Clinical, muscle pathology and molecular genetic analysis of myofibrillar myopathy 3 associated with MYOT gene mutation / 中华神经科杂志

ABSTRACT

Objective:To analyze the clinical phenotypic characteristics, muscle pathology, genetic mutations and related proteins of myofibrillar myopathy 3 caused by mutation in MYOT gene, and to conduct a literature review and summary of this disease. Methods:A retrospective analysis of the clinical phenotypic characteristics, muscle pathology and genetic test results of a patient with myofibrillar myopathy 3 caused by mutation in MYOT gene diagnosed in Qilu Hospital of Shandong University in December 2018 was conducted. Whole exon sequencing was applied to conduct high-throughput screening of pathogenic genes in the patient. After finding candidate pathogenic mutation, Sanger sequencing was applied to verify the mutation sites in the patient and family members. Meanwhile, functional verification was carried out on the mutation sites found in MYOT gene, and the relevant literature was reviewed. Results:The patient was a 47-year-old woman with weakness in her lower limbs for 8 years. Electromyography showed myogenic changes. The muscle pathology suggested that there was deposition of abnormal substances and rimmed vacuoles within some muscle fibers. Gene testing showed that the patient was a carrier of the MYOT gene c.170C>T (p.Thr57Ile) heterozygous mutation, and her son and daughter also carried the same mutation at the same site. The son of the patient had an elevated creatine kinase level and spontaneous potential was occasionally observed on electromyography, while the daughter had no abnormalities. Two younger brothers did not carry the mutation. Protein functional studies suggested that the mutation of MYOT gene c.170C>T mutation can lead to the change of partial spatial structure of myotilin, and the abnormal aggregation of p62 protein and myotilin was involved in the pathogenesis of the disease. Literature review revealed that c.170C>T (p.Thr57Ile) mutation has only been reported in foreign populations. This is the first detailed report on the clinical phenotype, muscle pathology and gene function of MYOT-related myofibrillar myopathy type 3 in China. Conclusions:The clinical manifestations of myofibrillar myopathy type 3 caused by MYOT gene mutation are heterogeneous, mainly manifested as muscle weakness in the distal or proximal extremities. Muscle pathology reveals abnormal protein deposits and rimmed vacuoles within some muscle fibers. Accurate diagnosis of the disease depends on gene detection. The co-localization of p62 protein and myotilin protein provides a new idea for the diagnosis and molecular mechanism research of the disease.