Congenital myasthenic syndrome (CMS) is a group of clinical and genetic heterogeneous diseases caused by impaired neuromuscular transmission due to genetic defects. At present, it has been reported that more than 30 genes can cause CMS. All CMS subtypes have the clinical features of fatigue and muscle weakness, but age of onset, symptoms, and treatment response vary with the molecular mechanisms underlying genetic defects. Pharmacotherapy and symptomatic/supportive treatment are the main methods for the treatment of CMS, and antisense oligonucleotide technology has been proven to be beneficial for CHRNA 1-related CMS in animals. Since CMS is a group of increasingly recognized clinical and genetic heterogeneous diseases, an understanding of the latest knowledge and research advances in its clinical features, genetic research, and treatment helps to give early diagnosis and treatment as well as gain a deeper understanding of the pathogenesis of CMS, so as to make new breakthroughs in the treatment of CMS.
Animals ; Humans ; Mutation ; Myasthenic Syndromes, Congenital ; therapy

OBJECTIVE: To explore the genetic basis for a female patient featuring unstable head upright and hypotonia of limbs. METHODS: The child was examined clinically. Peripheral blood samples of the child, her parents and siblings were collected. Genomic DNA was extracted and subjected to next generation sequencing (NGS). Suspected variant was verified by Sanger sequencing and bioinformatic analysis. RESULTS: DNA sequencing found that the patient has carried a de novo heterozygous c.354C>A (p.N118K) variant of the CHRND gene, which was not found in her parents and sibling. Bioinformatics analysis predicted that the variant was likely to be pathogenic. Literature review suggested that the phenotype of the patient was very similar to previously reported ones. CONCLUSION The child was diagnosed with slow-channel congenital myasthenic syndrome (SCCMS) type 3A caused by heterozygous variant of the CHRND gene. NGS has provided a powerful tool for the diagnosis of such disorders.
Child ; Female ; Genetic Testing ; Heterozygote ; High-Throughput Nucleotide Sequencing ; Humans ; Mutation ; Myasthenic Syndromes, Congenital ; genetics ; pathology ; Receptors, Cholinergic ; genetics

BACKGROUNDCongenital myasthenic syndromes are a group of rare disorders that are clinically and genetically heterogeneous and caused by mutations in the genes encoding proteins of the neuromuscular junction. Here, we described a Chinese family that presented with phenotypes of classic slow-channel congenital myasthenic syndrome (SCCMS).

METHODSClinical characteristics and electrophysiological features of three patients from a Chinese family were examined, and next-generation sequencing followed by direct sequencing was carried out.

RESULTSThe patients revealed variability in clinical and electrophysiological features. However, weakness, scoliosis, and repetitive-compound muscle action potential were found in all affected members in the family. A heterozygous C>T missense mutation at nucleotide 865 in acetylcholine receptor epsilon-subunit (CHRNE) gene that causes a leucine-to-phenylalanine substitution at position 289 (L289F) was found.

CONCLUSIONSWe reported a SCCMS family of Chinese origin. In the family, classical clinical phenotype with phenotypic variability among different members was found. Genetic testing could help diagnose this rare disease.

Adult ; DNA Mutational Analysis ; Electrophysiology ; Female ; Humans ; Male ; Mutation, Missense ; genetics ; Myasthenic Syndromes, Congenital ; genetics ; physiopathology ; Receptors, Nicotinic ; genetics ; Young Adult

BACKGROUND AND PURPOSE: Mutations of the skeletal muscle sodium channel gene SCN4A, which is located on chromosome 17q23-25, are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis (HYPP), hypokalemic periodic paralysis, paramyotonia congenita (PMC), potassium-aggravated myotonia, and congenital myasthenic syndrome. This study analyzed the clinical and mutational spectra of skeletal muscle sodium channelopathy in Korean subjects. METHODS: Six unrelated Korean patients with periodic paralysis or nondystrophic myotonia associated with SCN4A mutations were included in the study. For the mutational analysis of SCN4A, we performed a full sequence analysis of the gene using the patients' DNA. We also analyzed the patients' clinical history, physical findings, laboratory tests, and responses to treatment. RESULTS: We identified four different mutations (one of which was novel) in all of the patients examined. The novel heterozygous missense mutation, p.R225W, was found in one patient with mild nonpainful myotonia. Our patients exhibited various clinical phenotypes: pure myotonia in four, and PMC in one, and HYPP in one. The four patients with pure myotonia were initially diagnosed as having myotonia congenita (MC), but a previous analysis revealed no CLCN1 mutation. CONCLUSIONS: Clinical differentiating between sodium-channel myotonia (SCM) and MC is not easy, and it is suggested that a mutational analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of SCM and MC.
Channelopathies ; Diagnosis, Differential ; DNA ; Humans ; Hypokalemic Periodic Paralysis ; Muscle, Skeletal ; Mutation, Missense ; Myasthenic Syndromes, Congenital ; Myotonia ; Myotonia Congenita ; Myotonic Disorders ; Paralyses, Familial Periodic ; Paralysis ; Paralysis, Hyperkalemic Periodic ; Sequence Analysis ; Sodium ; Sodium Channels