A variants highlights genetic heterogeneity and supports further investigation into disease mechanisms and therapeutic targets.

• Keywords: Chorea-acanthocytosis (ChA); VPS13A gene; Whole-exome sequencing (WES); Genetic heterogeneity; Disease course and survival