Journal article
Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants
Brain (London, England : 1878), Vol.146(10), pp.4336-4349
10/2023
DOI: 10.1093/brain/awad187
PMCID: PMC10545504
PMID: 37284795
Abstract
Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It is an X-linked disorder characterised by progressive sensory and motor neuropathy with males affected more severely than females. Many reported GJB1 variants remain classified as variants of uncertain significance (VUS).
In this large, international, multicentre study we prospectively collected demographic, clinical and genetic data on patients with CMT associated with GJB1 variants. Pathogenicity for each variant was defined using adapted American College of Medical Genetics criteria. Baseline and longitudinal analyses were conducted to study genotype-phenotype correlations, to calculate longitudinal change using the CMT Examination Score (CMTES), to compare males versus females, and pathogenic/likely pathogenic (P/LP) variants versus VUS.
We present 387 patients from 295 families harbouring 154 variants in GJB1. Of these, 319 patients (82.4%) were deemed to have P/LP variants, 65 had VUS (16.8%) and 3 benign variants (0.8%; excluded from analysis); an increased proportion of patients with P/LP variants compared with using ClinVar’s classification (74.6%). Male patients (166/319, 52.0%, P/LP only) were more severely affected at baseline. Baseline measures in patients with P/LP variants and VUS showed no significant differences, and regression analysis suggested the disease groups were near identical at baseline. Genotype-phenotype analysis suggested c.-17G>A produces the most severe phenotype of the five most common variants, and missense variants in the intracellular domain are less severe than other domains. Progression of disease was seen with increasing CMTES over time up to 8 years follow-up. Standard response mean (SRM), a measure of outcome responsiveness, peaked at 3 years with moderate responsiveness (change in CMTES (ΔCMTES) = 1.3 ± 2.6, p = 0.00016, SRM = 0.50). Males and females progressed similarly up to 8 years, but baseline regression analysis suggested that over a longer period, females progress more slowly. Progression was most pronounced for mild phenotypes (CMTES = 0-7; 3-year ΔCMTES = 2.3 ± 2.5, p = 0.001, SRM = 0.90).
Enhanced variant interpretation has yielded an increased proportion of GJB1 variants classified as P/LP and will aid future variant interpretation in this gene. Baseline and longitudinal analysis of this large cohort of CMTX1 patients describes the natural history of the disease including the rate of progression; CMTES showed moderate responsiveness for the whole group at 3 years and higher responsiveness for the mild group at 3, 4 and 5 years. These results have implications for patient selection for upcoming clinical trials.
Details
- Title: Subtitle
- Genetic analysis and natural history of Charcot-Marie-Tooth disease CMTX1 due to GJB1 variants
- Creators
- Christopher J Record - National Hospital for Neurology and NeurosurgeryMariola Skorupinska - National Hospital for Neurology and NeurosurgeryMatilde Laura - National Hospital for Neurology and NeurosurgeryAlexander M Rossor - National Hospital for Neurology and NeurosurgeryDavide Pareyson - Fondazione IRCCS Istituto Neurologico Carlo BestaChiara Pisciotta - Fondazione IRCCS Istituto Neurologico Carlo BestaShawna M E Feely - University of IowaThomas E Lloyd - Johns Hopkins MedicineRita Horvath - University of CambridgeReza Sadjadi - Massachusetts General HospitalDavid N Herrmann - University of RochesterJun Li - Methodist HospitalDavid Walk - University of MinnesotaSabrina W Yum - Children's Hospital of PhiladelphiaRichard A Lewis - Cedars-Sinai Medical CenterJohn Day - Stanford UniversityJoshua Burns - The University of SydneyRichard S Finkel - Nemours Children’s ClinicMario A Saporta - University of MiamiSindhu Ramchandren - Wayne State UniversityMichael D Weiss - University of WashingtonGyula Acsadi - Connecticut Children's Medical CenterVera Fridman - University of Colorado DenverFrancesco Muntoni - Great Ormond Street HospitalRoy Poh - National Hospital for Neurology and NeurosurgeryJames M Polke - National Hospital for Neurology and NeurosurgeryStephan Zuchner - University of MiamiMichael E Shy - University of IowaSteven S Scherer - University of PennsylvaniaMary M Reilly - National Hospital for Neurology and Neurosurgery
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.146(10), pp.4336-4349
- DOI
- 10.1093/brain/awad187
- PMID
- 37284795
- PMCID
- PMC10545504
- NLM abbreviation
- Brain
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- name: The Inherited Neuropathies Consortium; name: Rare Disease Clinical Research Network, award: U54NS065712; name: International Centre for Genomic Medicine in Neuromuscular Diseases; DOI: 10.13039/501100007155, name: Medical Research Council, award: MRC MR/S005021/1; DOI: 10.13039/100000065, name: National Institutes of Neurological Diseases and Stroke and office of Rare Diseases, award: 1UOINS109403-01, R21TROO3034; DOI: 10.13039/100005202, name: Muscular Dystrophy Association, award: MDA510281; DOI: 10.13039/100002721, name: Charcot Marie Tooth Association; name: National Institute for Health Research University College London Hospitals Biomedical Research Centre; name: Judy Seltzer Levenson Memorial Fund; name: CMT Research; DOI: 10.13039/100015539, name: Australian Government, award: MRFF#1152226, NHMRC#2015970, 1U01 NS109403; name: American Orthotic and Prosthetic Association; DOI: 10.13039/501100003196, name: Italian Ministry of Health; name: Leonard E. Walk Neuropathy Research and Education fund; DOI: 10.13039/100007249, name: University of Minnesota Foundation
- Language
- English
- Electronic publication date
- 06/07/2023
- Date published
- 10/2023
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984426744402771
Metrics
18 Record Views