TY - JOUR
T1 - Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia
T2 - A Multicenter Study of 59 Patients
AU - Traschütz, Andreas
AU - Schirinzi, Tommaso
AU - Laugwitz, Lucia
AU - Murray, Nathan H.
AU - Bingman, Craig A.
AU - Reich, Selina
AU - Kern, Jan
AU - Heinzmann, Anna
AU - Vasco, Gessica
AU - Bertini, Enrico
AU - Zanni, Ginevra
AU - Durr, Alexandra
AU - Magri, Stefania
AU - Taroni, Franco
AU - Malandrini, Alessandro
AU - Baets, Jonathan
AU - de Jonghe, Peter
AU - de Ridder, Willem
AU - Bereau, Matthieu
AU - Demuth, Stephanie
AU - Ganos, Christos
AU - Basak, A. Nazli
AU - Hanagasi, Hasmet
AU - Kurul, Semra Hiz
AU - Bender, Benjamin
AU - Schöls, Ludger
AU - Grasshoff, Ute
AU - Klopstock, Thomas
AU - Horvath, Rita
AU - van de Warrenburg, Bart
AU - Burglen, Lydie
AU - Rougeot, Christelle
AU - Ewenczyk, Claire
AU - Koenig, Michel
AU - Santorelli, Filippo M.
AU - Anheim, Mathieu
AU - Munhoz, Renato P.
AU - Haack, Tobias
AU - Distelmaier, Felix
AU - Pagliarini, David J.
AU - Puccio, Hélène
AU - Synofzik, Matthis
N1 - Publisher Copyright:
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85086169325&partnerID=8YFLogxK
U2 - 10.1002/ana.25751
DO - 10.1002/ana.25751
M3 - Article
C2 - 32337771
AN - SCOPUS:85086169325
VL - 88
SP - 251
EP - 263
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 2
ER -