CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis

Abstract

BackgroundThe international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them.MethodsWe analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES).Results997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported.ConclusionsOur findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT.Clinical trial registrationID number NCT01193075.

Target-enrichment sequencing and copy number evaluation in inherited polyneuropathy

“…[5][6][7][8] One large prospective study indicated that as many as 42% of patients with previously undiagnosed polyneuropathy coming to tertiary care referral had familial occurrence.…”

Charcot Marie Tooth disease type 4J with complex central nervous system features

“…Charcot Marie Tooth disease type 4J (CMT4J) is a rare inherited peripheral neuropathy, affecting 0.24% of people with CMT,1 caused by biallelic disease causing variants in the FIG4 gene. CMT4J may present either as an early and severe, or a late onset and more slowly progressive disease.…”

PMP22 exon 4 deletion causes ER retention of PMP22 and a gain‐of‐function allele in CMT1E

“…Roughly half of these patients have CMT1A,2 a demyelinating neuropathy caused by a 1.4‐Mb duplication in chromosome 17p12 that contains the peripheral myelin protein 22 gene, PMP22 , an integral membrane protein expressed in PNS compact myelin 3, 4. CMT1A is hypothesized to occur as a result of nonallelic homologous recombination (NAHR)5, 6, 7 in a region of 17p12 surrounding and including the PMP22 gene, causing increased expression of the normal gene product.…”

“…Mutations within the PMP22 gene are classified as CMT1E 2. Most CMT1E mutations are missense mutations probably resulting in a gain‐of‐new protein function 8.…”