Abstract: Objective To explore the clinical, pathological and gene mutation characteristics of a family with centronuclear myopathy. Methods A family of centronuclear myopathy was recently confirmed by clinical diagnosis and muscle pathology in the Neuromuscular Pathology Laboratory of our hospital. The clinical data of patients were analyzed in this family, including onset age, symptoms, muscle strength, serum creatine kinase(CK)and electromyography. Muscle biopsy was performed on the proband, frozen muscle tissue specimens was stained with routine staining, and then immunohistochemistry and enzyme staining were conducted. Then DNA was extracted from the peripheral blood of the proband for high-throughput sequencing, neuromuscular disease-related genes were analyzed, and a missense mutation of MTM1 gene was found. Subsequently, the peripheral blood of the patients parents and other family members were sampled for Sanger sequencing, the sequencing results were compared with the normal sequence, and the pathogenicity of the mutation was analyzed. Results There were 3 patients in the pedigree. The proband felt limb weakness since childhood, ptosis of eyelids, weakness of facial muscles, and was unable to run and lift heavy objects. He had long and narrow face, inverted V-shaped upper lip, slender fingers and toes, and progressive aggravation of symptoms. Physical examination showed that the probands bilateral eyes could not close completely, the parotid force was weak, the speech was ambiguous, the proximal muscle strength of extremities was grade 4-, and the distal muscle strength was grade 4+. The probands serum CK increased slightly, and electromyography showed myogenic damage. The other two patients had similar symptoms. The muscle pathology of the proband showed typical central nuclear myopathy: the sizes of muscle fibers were obviously different; central nuclear muscle fibers significantly increased and accounted for 60% of all muscle fibers; type I fibers were atrophic with type I fiber predominance; nicotinamide adenine dinucleotide-tetrazolium reductase(NADH-TR)staining showed most centronuclei were surrounded by a rim of accentuated staining and characteristic radiating sarcoplasmic strands. Gene sequencing confirmed that the proband and the other two patients carried the missense mutation(p.D84V)of MTM1 gene, and the mutation was co-segregated with the phenotype in the family. By reviewing literature and searching databases, we confirmed that the mutation had never been reported before. Bioinformatics analysis predicted that the mutation was a possible pathogenic mutation. Based on the comprehensive analysis of the patients phenotype, muscle pathology, prediction of mutation pathogenicity and co-segregation of the mutation with phenotype in the family, the MTM1 gene c.251A>T mutation was the pathogenic mutation of the family. Conclusion This study confirms a pedigree with central nuclear myopathy by clinical examination, pathological staining of muscle biopsy and genetic analysis. Genetic analysis shows that MTM1 gene c.251A>T(p.D84V)is the pathogenic mutation of this pedigree. This mutation is reported for the first time at home and abroad. This study expands the mutation spectrum of MTM1 gene.

Key words: Centronuclear myopathy, MTM1 gene, Muscle pathology, X-chromosome, Congenital myopathy