RESUMO
Mutations in the myelin protein zero (MPZ) gene are the third most frequent cause of hereditary motor and sensory neuropathies (HMSN), also called Charcot-Marie-Tooth disorders (CMT). Only in case of recurrent mutations occurring in the MPZ gene is it possible to draw phenotype-genotype correlations essential for establishing the prognosis and outcomes of CMT1. We have surveyed a cohort of 67 Polish patients from CMT families with demyelinating neuropathy for mutations in the MPZ gene. In this study, we report two CMT families in which the Ile135Thr and Pro132Leu mutations have been identified for the MPZ gene. These MPZ gene mutations had not been identified hitherto in the Polish population. The Pro132Leu mutation segregates with a severe early-onset dysmyelinating-hypomyelinating neuropathy, whereas the Ile135Thr substitution is associated with the classical phenotype of CMT1. To the best of our knowledge, we present here, for the first time, morphological data obtained in two sural nerve biopsies pointing to a hypomyelination-dysmyelination process in a family harboring the Pro132Leu mutation in the MPZ gene.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Mutação de Sentido Incorreto , Proteína P0 da Mielina/genética , Adolescente , Adulto , Doença de Charcot-Marie-Tooth/epidemiologia , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/epidemiologia , Humanos , Lactente , Masculino , Nervo Mediano/fisiopatologia , Proteínas da Mielina/genética , Bainha de Mielina/genética , Bainha de Mielina/patologia , Condução Nervosa/genética , Linhagem , Polônia/epidemiologia , Prevalência , Nervo Sural/patologia , Adulto JovemRESUMO
Over 40 mutations in the GDAP1 gene have been shown to segregate with Charcot-Marie-Tooth disease (CMT). Among these, only two mutations, i.e., S194X and Q163X have been reported in a sufficient number of CMT families to allow for the construction of reliable phenotype-genotype correlations. Both the S194X and Q163X mutations have been shown to segregate with an early-onset and severe neuropathy resulting in loss of ambulance at the beginning of the second decade of life. In this study, we identified the L239F mutation in the GDAP1 gene in one Bulgarian and five Polish families. We hypothesized that the L239F mutation may result from a founder effect in the European population since this mutation has previously been reported in Belgian, Czech, and Polish patients. In fact, we detected a common disease-associated haplotype within the 8q13-q21 region in the Polish, German, Italian, Czech, and Bulgarian CMT families. Like the previously detected "regional" S194X and Q163X mutations, respectively present in Maghreb countries and in patients of Spanish descent, the L239F mutation seems to be the most common GDAP1 pathogenic variant in the Central and Eastern European population. Given the likely presence of a common ancestor harboring the L239F mutation, we decided to compare the phenotypes of the CMT (L239F) patients collected in this study with those of previously reported cases. In contrast to CMT4A caused by the S194X and Q163X mutations, the CMT phenotype resulting from the L239F substitution represents a milder clinical entity with a long-preserved period of ambulance at least until the end of the second decade of life.
Assuntos
Doença de Charcot-Marie-Tooth/genética , Efeito Fundador , Proteínas do Tecido Nervoso/genética , Adolescente , Adulto , Idade de Início , Doença de Charcot-Marie-Tooth/patologia , Criança , Pré-Escolar , Cromossomos Humanos Par 8/genética , Europa (Continente) , Feminino , Estudos de Associação Genética , Loci Gênicos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Mutação , Proteínas/genética , Adulto JovemRESUMO
A case is presented of a 34-year-old man who developed weakness of the proximal muscles of the extremities, particularly lower, slight myalgia, and vegetative symptoms (dryness in the mouth). Those symptoms progressed within a month. On examination weakness of the muscles of the extremities was found as well as weak tendon reflexes, slight atrophy of muscles of the arms and thighs and apokamnosis. Edrophonium test was slightly positive. Electrostimulation revealed changes typical of the Lambert-Eaton syndrome: low amplitude of the compound muscle action potential on single stimulus, decreasing amplitude of the subsequent responses to 3 Hz stimulation, marked facilitation on 30 Hz stimulation. Neoplastic etiology was excluded by chest X-ray and CT, as well as by bronchoscopy, abdominal and prostatic USG, and thyroid USG and scintigraphy. Antibodies to AChR were not found in the serum. The titre of the antibodies against voltage-gated calcium channels was highly positive which was decisive in the diagnosing of the Lambert-Eaton syndrome. The patient was treated with pyridostigmine, corticosteroids, cyclophosphamide and immunoglobulins. Ten years of follow-up have fully confirmed the diagnosis of a non-neoplastic Lambert-Eaton syndrome.
