Clinicopathological-genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre.

Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. The aim of this study was to characterize the clinical, physiological, pathohistological and genetic features of nine unrelated Chinese patients with CMS from a single neuromuscular centre. A total of nine patients aged from neonates to 34 years were enrolled who exhibited initial symptoms. Physical examinations revealed that all patients exhibited muscle weakness. Muscle biopsies demonstrated multiple myopathological changes, including increased fibre size variation, myofibrillar network disarray, necrosis, myofiber grouping, regeneration, fibre atrophy and angular fibres. Genetic testing revealed six different mutated genes, including AGRN (2/9), CHRNE (1/9), GFPT1 (1/9), GMPPB (1/9), PLEC (3/9) and SCN4A (1/9). In addition, patients exhibited differential responses to pharmacological treatment. Prompt utilization of genetic testing will identify novel variants and expand our understanding of the phenotype of this rare syndrome. Our findings contribute to the clinical, pathohistological and genetic spectrum of congenital myasthenic syndrome in China.

Findings of limb-girdle muscular dystrophy R7 telethonin-related patients from a Chinese neuromuscular center.

Limb-girdle muscular dystrophy (LGMD) is a group of clinically and genetically heterogeneous neuromuscular disorders. LGMD-R7, which is caused by telethonin gene (TCAP) mutations, is one of the rarest forms of LGMD, and only a small number of LGMD-R7 cases have been described and mostly include patients from Brazil. A total of two LGMD-R7 patients were enrolled at a Chinese neuromuscular center. Demographic and clinical data were collected. Laboratory investigations and electromyography were performed. Routine and immunohistochemistry staining of muscle specimens was performed, and a next-generation sequencing panel array for genes associated with hereditary neuromuscular disorders was used for analysis. The patients exhibited predominant muscle weakness. Electromyography revealed myopathic changes. The muscle biopsy showed myopathic features, such as increased fiber size variation, muscle fiber atrophy and regeneration, slight hyperplasia of the connective tissue, and disarray of the myofibrillar network. Two patients were confirmed to have mutations in the open reading frame of TCAP by next-generation sequencing. One patient had compound heterozygous mutations, and the other patient harbored a novel homozygous mutation. Western blotting analysis of the skeletal muscle lysate confirmed the absence of telethonin in the patients. We described two LGMD-R7 patients presenting a classical LGMD phenotype and a novel homozygous TCAP mutation. Our research expands the spectrum of LGMD-R7 due to TCAP mutations based on patients from a Chinese neuromuscular center.

Expanding the clinicopathological-genetic spectrum of GNE myopathy by a Chinese neuromuscular centre.

GNE myopathy is a heterogeneous group of ultrarare neuromuscular disorders caused by mutations in the GNE gene. An estimated prevalence of 1~21/1,000,000 leads to a deficiency of data and a lack of availability of samples to conduct clinical research on this neuromuscular disorder. Although GNE, which is the mutated gene responsible for the disease, is well known as the key enzyme in the biosynthesis pathway of sialic acid, the clinicopathological-genetic spectrum of GNE mutant patients is still unclear and expanding. This study presents ten unrelated patients with GNE myopathy, discovering five novel missense mutations. Clinical, electrophysiological, imaging, pathological and genetic data are presented in a retrospective manner. Interestingly, several patients in the cohort were found to have peripheral neuropathy and inflammatory cell infiltration in muscle biopsies, which have seldom been reported. This study, conducted by a neuromuscular centre in China, is the first attempt to highlight these abnormal clinicopathological features and associate them with genetic mutations in GNE myopathy.

Clinicopathological features of titinopathy from a Chinese neuromuscular center.

Titin, one of the largest proteins in humans, is a major component of muscle sarcomeres. Pathogenic variants in the titin gene (TTN) have been reported to cause a range of skeletal muscle diseases, collectively known as titinopathy. Titinopathy is a heterogeneous group of disabling diseases characterized by muscle weakness. In our study, we aimed to establish the clinicopathological-genetic spectrum of titinopathy from a single neuromuscular center. Three patients were diagnosed as having definite titinopathy, and additional three patients were diagnosed as having possible titinopathy according to the diagnostic criteria. All the patients showed initial symptoms from age one to 40 years. Physical examination revealed that five patients had muscle weakness, and that one patient experienced behavioral changes. Muscle biopsy specimens obtained from all six patients demonstrated multiple myopathological changes, including increased fiber size variation, muscle fiber hypertrophy or atrophy, formation of centralized cell nuclei, necklace cytoplasmic bodies, and formation of rimmed vacuoles and cores. Genetic testing revealed 11 different TTN alterations, including missense (6/11), nonsense (2/11), frameshift (2/11), and splicing (1/11) mutations. Our study provides further evidence that TTN mutations are more likely to be responsible for an increasing proportion of various myopathies, such as hereditary myopathy with early respiratory failure (HMERF), core myopathy, and distal myopathy with rimmed vacuoles, than currently recognized mutations. Our findings expand the clinical, pathohistological and genetic spectrum of titinopathy.

Investigation of adult-onset multiple acyl-CoA dehydrogenase deficiency associated with peripheral neuropathy.

Multiple Acyl-CoA dehydrogenase deficiency (MADD), one of the most common lipid storage myopathies (LSMs), is a heterogeneous inherited muscular disorder that is pathologically characterized by numerous lipid droplets in muscle fibers due to lipid metabolism disturbance. MADD exhibits a wide range of clinical features, including skeletal muscle weakness and multisystem dysfunctions. However, MADD, as well as other types of LSM, associated with peripheral neuropathy has rarely been reported during the past four decades. Here, we present four Chinese patients affected by MADD with peripheral neuropathy in our neuromuscular center. Clinically, these four patients showed skeletal muscle weakness and prominent paresthesia. Muscle biopsy detected characteristic myopathological patterns of LSM, such as obvious lipid droplets in muscle fibers. Sural nerve biopsy revealed a severe reduction in number of myelinated nerve fibers, which is a typical neuropathological pattern of peripheral neuropathy. Causative ETFDH mutations were found in all four cases. The skeletal muscle weakness was rapidly improved after some treatments while paresthesia showed unsatisfactory improvement. The features of previously reported patients of this specific type are also summarized in this paper. We propose that MADD with peripheral neuropathy may be a new phenotypic subtype because the pathology and reaction to riboflavin treatment are different from those of traditional MADD, although further research on the precise pathogenesis and mechanisms is needed.

Comparative immunoprofiling of polymyositis and dermatomyositis muscles.

The morphological, immunohistochemical, and immunopathological analyses of muscle biopsy are essential for the diagnosis of idiopathic inflammatory myopathies (IIMs). However, they are also one of the most common causes of misdiagnosis. Although several diagnostic criteria have been proposed for the diagnosis of IIMs, misdiagnosis still remains common in clinical practice. The present study aims to characterize the inflammatory profile of IIMs, including the expression of MHC-I, MHC-II, MAC and infiltrating cells. We also investigated the sensitivity and specificity of MHC-I and MHC-II immunostaining for the diagnosis of IIMs. We found that the expression of MHC-I and MHC-II was both higher in IIMs than in non-inflammatory myopathies (NIMs). The distribution of MHC-I in IIMs is different from that of MHC-II. MHC-I is mainly located in the sarcoplasms, while MHC-II is located mostly on the sarcolemmas. Moreover, our findings suggest that MAC may be a potential marker to diagnose DM, and the combination of MHC-I and MHC-II immunostaining results in a higher sensitivity and specificity for IIM diagnosis, especially for DM. In addition, infiltrating cells in PM were mainly CD8+ cells, but we found in DM and NIMs they were primarily CD4+ cells, which is consistent with previous studies. Lastly, glucocorticoid treatment and disease duration have little effect on the MHC-I and MHC-II expression pattern. Our findings indicate that the immunostaining of inflammatory markers such as MHC-I, MHC-II, CD4, CD8, CD303 and MAC are of diagnostic value for IIMs regardless of the immunosuppression regime and disease duration.

[Congenital myopathy with type 1 fiber predominance in two children].

Non-progressive congenital myopathy is a group of muscle diseases occurring at birth or during teenage years. A number of new reports of congenital myopathy, such as homogeneous bodies myopathy, muscle quality control myopathy and type 1 fiber predominance have recently been reported, but they lack of sufficient quantity and constant clinico-pathologic manifestations. This paper reports two cases of congenital myopathy with type 1 fiber predominance confirmed by muscle biopsy. The clinical manifestations of the two children (a 4.5-year-old girl and an 11-year-old boy) included non-progressive symptoms of muscle weakness, skeletal deformities and other clinical features of congenital myopathy. The physical examinations showed a long face or figure and funnel chest or kyphosis/scoliosis, high palatal arch and wing-like shoulder. Serum levels of creatine kinase were normal but slightly elevated serum lactate dehydrogenase levels were noted in the two children. The skeletal muscle biopsy by ATPase staining showed that type 1 fibers accounted for more than 90% of the total number of muscle fibers. No other abnormal pathological changes, such as central cores, muscle tube and central nuclei, were found in the two children.