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Clinico‐Genetic, Imaging and Molecular Delineation of COQ8A ‐Ataxia: A Multicenter Study of 59 Patients
Author(s) -
Traschütz Andreas,
Schirinzi Tommaso,
Laugwitz Lucia,
Murray Nathan H.,
Bingman Craig A.,
Reich Selina,
Kern Jan,
Heinzmann Anna,
Vasco Gessica,
Bertini Enrico,
Zanni Ginevra,
Durr Alexandra,
Magri Stefania,
Taroni Franco,
Malandrini Alessandro,
Baets Jonathan,
Jonghe Peter,
Ridder Willem,
Bereau Matthieu,
Demuth Stephanie,
Ganos Christos,
Basak A. Nazli,
Hanagasi Hasmet,
Kurul Semra Hiz,
Bender Benjamin,
Schöls Ludger,
Grasshoff Ute,
Klopstock Thomas,
Horvath Rita,
Warrenburg Bart,
Burglen Lydie,
Rougeot Christelle,
Ewenczyk Claire,
Koenig Michel,
Santorelli Filippo M.,
Anheim Mathieu,
Munhoz Renato P.,
Haack Tobias,
Distelmaier Felix,
Pagliarini David J.,
Puccio Hélène,
Synofzik Matthis
Publication year - 2020
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.25751
Subject(s) - ataxia , missense mutation , atrophy , cohort , medicine , magnetic resonance imaging , neuroimaging , hyperintensity , dystonia , pediatrics , psychology , pathology , psychiatry , phenotype , genetics , biology , radiology , gene
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