Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients.

OBJECTIVE: To foster trial-readiness of COQ8A-ataxia, we map the clinico-genetic, molecular and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modelling, in vitro mutation analyses, MRI markers, disease progression and CoQ10 response data. RESULTS: 59 patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modelling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs. 53%, p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14/30 patients, and by quantitative longitudinal assessments in 8/11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that >/=48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way towards large-scale natural history studies and treatment trials in COQ8A-ataxia. This article is protected by copyright. All rights reserved.