ABSTRACT
BACKGROUND AND PURPOSE: Charcot-Marie-Tooth disease (CMT) type 1A (CMT1A) is the demyelinating form of CMT that is significantly associated with PMP22 duplication. Some studies have found that the disease-related disabilities of these patients are correlated with their compound muscle action potentials (CMAPs), while others have suggested that they are related to the nerve conduction velocities. In the present study, we investigated the correlations between the disease-related disabilities and the electrophysiological values in a large cohort of Korean CMT1A patients. METHODS: We analyzed 167 CMT1A patients of Korean origin with PMP22 duplication using clinical and electrophysiological assessments, including the CMT neuropathy score and the functional disability scale. RESULTS: Clinical motor disabilities were significantly correlated with the CMAPs but not the motor nerve conduction velocities (MNCVs). Moreover, the observed sensory impairments matched the corresponding reductions in the sensory nerve action potentials (SNAPs) but not with slowing of the sensory nerve conduction velocities (SNCVs). In addition, CMAPs were strongly correlated with the disease duration but not with the age at onset. The terminal latency index did not differ between CMT1A patients and healthy controls. CONCLUSIONS: In CMT1A patients, disease-related disabilities such as muscle wasting and sensory impairment were strongly correlated with CMAPs and SNAPs but not with the MNCVs or SNCVs. Therefore, we suggest that the clinical disabilities of CMT patients are determined by the extent of axonal dysfunction.
Subject(s)
Humans , Action Potentials , Axons , Charcot-Marie-Tooth Disease , Cohort Studies , Muscles , Neural ConductionABSTRACT
Antecedentes: El gen PMP22 se encuentra duplicado en pacientes con Charcot-Marie-Tooth 1A (CMT1A); se ha descrito que el origen de la duplicación es el intercambio desigual de las cromátidas durante la meiosis entre dos regiones de 24 kb denominadas sitios REPCMT1A, encontrándose un REP proximal y un REP distal, los cuales tienen una homología de 98%. Dentro de cada uno de estos sitios existen zonas denominadas puntos calientes de mutación (hot spot), donde se presenta el mayor número de variantes y mutaciones que pudieran dar origen al intercambio desigual. El objetivo de este trabajo fue diseñar un conjunto de microsondas para elaborar un microarreglo con el cual pueda detectarse la presencia de variantes y puntos de mutación en los sitios REP-proximal y REP-distal CMT1A. Material y métodos A partir de las secuencias informadas de los REP distal y proximal, se delimitaron los sitios hot spot dentro de las regiones proximal y distal. Estas secuencias se alinearon, se empalmaron y se detectaron 12 zonas de diferencia secuencial. Resultados y conclusiones. Se diseñaron y analizaron 24 microsondas mediante el programa Genosensor Probe Designer. Las sondas podrán ser sintetizadas y utilizadas en un microarreglo que permita encontrar variaciones, puntos de mutación, y facilitar el diagnóstico de pacientes con CMT1A.
BACKGROUND: Gene PMP22 is duplicated in patients with CMT1A. Duplication is due to an unequal chromatid interchange during meiosis that takes place between two 24 Kb regions named REP-CMT1A proximal and distal sites. Homology is approximately 98%. Within each one of the sites we find zones termed hot spots where a greater number of variants and mutations could give origin to an unequal interchange. The aim of this study was to design a set of probes to create a microarray that could detect the presence of variants and mutation points in distal and proximal REP sites among patients with CMT1A. MATERIAL AND METHODS: With reported sequences of distal and proximal REPs, we determined hot spot sites within proximal and distal regions. These sequences were aligned and matched, hence 12 zones were detected. RESULTS AND CONCLUSIONS: Twenty four probes were designed and analyzed using the Genosensor Probe Designer program. Probes could be synthesized and used in a microarray that is able to find variations and mutation points and facilitates diagnosis of patients with CMT1A.
Subject(s)
Humans , Oligonucleotide Array Sequence Analysis/methods , Charcot-Marie-Tooth Disease/genetics , Myelin Proteins/genetics , Proteins/geneticsABSTRACT
Charcot-Marie-Tooth disease (CMT) with hearing impairment is a clinically distinct rare entity described in a few families, usually with a demyelinating neuropathy. The molecular basis for this disease has not been established with certainty. Audiological evaluation has revealed auditory neuropathy in the affected individual. We report a CMT1A family with sensorineural hearing loss and a novel frame shift mutation Ala106fs (318delT) in the PMP22 gene.
Subject(s)
Humans , Charcot-Marie-Tooth Disease , Deafness , Frameshift Mutation , Hearing Loss , Hearing Loss, SensorineuralABSTRACT
BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant inherited demyelinating peripheral neuropathy characterized by progressive distal muscular atrophy and marked slowing of nerve conduction velocities. A 1.5 Mb DNA duplication within chromosome 17p11.2-p12 has been reported. This disease appears to be caused by an altered copy number of the PMP-22 gene within the critical region. METHODS: DNA analysis was carried out for 158 persons from 40 unrelated families. PCR was done by D17S122 and D17S261. The DNA of the patients was ana-lyzed to detect three alleles for the presence of duplication. RESULTS: CMT1A duplication was found in 7 families (64%) of the patients with CMT1 by D17S122, but not by D17S261. CONCLUSIONS: We have found seven families of Charcot-Marie-Tooth disease type 1A with chromosome 17p11.2-p12 duplication by D17S122. We recommend the screening test by D17S122 for the detection of CMT1A in Korean because genetic analysis done by D17S261 was not informative.
Subject(s)
Humans , Alleles , Charcot-Marie-Tooth Disease , DNA , Mass Screening , Molecular Biology , Muscular Atrophy , Neural Conduction , Peripheral Nervous System Diseases , Polymerase Chain ReactionABSTRACT
BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant inherited demyelinating peripheral neuropathy characterized by progressive distal muscular atrophy and marked slowing of nerve conduction velocities. A 1.5 Mb DNA duplication within chromosome 17p11.2-p12 has been reported. This disease appears to be caused by an altered copy number of the PMP-22 gene within the critical region. METHODS: DNA analysis was carried out for 158 persons from 40 unrelated families. PCR was done by D17S122 and D17S261. The DNA of the patients was ana-lyzed to detect three alleles for the presence of duplication. RESULTS: CMT1A duplication was found in 7 families (64%) of the patients with CMT1 by D17S122, but not by D17S261. CONCLUSIONS: We have found seven families of Charcot-Marie-Tooth disease type 1A with chromosome 17p11.2-p12 duplication by D17S122. We recommend the screening test by D17S122 for the detection of CMT1A in Korean because genetic analysis done by D17S261 was not informative.