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 - Funding Information:
This study was supported via the European Union?s Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607; to M.S., A.D., M.A., P.dJ., H.H., H.P., B.v.d.W., M.K., and F.M.S.) and grant 779257 ?Solve-RD? (to M.S., B.v.d.W., and P.dJ.). B.v.d.W. receives additional research support from ZonMW, Hersenstichting, Gossweiler Foundation, and Radboud University Medical Centre. This study was supported by the German Bundesministerium f?r Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin ?mitOmics? (FKZ 01ZX1405C to T.B.H). A.T. receives funding from the University of T?bingen, Medical Faculty, for the Clinician Scientist Program Grant #439?0?0. S.M. and F.T. are funded by the Italian Ministry of Health grants GR-2016-02363337 and RF-2016-02361285, respectively. F.D. was supported by a grant of the German Research Foundation / Deutsche Forschungsgemeinschaft (DI 1731/2-2). C.G. holds a research grant from the VolkswagenStiftung (Freigeist Fellowship), and was supported by the Deutsche Forschungsgemeinschaft (DFG; GA2031/1-1 and GA2031/1-2), the German Parkinson Society and Actelion Pharmaceuticals. G.Z. was funded by the Italian Ministry of Health Ricerca Finalizzata NET-2013-02356160. The work was supported by the NIH R35GM131795 (to D.J.P.), NIH T32GM008505 and NSF DGE-1747503 (to N.H.M.). R.H. is a Wellcome Trust Investigator (109915/Z/15/Z), who receives support from the Medical Research Council (UK) (MR/N025431/1), the European Research Council (309548), the Wellcome Trust Pathfinder Scheme (201064/Z/16/Z), and the Newton Fund (UK/Turkey, MR/N027302/1). J.B. is supported by a Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO) under grant agreement number 1805016N. A.N.B. is supported by the Suna and Inan Kirac Foundation and Ko? University School of Medicine. We thank the patients and relatives for their continuous participation in this study. We are grateful to Florian Harmuth and Rebecca Buchert (University of T?bingen) as well as Tine Deconinck (University of Antwerp) for their help in gathering the genetic data of the patients, to G?l Demet Kaya and Murat G?ltekinto (Erciyes University, Kayseri) for their help in gathering clinical data, to Antje Bornemann (University of T?bingen) for her help in interpretation of muscle biopsies, to Ralf-Dieter Hilgers for statistical advice, and to Gulsah Simsir (Koc University) for the excellent technical assistance.
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.
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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 -