Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients

Andreas Traschütz, Tommaso Schirinzi, Lucia Laugwitz, Nathan H. Murray, Craig A. Bingman, Selina Reich, Jan Kern, Anna Heinzmann, Gessica Vasco, Enrico Bertini, Ginevra Zanni, Alexandra Durr, Stefania Magri, Franco Taroni, Alessandro Malandrini, Jonathan Baets, Peter de Jonghe, Willem de Ridder, Matthieu Bereau, Stephanie DemuthChristos Ganos, A. Nazli Basak, Hasmet Hanagasi, Semra Hiz Kurul, Benjamin Bender, Ludger Schöls, Ute Grasshoff, Thomas Klopstock, Rita Horvath, Bart van de Warrenburg, Lydie Burglen, Christelle Rougeot, Claire Ewenczyk, Michel Koenig, Filippo M. Santorelli, Mathieu Anheim, Renato P. Munhoz, Tobias Haack, Felix Distelmaier, David J. Pagliarini, Hélène Puccio, Matthis Synofzik

Research output: Contribution to journalArticlepeer-review


Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, 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 modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling 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 of 30 patients, and by quantitative longitudinal assessments in 8 of 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 toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251–263.

Original languageEnglish
Pages (from-to)251-263
Number of pages13
JournalAnnals of Neurology
Issue number2
Publication statusPublished - Aug 1 2020

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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