389 research outputs found
Mutations in noncoding regions of GJB1 are a major cause of X-linked CMT
OBJECTIVE: To determine the prevalence and clinical and genetic characteristics of patients with X-linked Charcot-Marie-Tooth disease (CMT) due to mutations in noncoding regions of the gap junction β-1 gene (GJB1).
METHODS: Mutations were identified by bidirectional Sanger sequence analysis of the 595 bases of the upstream promoter region, and 25 bases of the 3Ⲡuntranslated region (UTR) sequence in patients in whom mutations in the coding region had been excluded. Clinical and neurophysiologic data were retrospectively collected.
RESULTS: Five mutations were detected in 25 individuals from 10 kindreds representing 11.4% of all cases of CMTX1 diagnosed in our neurogenetics laboratory between 1996 and 2016. Four pathogenic mutations, c.-17G>A, c.-17+1G>T, c.-103C>T, and c.-146-90_146-89insT were detected in the 5â˛UTR. A novel mutation, c.*15C>T, was detected in the 3ⲠUTR of GJB1 in 2 unrelated families with CMTX1 and is the first pathogenic mutation in the 3â˛UTR of any myelin-associated CMT gene. Mutations segregated with the phenotype, were at sites predicted to be pathogenic, and were not present in the normal population.
CONCLUSIONS: Mutations in noncoding DNA are a major cause of CMTX1 and highlight the importance of mutations in noncoding DNA in human disease. Next-generation sequencing platforms for use in inherited neuropathy should therefore include coverage of these regions
Reliability of the Charcot-Marie-Tooth functional outcome measure
The CMTâFOM is a 13âitem clinical outcome assessment (COA) that measures physical ability in adults with CharcotâMarieâTooth disease (CMT). Testâretest reliability, internal consistency and convergent validity have been established for the CMTâFOM. This current study sought to establish interârater reliability. Following an inâperson training of six international clinical evaluators we recruited 10 participants with genetically diagnosed CMT1A, (aged 18â74âyears, 6 female). Participants were evaluated using the CMTâFOM over 2âdays. Participants were given at least a 3 hour rest between evaluations, and were assessed twice each day. Following the provision of training by master trainers, all 13 items of the CMTâFOM exhibited excellent interârater reliability for raw scores (ICC1,1 0.825â0.989) and zâscores (ICC1,1 0.762â0.969). Reliability of the CMTâFOM total score was excellent (ICC1,1 0.983, 95% CI 0.958â0.995). The CMTâFOM is a reliable COA used by clinical evaluators internationally. The next steps are to establish further validation through psychometric evaluation of the CMTâFOM in the Accelerate Clinical Trials in CMT (ACTâCMT) study
Axonal swellings predict the degeneration of epidermal nerve fibers in painful neuropathies
Objective: To correlate the density of swellings in intraepidermal nerve fibers (IENF) with the longitudinal measurement of the epidermal innervation density in patients with painful neuropathy and to assess the predictive value of IENF swelling to progression of neuropathy. Methods: Fifteen patients with persistent pain in the feet underwent neurologic examination, nerve conduction studies, quantitative sensory examination, and skin biopsies at proximal thigh and distal leg. In all patients and in 15 healthy subjects, IENF density and swelling ratio (no. swellings/no. IENF) were quantified at distal leg. Follow-up study, including IENF density and swelling ratio quantification, was performed a mean of 19.2 months later. Double staining confocal microscope studies using anti-human protein-gene-product 9.5, anti-tubule, anti-neurofilament, and anti-synaptophysin antibodies were performed to assess specific accumulation within swellings. Ultrastructural investigation of IENF was also carried out. Results: Patients with neuropathy had lower density of IENF and higher swelling ratio than healthy subjects (p<0.01) at distal leg. At follow-up, patients showed a parallel decrease in both IENF density (p=0.02) and swelling ratio (p=0.002). However, swelling ratio remained higher (p=0.03) than in controls. Progression of neuropathy was confirmed by the decay in sural nerve sensory nerve action potential amplitude. Double immunostaining studies suggest accumulation of tubules and ubiquitin-associated proteins within swellings. Swollen and vacuolated IENF were identified in patients with neuropathy by conventional and immuno-electron microscopy. Conclusions: Increased swelling ratio predicted the decrease in IENF density in patients with painful neuropathy. Its quantification could support earlier diagnosis of sensory axonopathy
Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation
Mutations in the gene coding for the Schwann cell transcription factor early growth response 2 (EGR2), which seems to regulate myelinogenesis and hindbrain development, have been observed in few cases of inherited neuropathy. The authors describe a unique combination of cranial nerve deficits in one member of a Charcot-Marie-Tooth 1 family carrying an EGR2 mutation (Arg381His). This finding further supports the role of EGR2 in cranial nerve development
A slowly progressive mitochondrial encephalomyopathy widens the spectrum of AIFM1 disorders
To date, 3 AIFM1 (apoptosis inducing factor mitochondrial 1, located on Xq26.1) mutations have been reported: 2 missense changes (c.923G>A/p.Gly308Glu; c.1478A>T/p.Glu493Val) and a 3-basepair deletion (c.601delAGA/p.Arg201del). Two mutations have been described in early-onset severe mitochondrial encephalomyopathy related to impaired oxidative phosphorylation.(1,2) A third mutation is associated with Cowchock syndrome, or Charcot-Marie-Tooth X4 (CMTX4), a slowly progressive disorder characterized by axonal neuropathy, hearing loss, and mental retardation.(3,4</SUP
Cross-sectional analysis of a large cohort with X-linked Charcot-Marie-Tooth disease (CMTX1)
OBJECTIVE: To extend the phenotypic description of Charcot-Marie-Tooth disease (CMTX1) and to draw new genotype-phenotype relationships. METHODS: Mutations in GJB1 cause the main X-linked form of CMTX (CMTX1). We report cross-sectional data from 160 patients (from 120 different families, with 89 different mutations) seen at the Inherited Neuropathies Consortium centers. RESULTS: We evaluated 87 males who had a mean age of 41 years (range 10-78 years) and 73 females who had a mean age of 46 years (range 15-84 years). Sensory-motor polyneuropathy affects both sexes, more severely in males than in females, and there was a strong correlation between age and disease burden in males but not in females. Compared with females, males had more severe reduction in motor and sensory neurophysiology parameters. In contrast to females, the radial nerve sensory response in older males tended to be more severely affected compared with younger males. Median and ulnar nerve motor amplitudes were also more severely affected in older males, whereas ulnar nerve motor potentials tended to be more affected in older females. Conversely, there were no statistical differences between the sexes in other features of the disease, such as problems with balance and hand dexterity. CONCLUSIONS: In the absence of a phenotypic correlation with specific GJB1 mutations, sex-specific distinctions and clinically relevant attributes need to be incorporated into the measurements for clinical trials in people with CMTX1. CLINICALTRIALSGOV IDENTIFIER: NCT01193075
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