Journal article
Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study
Brain (London, England : 1878), Vol.143(12), pp.3589-3602
12/01/2020
DOI: 10.1093/brain/awaa323
PMCID: PMC7805791
PMID: 33415332
Abstract
Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role in mitochondrial fusion. Mutations in MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form of CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies of CMT2A have described the phenotypic spectrum of the disease, but longitudinal natural history studies are lacking. In this large multicentre prospective cohort study of 196 patients with dominant and autosomal recessive CMT2A, we present an in-depth genotype-phenotype study of the baseline characteristics of patients with CMT2A and longitudinal data (1-2 years) to describe the natural history. A childhood onset of autosomal dominant CMT2A is the most predictive marker of significant disease severity and is independent of the disease duration. When compared to adult onset autosomal dominant CMT2A, it is associated with significantly higher rates of use of ankle-foot orthoses, full-time use of wheelchair, dexterity difficulties and also has significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment. Analysis of longitudinal data using the CMTESv2 and its Rasch-weighted counterpart, CMTESv2-R, show that over 1 year, the CMTESv2 increases significantly in autosomal dominant CMT2A (mean change 0.84 ± 2.42; two-tailed paired t-test P = 0.039). Furthermore, over 2 years both the CMTESv2 (mean change 0.97 ± 1.77; two-tailed paired t-test P = 0.003) and the CMTESv2-R (mean change 1.21 ± 2.52; two-tailed paired t-test P = 0.009) increase significantly with respective standardized response means of 0.55 and 0.48. In the paediatric CMT2A population (autosomal dominant and autosomal recessive CMT2A grouped together), the CMT Pediatric Scale increases significantly both over 1 year (mean change 2.24 ± 3.09; two-tailed paired t-test P = 0.009) and over 2 years (mean change 4.00 ± 3.79; two-tailed paired t-test P = 0.031) with respective standardized response means of 0.72 and 1.06. This cross-sectional and longitudinal study of the largest CMT2A cohort reported to date provides guidance for variant interpretation, informs prognosis and also provides natural history data that will guide clinical trial design.
Details
- Title: Subtitle
- Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study
- Creators
- Menelaos Pipis - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKShawna M E Feely - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAJames M Polke - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKMariola Skorupinska - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKLaura Perez - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USARosemary R Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAMatilde Laura - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKJasper M Morrow - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKIsabella Moroni - Department of Pediatric Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyChiara Pisciotta - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyFranco Taroni - Unit of Medical Genetics and Neurogenetics, Department of Diagnostics and Technology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalyDragan Vujovic - Department of Neurology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAThomas E Lloyd - Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USAGyula Acsadi - Connecticut Children's Medical Center, Hartford, CT, USASabrina W Yum - The Children's Hospital of Philadelphia, and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USARichard A Lewis - Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USARichard S Finkel - Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN, USADavid N Herrmann - Department of Neurology, University of Rochester, Rochester, NY, USAJohn W Day - Department of Neurology, Stanford Health Care, Stanford, CA, USAJun Li - Department of Neurology, Wayne State University School of Medicine, Detroit, MI, USAMario Saporta - Department of Neurology, University of Miami Miller School of Medicine, Miami, Florida, USAReza Sadjadi - Massachusetts General Hospital, Boston, Massachusetts, USADavid Walk - Department of Neurology, University of Minnesota, Minneapolis, Minnesota, USAJoshua Burns - University of Sydney School of Health Sciences and Children's Hospital at Westmead, Sydney, AustraliaFrancesco Muntoni - Dubowitz Neuromuscular Centre, NIHR Biomedical Research Centre at UCL Great Ormond Street Institute of Child Health and Great Ormond Street Hospital, London, UKSindhu Ramchandren - PRA Health Services, Raleigh, NC, USARita Horvath - Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UKNicholas E Johnson - Virginia Commonwealth University, Richmond, VA, USAStephan Züchner - Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USADavide Pareyson - Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, ItalySteven S Scherer - Department of Neurology, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAAlexander M Rossor - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UKMichael E Shy - Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAMary M Reilly - MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.143(12), pp.3589-3602
- DOI
- 10.1093/brain/awaa323
- PMID
- 33415332
- PMCID
- PMC7805791
- NLM abbreviation
- Brain
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Publisher
- England
- Grant note
- U54 NS053672 / NINDS NIH HHS 201064/Z/16/Z / Wellcome Trust MR/N025431/2 / Medical Research Council 109915/Z/15/Z / Wellcome Trust MR/N010035/1 / Medical Research Council MR/N025431/1 / Medical Research Council G1000848 / Medical Research Council U54 NS065712 / NINDS NIH HHS KL2 TR002737 / NCATS NIH HHS
- Language
- English
- Date published
- 12/01/2020
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070010602771
Metrics
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