RESUMO
BACKGROUND: Myotubular myopathy is a rare X-linked congenital myopathy characterized by marked neonatal hypotonia and respiratory insufficiency, facial and ocular involvement, and muscle biopsy with prominent central nuclei in the majority of muscle fibers. It is caused by mutations in MTM1, which codes for the phosphoinositides phosphatase myotubularin. In this work, we established and detailed a new cohort of six patients at the clinical, histologic, and genetic levels. PATIENTS AND METHODS: Patients were recruited after screening 3065 muscle biopsy reports from two large biopsy banks in Sao Paulo, Brazil from the years 2008 to 2013, and from referrals to a neuromuscular outpatient clinic between 2011 and 2013. We reviewed biopsy slides, evaluated patients, and Sanger sequenced MTM1 in the families. RESULTS: All patients but one had classic phenotypes with a stable course after a severe onset. Two patients died suddenly from hypovolemic shock. Muscle biopsies had been performed in five patients, all of whom showed a classic pattern with a predominance of centrally located nuclei and increased oxidative activity in the center of the fibers. Two patients showed necklace fibers, and two families had novel truncating mutations in MTM1. CONCLUSIONS: X-linked myotubular myopathy is rare in the Brazilian population. Necklace fibers might be more prevalent in this condition than previously reported. Direct Sanger sequencing of MTM1 on clinical suspicion avoids the need of a muscle biopsy.
Assuntos
Músculo Esquelético/patologia , Miopatias Congênitas Estruturais/genética , Miopatias Congênitas Estruturais/patologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Biópsia , Brasil , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Face/anormalidades , Humanos , Lactente , Masculino , Miopatias Congênitas Estruturais/epidemiologia , Miopatias Congênitas Estruturais/fisiopatologia , FenótipoRESUMO
PURPOSE OF REVIEW: Considerable progress has been made in molecular genetic research and in identifying the underlying pathogenesis of congenital myopathies, with implications for genetic counseling. Therefore an overview of such advances in the last two years is most timely and relevant for a more precise delineation of these disorders. RECENT FINDINGS: New mutations have been described on the ryanodine receptor gene, including the carboxyl-terminus region, and experimental models developed to explain their role in central core disease. Phenotype-genotype correlations for nemaline myopathy have improved our understanding of those related to gene mutations. In multi-minicore disease, collaborative studies support genetic heterogeneity and autosomal-recessive inheritance. Research on X-linked myotubular myopathies has revealed a high percentage of mothers of sporadic cases as carriers. Although not initially included within the congenital myopathies, desmin-related or myofibrillar myopathies are described here because they are closely related to other congenital myopathies with intracytoplasmic inclusions. Western blot for myotubularin and desmin has been proposed as a useful diagnostic test for both X-linked myotubular myopathy and desmin-related myopathy, and in-vitro and mouse models for the latter have provided insights into its pathogenesis. Several entities still await genetic characterization. Here we focus on clinical features, inheritance, and molecular genetics. SUMMARY: Advances in immunohistochemistry and molecular genetics in congenital muscular dystrophies have enriched our knowledge of this heterogeneous group of disorders, leading to more accurate classification and differentiation between the various congenital myopathies.