Andreas Traschütz1,2, Tommaso Schirinzi3,4, Lucia Laugwitz5,6, Nathan H Murray7,8, Craig A Bingman7,8, Selina Reich1,2, Jan Kern6, Anna Heinzmann9,10, Gessica Vasco3, Enrico Bertini11, Ginevra Zanni11, Alexandra Durr9,10, Stefania Magri12, Franco Taroni12, Alessandro Malandrini13, Jonathan Baets14,15,16, Peter de Jonghe14,15,16, Willem de Ridder14,15,16, Matthieu Bereau17,18, Stephanie Demuth19, Christos Ganos20, A Nazli Basak21, Hasmet Hanagasi22, Semra Hiz Kurul23, Benjamin Bender24, Ludger Schöls1,2, Ute Grasshoff5, Thomas Klopstock25,26,27, Rita Horvath28,29, Bart van de Warrenburg30, Lydie Burglen31,32,33, Christelle Rougeot31,34, Claire Ewenczyk9,10,35, Michel Koenig36, Filippo M Santorelli37, Mathieu Anheim38,39,40, Renato P Munhoz41, Tobias Haack5, Felix Distelmaier42, David J Pagliarini7,8, Hélène Puccio43,44,45,46, Matthis Synofzik1,2. 1. Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany. 2. German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany. 3. Neurorehabilitation Unit, Department of Neurosciences, IRCCS Bambino Gesù Children Hospital, Rome, Italy. 4. Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy. 5. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 6. Department of Pediatric Neurology, University Children's Hospital, Tübingen, Germany. 7. Morgridge Institute for Research, Madison, WI, USA. 8. Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA. 9. Brain and Spine Institute (ICM), Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France. 10. AP-HP, Department of Genetics, Pitié-Salpêtrière University Hospital, Paris, France. 11. Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. 12. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 13. Department of Medicine, Surgery, and Neurosciences, University of Siena, Unit of Neurology and Neurometabolic Disorders, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 14. Neurogenetics Group, University of Antwerp, Antwerp, Belgium. 15. Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 16. Department of Neurology, Antwerp University Hospital, Antwerp, Belgium. 17. Service de Neurologie, Université de Franche-Comté, CHRU de Besançon, Besançon, France. 18. Unité Extrapyramidale, Département des Neurosciences Cliniques, HUG, Faculté de Médecine, Université de Genève, Geneva, Switzerland. 19. Praxis für Humangenetik Erfurt, Erfurt, Germany. 20. Department of Neurology, Charité University Medicine Berlin, Berlin, Germany. 21. Suna and Inan Kıraç Foundation, Neurodegeneration Research Laboratory, KUTTAM, Koç University School of Medicine, Istanbul, Turkey. 22. Behavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. 23. Departments of Pediatric Neurology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey. 24. Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany. 25. Department of Neurology, Friedrich-Baur-Institute, Ludwig-Maximilians University of Munich, Munich, Germany. 26. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. 27. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. 28. Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. 29. Institute of Genetic Medicine, Newcastle University, Newcastle, UK. 30. Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands. 31. Centre de Référence Maladies Rares "Malformations et Maladies Congénitales du Cervelet", Paris-Lyon-Lille, France. 32. Département de Génétique et Embryologie Médicale, APHP, GHUEP, Hôpital Armand Trousseau, Paris, France. 33. Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France. 34. Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Bron, France. 35. Hôpitaux universitaires Pitié Salpêtrière - Charles Foix, Service de Génétique, Paris, France. 36. EA7402 Institut Universitaire de Recherche Clinique, and Laboratoire de Génétique Moléculaire, CHU and Université de Montpellier, Montpellier, France. 37. IRCCS Fondazione Stella Maris, Pisa, Italy. 38. Service de Neurologie, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France. 39. Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France. 40. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), INSERM-U964/CNRS-UMR7104/Université de Strasbourg, Illkirch, France. 41. Movement Disorders Centre, Toronto Western Hospital, University of Toronto, Krembil Research Institute, Toronto, Ontario, Canada. 42. Department of General Pediatrics, Neonatology, and Pediatric Cardiology, University Children's Hospital Duesseldorf, Medical Faculty, Heinrich Heine University, Duesseldorf, Germany. 43. Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France. 44. INSERM, U1258, Illkirch, France. 45. CNRS, UMR7104, IIllkirch, France. 46. Université de Strasbourg, Strasbourg, France.
Abstract
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.
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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