RESUMEN
Charcot-Marie-Tooth (CMT) type-1 (CMT1) neuropathy is characterized by peripheral nerve demyelination and has been divided into several subtypes. The most frequent among these, subtype 1A, is related to a microduplication of the region p11.2 of chromosome 17. This region contains the PMP-22 gene which is involved in peripheral nerve myelination. Since motor nerve conduction velocity (MNCV) is closely related to nerve myelination, we compared type-1A patient MNCVs versus non-A CMT1 patient MNCVs, in 57 CMT1A patients and 21 non-A type-1 patients. Patients with the 17p11.2 duplication have MNCVs that are significantly more reduced (about 20 m/s) compared to patients without the 17p11.2 duplication (about 30 m/s). This study also permits a model of the MNCV in the median nerve (MedMNCV) of CMT1 patients, with age, gender and molecular status as parameters. Furthermore, in order to help clinicians to diagnose subtypes of CMT1 patients, the probability for type 1A is modeled as a function of MedMNCV only.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/fisiopatología , Nervio Mediano/fisiopatología , Conducción Nerviosa/fisiología , Adolescente , Adulto , Distribución por Edad , Niño , Preescolar , Cromosomas Humanos Par 17 , ADN/análisis , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
We report studies on two patients (a mother and her daughter) presenting with a Charcot-Marie-Tooth type 1 (CMT1) phenotype: low nerve conduction velocities of 13-15 m/s and an early onset at the age of walking. DNA analysis of the gene coding for the major peripheral myelin protein PO showed a new point mutation in exon 2, which resulted in substitution of a phenylalanine for serine at amino acid position 63 of PO. This is the third mutation reported at this codon, the two previously described leading to CMT1B (serine 63 deletion), or to Dejerine-Sottas disease (cysteine for serine 63 substitution), suggesting that different phenotypes can result from alteration of a single amino acid, depending on the type of the change involved.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteína P0 de la Mielina/genética , Proteínas de la Mielina/genética , Adulto , Secuencia de Bases , Cartilla de ADN , Heterogeneidad Genética , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Nervios Periféricos , Mutación Puntual , SerinaRESUMEN
We performed DNA analysis in four families with hereditary neuropathy with liability to pressure palsy (HNPP). An interstitial deletion of the 17 p11.2 region was found in typically affected patients as well as in as yet asymptomatic patients. The opportunity for an individual genotyping permitted to ascertain a de novo deletion in one clinically affected case with no relevant familial history. DNA analysis thus becomes the most sensitive tool in diagnosing HNPP, since potentially affected patients may lack either informative familial history, or clinical symptoms or even suggestive EMG or histopathological data (tomaculas).
Asunto(s)
ADN/análisis , Neuropatía Hereditaria Motora y Sensorial/genética , Adolescente , Adulto , Alelos , Deleción Cromosómica , Femenino , Genotipo , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Nervio Mediano/fisiopatología , Persona de Mediana Edad , Mutagénesis , Nervio Peroneo/fisiopatología , Mutación Puntual , Nervio Tibial/fisiopatología , Nervio Cubital/fisiopatologíaRESUMEN
Charcot-Marie-Tooth type 1 (CMT1) disease is an autosomal dominant neuropathy of the peripheral nerve. The majority of CMT 1 cases are due to a duplication of an 1.5-Mb DNA fragment on chromosome 17p11.2 (CMT 1a). Micromutations were found in the gene for peripheral myelin protein 22 (PMP22) located in the duplicated region of CMT 1a, and in the peripheral myelin protein zero (PO) located on chromosome 1q21-q23 (CMT 1b). We have characterized two new mutations in the PO gene in two french families presenting CMT disease. Both mutations occur in the extracellular domain of the PO protein. One mutation is a de novo mutation and is from paternal origin.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Proteína P0 de la Mielina/genética , Mutación Puntual/genética , Secuencia de Bases , Análisis Mutacional de ADN , Humanos , Datos de Secuencia Molecular , Polimorfismo Conformacional Retorcido-SimpleAsunto(s)
Enfermedad de Charcot-Marie-Tooth/genética , Cromosomas Humanos Par 1 , Proteínas de la Mielina/genética , Polimorfismo de Longitud del Fragmento de Restricción , Desoxirribonucleasas de Localización Especificada Tipo II , Genes Dominantes , Humanos , Masculino , Proteína P0 de la Mielina , LinajeRESUMEN
Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant peripheral neuropathy which is characterized by recurrent episodes of truncular palsies. We have analyzed the D17S122 locus in 7 French families, including 18 affected members, with microsatellite RM11GT and the RFLP probe VAW409R3a. Only one allele could be detected in all affected individuals with the highly polymorphic RM11GT marker. Allele segregation at D17S122 showed no contribution from the affected parent to the affected child, demonstrating that an interstitial deletion within the 17p11.2 region is associated with HNPP in the 7 families studied. This same region is duplicated, however, in another inherited neuropathy, Charcot-Marie-Tooth 1A disease. This would be the first example of two dominantly inherited diseases caused by a 'in mirror image' deletion/duplication mechanism where a gene dosage effect would be sufficient to produce two different phenotypes characterized by abnormal myelination of the peripheral nerves. The RM11GT microsatellite is an informative tool for the molecular diagnosis of HNPP.