Disferlinopatias: heterogeneidade clínica, genética e prognóstico funcional em quinze doentes

Abstract

Introdução: As disferlinopatias são doenças musculares de transmissão autossómica recessiva provocadas por mutações no gene da disferlina (DYSF). Os fenótipos mais comuns são a Miopatia de Myoshi (MM) e a Distrofia Muscular das Cinturas 2B (DMC 2B).Objectivos: Descrever as características clínicas, laboratoriais, moleculares e a evolução clínica de quinze doentes com disferlinopatia.Metodologia: Registaram-se dados demográficos, clínicos, laboratoriais e moleculares de quinze doentes com diagnóstico de disferlinopatia. Foi avaliada a marcha, existência de sintomatologia cardiorrespiratória e resultados de electrocardiograma, provas de função respiratória e radiografia torácica.Resultados: Quinze doentes (oito do género masculino), com idade média actual de 47+/-16 anos. A idade média dos primeiros sintomas foi 24+/-14 anos e o tempo médio até ao diagnóstico molecular de 12+/-12 anos. Na observação inicial, o fenótipo DMC 2B observou-se em oito doentes, o de MM em três, hipercreatinémia (hiperCK) isolada em dois, proximodistal num doente e Miopatia Distal do Compartimento Anterior (MDCA) noutro doente. Atualmente, oito doentes apresentam generalização da fraqueza muscular (um DMC 2B e sete proximodistais) e sete doentes mantêm o fenótipo inicial (quatro DMC 2B, um hiperCK, um MDCA, um proximodistal). No momento do diagnóstico, todos os doentes tinham marcha autónoma, sendo que nove perderam capacidade de marcha e três fazem atualmente marcha com apoio (tempo médio até perda de marcha autónoma de 17+/-9 anos). Sete doentes referiram dispneia e/ou ortopneia. 18% das radiografias torácicas apresentaram aumento do índice cardiotorácico (ICT) e foram encontradas anomalias em 50% das provas de função respiratória (PFR) e 54% dos electrocardiogramas (ECG). Valores séricos de creatina quinase (CK) estavam elevados em todos os doentes. Observaram-se treze mutações diferentes no gene DYSF, dez em homozigotia e cinco em heterozigotiaConclusões: O reconhecimento da heterogeneidade fenotípica e molecular e da evolução clínica das disferlinopatias evidenciada nesta série poderá contribuir para o diagnóstico mais precoce e dirigido desta doença.

Introduction: Dysferlinopathies are a group of autosomal recessive muscular dystrophies caused by mutations in the dysferlin gene (DYSF). Dysferlin deficiency leads to several phenotypes, with Myoshi Myopathy (MM) and Limb Girdle Muscular Dystrohy 2B (LGMD 2B) being the most common ones. Aim: Describe the clinical, laboratorial and molecular findings of fifteen patients with muscle disease caused by pathogenic mutations in the DYSF gene, as well as the progression of the disease. Methods: A total of fifteen patients with molecular confirmed dysferlinopathy were clinical and laboratory assessed. The initial and actual pattern of muscle weakness, the gait, the rate of progression and distribution of the muscle weakness, the presence of cardiorespiratory symptoms and the results of electrocardiogram, thoracic radiography and respiratory function were evaluated. Results: Fifteen patients (eight males) with a mean age at the present evaluation of 47±16 years old. The mean age of onset of the disease was 24±14 years and the mean time until the molecular confirmation was 12±12 years. At the initial evaluation, five different phenotypes were identified: eight patients with LGMD2B, three with MM, two with HiperCK, one with proximodistal phenotype (Mixed type) and one with distal anterior compartment myopathy (DACM). At the last clinical evaluation, eight of them presented generalization of the weakness (one LGMD2B and seven proximodistal phenotype) and seven maintained their initial phenotype (four LGMD2B, one hiperCK, one DACM and one proximodistal). At the first clinical examination, all patients were able to walk without support and presently nine became wheelchair-bound and three needed walking assistance (mean time to loss of autonomous walk of 17 ±9 years). Seven patients referred dyspnea and/or orthopnea. 18% of thoracic x-rays presented an enlargement of the cardiothoracic index and abnormalities were found in 50% of the respiratory function tests and in 54% of the electrocardiograms. All patients had elevated serum creatine kinase (CK) levels. Thirteen sequence variations were identified in DYSF gene. Ten patients carried a single homozygous mutation; five patients had two compound heterozygous mutations. Conclusions: Dysferlinopathies are clinical and genetic heterogeneous muscle diseases with progression in the majority of the patients. The recognition of this features evidenced in this series, may contribute to the earlier and directed diagnosis of this disease.