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

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.

A patient with myofibrillar myopathy caused by BAG3 gene mutation / 中华神经科杂志

Objective To study the clinical,pathological and genetic features of myofibrillar myopathy caused by BAG3 gene mutation.Methods The clinical features and pathological findings of a patient with myofibrillar myopathy were analyzed.Genomic DNA of the patient was extracted from peripheral blood and the next generation sequencing was performed to explore the mutation of genes about myopathies.Results The patient presented with nine-year-old onset myopathy characterized by progressive difficulty for squatting,rigid spine and muscle atrophy in the limbs symmetrically.Peripheral neurogenic damages were found on electromyography.On muscle biopsy,myogenic and neurogenic damages with rimmed vacuoles appeared,and the deposited materials were positive for sarcoglycan,dystrophin-R and dystrophin-C.There was a reported heterozygous mutation in the exons of the BAG3 gene (c.626C ＞ T).Conclusion There is no specificity of clinical manifestation in myofibrillar myopathy,and the diagnosis of this disease mainly depends on muscle biopsy and genetic screening.

Clinical and pathological features of 12 cases with nemaline myopathy / 中华神经科杂志

Objective To study the clinical and pathological features of nemaline myopathy(NM) in 12 cases.Methods Clinical manifestations and pathological features of muscle-biopsy specimens were summarized and analyzed retrospectively in 12 NM cases.Results In 12 cases,7 patients with typical congenital type exhibited lower or four limbs weakness as the first symptom and benign course.Three patients with childhood onset type exhibited lower limbs weakness and progressive course,and this type of patient might have muscle atrophy.Two patients with adult onset type exhibited four limbs and throat muscle weakness,rapidly progressive course and obvious muscle atrophy,and one patient had already shown acute respiratory failure.High arched feet and elongated face were observed.Creatin kinase value in all patients was normal or mildly elevated,and all electromyography showed myogenic changes.In light microscopy,the nemaline bodies were observed in more than half muscle fibers,especially in type 1 fibers.All patients showed type 1 predominance and atrophy.Modified Gomori trichrome stains showed characteristic purplecolored rods.Muscle electron microscopy showed high electron dense nemaline bodies around nucleus and disorganized myofibrillar apparatus such as broken myofilaments,irregular myofibril and Z lines.Nemaline bodies under electron microscopy may be part of myofibril or high electron-dense bodies with no structure.Conclusions The 12 patients in this study with NM are divided into 3 types,of which adult onset type is the most severe one.The key diagnosis is based on the appearance of nemaline bodies in more than half of the muscle fibers and the muscle electron microscopy observation.

Histopathological Study of Extraocular Musele followinr Posterior Fixation Suture in Rabbits: Pathogenesis of Musele Fibrosis

The authors observed the histological and ultrastructural findings in a study of the fibrosis of the extraocular muscles following a posterior fixation suture in rabbits. the early findings demonstrated hyalinosis, clumping of the nuclei of muscle cells and collagenization of the muscle tissue. However, there was no evidence of collagen tissue in the degenerated muscle fiber, reserving cell membrane and basement membrane ultrastructurally. The late findings showed splitting and irregular stain of the muscle fibers, many nuclei of presumed muscle cell and filamentous structure at the collagen tissue in the extracellular space. Electron microscopic study showed atrophy and angulation with distortion of the myofibrillar matrix, along with other cytoplasmic degenerative phe nomena in the muscle fibers. Clumps of the well-arranged microfibrils(Mf) and irregularly arranged Mf with fine granular materials(FGM) were adjacent to the immature collagen fibrils. Many of the Mf and FGM were closely associated, and the number of the Mf and FGM decreased with the degree of maturity of the collagen fibrils. The anatomical structure of the myofibrill was identified as that of the Mf. From these findings, it would appear that formation of collagen fiber occurs in the extracellular space and that Mf and FGM are primarily responsible for the formation of the collagen fibils.