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

Ann Neurol. 2020 Apr 26. doi: 10.1002/ana.25751. [Epub ahead of print]

Authors/Editors: Traschütz A, Schirinzi T, Laugwitz L, Murray NH, Bingman CA, Reich S, Kern J, Heinzmann A, Vasco G, Bertini E, Zanni G, Durr A, Magri S, Taroni F, Malandrini A, Baets J, de Jonghe P, de Ridder W, Bereau M, Demuth S, Ganos C, Basak AN, Hanagasi H, Kurul SH, Bender B, Schöls L, Grasshoff U, Klopstock T, Horvath R, van de Warrenburg B, Burglen L, Rougeot C, Ewenczyk C, Koenig M, Santorelli FM, Anheim M, Munhoz RP, Haack T, Distelmaier F, Pagliarini DJ, Puccio H, Synofzik M.
Publication Date: 2020



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.

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