Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.
Adolescent
Adult
Aged
Cerebellar Ataxia
/ diagnostic imaging
Child
Child, Preschool
Cohort Studies
Cross-Sectional Studies
Female
Genetic Variation
/ genetics
Humans
Magnetic Resonance Imaging
/ methods
Male
Middle Aged
Mutation
/ genetics
Protein Structure, Secondary
Ubiquinone
/ chemistry
Young Adult
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
11
11
2019
revised:
16
04
2020
accepted:
17
04
2020
pubmed:
28
4
2020
medline:
15
12
2020
entrez:
28
4
2020
Statut:
ppublish
Résumé
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). 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. 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%. 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.
Identifiants
pubmed: 32337771
doi: 10.1002/ana.25751
pmc: PMC7877690
mid: NIHMS1646232
doi:
Substances chimiques
Ubiquinone
1339-63-5
ubiquinone 8
CQA993F7P8
Types de publication
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
251-263Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM131795
Pays : United States
Organisme : Wellcome Trust
ID : 201064/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N010035/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1000848
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N025431/2
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N025431/1
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : T32 GM008505
Pays : United States
Informations de copyright
© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.
Références
Orphanet J Rare Dis. 2013 Oct 28;8:173
pubmed: 24164873
Brain. 2016 Jul;139(Pt 7):e39
pubmed: 27095078
Brain. 2009 Oct;132(Pt 10):2688-98
pubmed: 19696032
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Mov Disord Clin Pract. 2018 Oct 09;5(6):635-639
pubmed: 30637285
Brain. 2011 Sep;134(Pt 9):2677-86
pubmed: 21788663
Lancet Neurol. 2016 Dec;15(13):1346-1354
pubmed: 27839651
Eur J Neurol. 2016 Jul;23(7):1188-94
pubmed: 27106809
Cerebellum. 2019 Jun;18(3):665-669
pubmed: 30847826
Lancet. 2015 May 2;385(9979):1748-1757
pubmed: 25907158
Mol Cell. 2016 Aug 18;63(4):608-620
pubmed: 27499294
Am J Hum Genet. 2008 Mar;82(3):661-72
pubmed: 18319074
J Neurol Neurosurg Psychiatry. 2012 Feb;83(2):174-8
pubmed: 22036850
Free Radic Biol Med. 2003 Mar 1;34(5):563-75
pubmed: 12614845
Mov Disord. 2018 Jul;33(7):1056-1076
pubmed: 29756227
Cell Chem Biol. 2018 Feb 15;25(2):154-165.e11
pubmed: 29198567
Nat Protoc. 2016 Jan;11(1):1-9
pubmed: 26633127
Free Radic Res. 2006 May;40(5):445-53
pubmed: 16551570
Neurol Res Pract. 2019 Aug 23;1:31
pubmed: 33324897
Mol Cell. 2015 Jan 8;57(1):83-94
pubmed: 25498144
Lancet Neurol. 2015 Nov;14(11):1101-8
pubmed: 26377379
Neurology. 2018 Oct 2;91(14):e1307-e1311
pubmed: 30158165
Neurology. 2006 Jun 13;66(11):1717-20
pubmed: 16769946
J Med Genet. 2015 Nov;52(11):779-83
pubmed: 26084283
Ann Neurol. 2016 Apr;79(4):646-58
pubmed: 26856398
Nat Protoc. 2007;2(9):2212-21
pubmed: 17853878
Brain. 2016 Feb;139(Pt 2):346-54
pubmed: 26626369
Neurol Genet. 2018 Oct 24;4(6):e279
pubmed: 30533525
J Neurol. 2018 Jul;265(7):1618-1624
pubmed: 29737427
Am J Hum Genet. 2008 Mar;82(3):623-30
pubmed: 18319072
J Neurol. 2016 Jul;263(7):1314-22
pubmed: 27142713
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8892-7
pubmed: 9671775
EMBO Mol Med. 2015 Mar 23;7(5):670-87
pubmed: 25802402
Behav Res Methods. 2007 May;39(2):175-91
pubmed: 17695343
Neuron. 2019 Feb 20;101(4):560-583
pubmed: 30790538
Nat Genet. 2014 Mar;46(3):310-5
pubmed: 24487276
Trends Biochem Sci. 2017 Oct;42(10):824-843
pubmed: 28927698
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
J Med Genet. 2012 Mar;49(3):187-91
pubmed: 22368301
Bioinformatics. 2015 May 15;31(10):1536-43
pubmed: 25583119
Parkinsonism Relat Disord. 2019 Nov;68:8-16
pubmed: 31621627