Journal article
Neuropathy due to bi-allelic SH3TC2 variants: Genotype-phenotype correlation and natural history
Brain (London, England : 1878), Vol.146(9), pp.3826-3835
09/2023
DOI: 10.1093/brain/awad095
PMCID: PMC10473553
PMID: 36947133
Abstract
Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic variants and the spectrum of disease manifestations are to date lacking. Gene replacement therapy has been shown to ameliorate the phenotype in a mouse model of CMT4C, emphasizing the need for natural history studies to inform clinical trial readiness. Data, including both genetic information and clinical characteristics, were compiled from the longitudinal, prospective dataset of the Inherited Neuropathy Consortium, a member of the Rare Diseases Clinical Research Network (INC-RDCRN). The Charcot Marie Tooth Neuropathy Score (CMTNS), Examination Score (CMTES) and the Rasch-weighted CMTES (CMTES-R) were used to describe symptoms, neurologic examinations, and neurophysiologic characteristics. Standardized response means were calculated at yearly intervals and a mixed model for repeated measures was used to estimate the change in CMTES and CMTES-R over time. 56 individuals (59% female), median age 27 years (range 2-67 years) with homozygous or compound heterozygous variants in SH3TC2 were identified, including 34 unique variants, 14 of which have not previously been published. 28 participants had longitudinal data available. While there was not a significant difference in the CMTES in those with protein-truncating versus non-protein-truncating variants, there were significant differences in the mean ulnar nerve compound muscle action potential amplitude, the mean radial sensory nerve action potential amplitude, and in the prevalence of scoliosis, suggesting the possibility of a milder phenotype in individuals with one or two non-protein-truncating variants. Overall, the mean value of the CMTES was 13, reflecting moderate clinical severity. There was a high rate of scoliosis (81%), scoliosis surgery (36%), and walking difficulty (94%) among study participants. The CMTES and CMTES-R appeared moderately responsive to change over extended follow-up, demonstrating a standardized response mean of 0.81 standard deviation units or 0.71 standard deviation units respectively, over 3 years. Our analysis represents the largest cross-sectional and only longitudinal study to date, of the clinical phenotype of both adults and children with CMT4C. With the promise of upcoming genetic treatments, this data will further define the natural history of the disease and inform study design in preparation for clinical trials.
Details
- Title: Subtitle
- Neuropathy due to bi-allelic SH3TC2 variants: Genotype-phenotype correlation and natural history
- Creators
- Tyler Rehbein - University of RochesterTong Tong Wu - University of RochesterSimona Treidler - Stony Brook UniversityDavide Pareyson - Fondazione IRCCS Istituto Neurologico Carlo BestaRichard Lewis - Cedars-Sinai Medical CenterSabrina W Yum - Children's Hospital of PhiladelphiaBrett A McCray - Johns Hopkins University School of MedicineSindhu Ramchandren - The Janssen Pharmaceutical Companies of Johnson & Johnson, Titusville, NJ, USAJoshua BurnsJun Li - Houston MethodistRichard S Finkel - St. Jude Children's Research HospitalSteven S Scherer - University of PennsylvaniaStephan Zuchner - University of MiamiMichael E Shy - University of IowaMary M Reilly - National Hospital for Neurology and NeurosurgeryDavid N Herrmann - University of RochesterInherited Neuropathy Consortium-Rare Diseases Clinical Research Network (INC-RDCRN)
- Resource Type
- Journal article
- Publication Details
- Brain (London, England : 1878), Vol.146(9), pp.3826-3835
- DOI
- 10.1093/brain/awad095
- PMID
- 36947133
- PMCID
- PMC10473553
- ISSN
- 0006-8950
- eISSN
- 1460-2156
- Grant note
- name: Inherited Neuropathy Consortium, award: U54 NS065712; name: Rare Disease Clinical Research Network; name: Office of Rare Disease Research; DOI: 10.13039/100005202, name: Muscular Dystrophy Association; name: CMT association; DOI: 10.13039/100000065, name: NINDS, award: 5 T32 NS 7338-32
- Language
- English
- Electronic publication date
- 03/22/2023
- Date published
- 09/2023
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984380369802771
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