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Background Congenital myasthenic syndrome (CMS) is a clinically and genetically heterogeneous neuromuscular disorder characterized by muscle weakness and caused by mutations in more than 35 different genes. This condition should not be overlooked as a subset of patients with CMS are treatable. However, the diagnosis of CMS is often difficult due to the broad variability in disease severity and course. Case report A five-year-old boy without remarkable family history was born with marked general muscle hypotonia and weakness, respiratory insufficiency, anomalies, and multiple joint contractures. Congenital myopathy was suspected based upon type 1 fiber predominance on muscle biopsy. However, he was diagnosed with CMS at age 4 years when his ptosis and ophthalmoplegia were found to be improved by edrophonium chloride and repetitive nerve stimulation showed attenuation of compound muscle action potentials. An exome sequencing identified a compound heterozygous missense variant of c.737C > T (p.A246V) and a novel intronic insertion c.1166 + 4_1166 + 5insAAGCCCACCAC in RAPSN. RT-PCR analysis which showed the skipping of exon 7 in a skeletal muscle sample confirmed that the intronic insertion was pathogenic. His myasthenic symptoms were remarkably improved by pyridostigmine. Conclusion The patient’s diagnosis of CMS was confirmed by exome sequencing, and RT-PCR revealed that the skipping of exon 7 in RAPSN was caused by a novel intronic insertion. The genetic information uncovered in this case should therefore be added to the collection of tools for diagnosing and treating CMS.

Congenital myasthenic syndromes (CMS) comprise a heterogeneous group of genetic disorders of the neuromuscular junction. Next generation sequencing has been increasingly used for molecular diagnosis in CMS patients. This study aimed to identify the disease-causing variants in Thai patients. We recruited patients with a diagnosis of CMS based on clinical and electrophysiologic findings, and whole exome sequencing was performed. Thirteen patients aged from 2 to 54 years (median: 8 years) from 12 families were enrolled. Variants were identified in 9 of 13 patients (69%). Five novel variants and two previously reported variant were found in the COLQ, RAPSN and CHRND gene. The previously reported c.393+1G>A splice site variant in the COLQ gene was found in a majority of patients. Five patients harbor the homozygous splice site c.393+1G>A variant, and two patients carry compound heterozygous c.393+1G>A, c.718-1G>T, and c.393+1G>A, c.865G>T (p.Gly289Ter) variants. The novel variants were also found in RAPSN (p.Cys251del, p.Arg282Cys) and CHRND (p.Met481del). Molecular diagnosis in CMS patients can guide treatment decisions and may be life changing, especially in patients with COLQ mutations.

Aim Congenital myasthenic syndromes (CMS) are rare, genetically and phenotypically diverse disorders of neuromuscular transmission. Data on prevalence among children are scarce. Whole exome sequencing facilitated discovery of novel CMS mutations and enabled targeted treatment. Our aim was to identify the prevalence, genetic subtypes and clinical characteristics of CMS in pediatric population of Slovenia. Methods In this observational, national, cross-sectional study, medical records were retrospectively reviewed. Children with genetically confirmed CMS, referred over a 19 – year period (2000–2018) to the University Medical Centre, Ljubljana, Slovenia, were included in the study. Genetic and phenotypic characteristics were collected and prevalence of CMS in children was calculated. Results Eight children with a confirmed genetic mutation in 5 different genes (CHRNE, CHRND, RAPSN, CHAT, MUSK) causative of the CMS were identified. Calculated prevalence of genetically confirmed CMS was 22.2 cases per 1.000.000 children at the end of 2018. Interpretation The prevalence of genetically confirmed CMS in Slovenian children at the end of 2018 exceeds previously reported prevalence by more than two-fold, which suggests that prevalence in the literature is likely to be underestimated. Two extremely rarely detected mutations in MUSK and CHRND gene were detected and patient's clinical descriptions add important information on genotype-phenotype correlation.

In this issue of Neuron, Xing et al. (2021) demonstrate that the multidomain scaffold protein Rapsn can form dense molecular condensates in vitro and in vivo via phase separation. The formation of Rapsn condensates is essential for clustering acetylcholine receptors on muscle membranes and for forming neuromuscular junctions.

Mutations in RAPSN are an important cause of congenital myasthenic syndrome (CMS), leading to endplate acetylcholine receptor deficiency. We present three RAPSN early-onset CMS patients (from a Brazilian cohort of 61 CMS patients). Patient 1 and patient 2 harbor the mutation p.N88K in homozygosity, while patient 3 harbors p.N88K in compound heterozygosity with another pathogenic variant (p.V165M; c.493G ≥ A). At onset, patient 3 presented with more severe symptoms compared to the other two, showing generalized weakness and repeated episodes of respiratory failure in the first years of life. During adolescence, she became gradually less symptomatic and does not require medication anymore, presenting better long-term outcomes than patients 1 and 2. This case series illustrates the variability of RAPSN early-onset CMS, with patient 3, despite severe onset, revealing an almost complete reversal of myasthenic symptoms, not limited to apneic episodes. Moreover, it suggests that RAPSN CMS may be underdiagnosed in non-European countries.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by members of the national French CMS Network: the difficulties in making a proper diagnosis; the course and long-term prognosis; and the response to therapy, especially for CMS that do not respond to cholinesterase inhibitors. CMS diagnosis is late in most cases because of confusion with other entities such as: congenital myopathies, due to the frequent presentation in patients of myopathies such as permanent muscle weakness, atrophy and scoliosis, and the abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy) seen on biopsy; seronegative autoimmune myasthenia gravis, when CMS is of late onset; and metabolic myopathy, with the presence of lipidosis in muscle. The long-term prognosis of CMS was studied in a series of 79 patients recruited with the following gene mutations: CHRNA; CHRNE; DOK7; COLQ; RAPSN; AGRN; and MUSK. Disease-course patterns (progressive worsening, exacerbation, stability, improvement) could be variable throughout life in a given patient. DOK7 patients had the most severe disease course with progressive worsening: of the eight wheelchair-bound and ventilated patients, six had mutations of this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first-line therapy for CMS patients, except for cases of slow-channel CMS, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss or RAPSN gene mutations. Ephedrine was given to 18 patients (eight DOK7, five COLQ, four AGRN and one RAPSN). Tolerability was good. Therapeutic responses were encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient who was allergic to ephedrine.

Congenital myasthenic syndromes are a heterogeneous group of inherited disorders that arise from impaired signal transmission at the neuromuscular synapse. They are characterized by fatigable muscle weakness. We performed whole-exome sequencing to determine the underlying defect in a group of individuals with an inherited limb-girdle pattern of myasthenic weakness. We identify DPAGT1 as a gene in which mutations cause a congenital myasthenic syndrome. We describe seven different mutations found in five individuals with DPAGT1 mutations. The affected individuals share a number of common clinical features, including involvement of proximal limb muscles, response to treatment with cholinesterase inhibitors and 3,4-diaminopyridine, and the presence of tubular aggregates in muscle biopsies. Analyses of motor endplates from two of the individuals demonstrate a severe reduction of endplate acetylcholine receptors. DPAGT1 is an essential enzyme catalyzing the first committed step of N-linked protein glycosylation. Our findings underscore the importance of N-linked protein glycosylation for proper functioning of the neuromuscular junction. Using the DPAGT1-specific inhibitor tunicamycin, we show that DPAGT1 is required for efficient glycosylation of acetylcholine-receptor subunits and for efficient export of acetylcholine receptors to the cell surface. We suggest that the primary pathogenic mechanism of DPAGT1 mutations is reduced levels of acetylcholine receptors at the endplate region. These individuals share clinical features similar to those of congenital myasthenic syndrome due to GFPT1 mutations, and their disorder might be part of a larger subgroup comprising the congenital myasthenic syndromes that result from defects in the N-linked glycosylation pathway and that manifest through impaired neuromuscular transmission. © 2012 The American Society of Human Genetics.

Congenital myasthenic syndromes (CMS) are rare genetic disorders characterized by impaired neuromuscular transmission. They are caused by mutations in synaptic, presynaptic and post synaptic proteins. Rapsyn is a postsynaptic peripheral membrane protein that anchors the nicotinic acetylcholine receptor to the motor endplate. CMS patients of Iraqi and Persian Jewish origin, carry a common founder mutation in the E box of the RAPSN promoter region (− 38A-G) that causes impaired transcriptional activities of the promoter region. We describe a Persian Jewish family with two siblings affected with typical CMS, harboring the common heterozygous (− 38A-G) E-box mutation associated with a previously unreported heterozygous p.224 insT causing an insertion of Threonine in the TPR6 domain. To the best of our knowledge, this is the first mutation in the TPR6 domain and might give supportive evidence to the role of this domain in rapsyn self association and consequently co-clustering with AchR in the post synaptic membrane.

A workshop on the respiratory management of congenital myasthenic syndromes (CMS) in childhood was held on 8 December 2009 at the UCL Institute of Neurology, UK. The workshop was sponsored by the Muscular Dystrophy Campaign and attended by 20 participants from 9 centres (8 in UK and 1 in Europe). The aim of the workshop was to review respiratory management of childhood CMS in major UK specialist centres and develop recommendations for standards of care to help anticipate and treat respiratory complications. The congenital myasthenic syndromes are a heterogeneous group of genetic disorders which result in impaired neuromuscular transmission and fatiguable weakness. Advances in molecular genetic diagnosis have lead to the identification of distinct genotypes [1] which are associated with particular patterns of respiratory decompensation. Many CMS children present with respiratory difficulties at birth and most are at risk of ventilatory failure with intercurrent respiratory illnesses. However, recurrent, life-threatening episodic apnoea in infancy and childhood (often precipitated by infection or even stress) is a particular feature of the presynaptic CMS caused by mutations in CHAT and postsynaptic CMS due to mutations in RAPSN. Other phenotypes, such as the synaptic CMS due to mutations in COLQ and the slow channel syndromes caused by mutations in the acetylcholine receptor subunits, cause an end plate myopathy which results in progressive respiratory muscle weakness and respiratory failure requiring long term ventilatory support. The fast channel syndromes are associated with recurrent and particularly severe respiratory crises in infancy and childhood. Other genotypes have diverse respiratory presentations, for example the post-synaptic CMS caused by mutations in DOK7 may be associated, in severe cases, with respiratory failure requiring ventilation at birth, or congenital stridor due to vocal cord palsy often necessitating tracheostomy, without any evidence of the limb gir

Contains fulltext : 70779.pdf (Publisher’s version ) (Closed access) Multiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). MPS are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. Previously, we and others reported that recessive mutations in the embryonal acetylcholine receptor g subunit (CHRNG) can cause both lethal and nonlethal MPS, thus demonstrating that pterygia resulted from fetal akinesia. We hypothesized that mutations in acetylcholine receptor-related genes might also result in a MPS/fetal akinesia phenotype and so we analyzed 15 cases of lethal MPS/fetal akinesia without CHRNG mutations for mutations in the CHRNA1, CHRNB1, CHRND, and rapsyn (RAPSN) genes. No CHRNA1, CHRNB1, or CHRND mutations were detected, but a homozygous RAPSN frameshift mutation, c.1177-1178delAA, was identified in a family with three children affected with lethal fetal akinesia sequence. Previously, RAPSN mutations have been reported in congenital myasthenia. Functional studies were consistent with the hypothesis that whereas incomplete loss of rapsyn function may cause congenital myasthenia, more severe loss of function can result in a lethal fetal akinesia phenotype.

The ENMC hosted a group of 18 experts on Congenital Myasthenic Syndromes (CMS). CMS are inherited disorders in which the safety margin of the neuromuscular transmission is compromised by one or more specific mechanism(s). CMS are caused by various genetic defects. The objectives of the workshop included progress in deciphering the molecular basis of CMS (sessions 1–4) and clinical conclusions for epidemiology, diagnosis and therapy (sessions 5–7). To date, genes known to cause CMS if mutated are the presynaptic choline acetyltransferase gene CHAT, the gene COLQ encoding the synaptic protein ColQ, the genes encoding the different subunits of the postsynaptic acetylcholine receptor (CHRNA1, CHRNB1, CHRND, CHRNE), the genes for the postsynaptic proteins rapsyn (RAPSN), muscle-specific receptor tyrosine kinase (MUSK) and the postsynaptic sodium channel (SCN4A). Since the last ENMC workshop on CMS in October 1999, four novel CMS genes have been identified, namely CHAT, RAPSN, SCN4A and MUSK. As a consequence, several new patients presenting with varying phenotypes of CMS have been described worldwide. In particular, mutations in RAPSN and CHAT turned out to be of high clinical relevance, on one hand because of their apparent worldwide frequency, on the other hand because of their specific clinical phenotype with the occurrence of sudden apneic episodes. Furthermore, considerable progress has been made using a variety of

The objective is mutation analysis of the RAPSN gene in a patient with sporadic congenital myasthenic syndrome (CMS). Mutations in various genes encoding proteins expressed at the neuromuscular junction may cause CMS. Most mutations affect the epsilon subunit gene of the acetylcholine receptor (AChR) leading to endplate AChR deficiency. Recently, mutations in the RAPSN gene have been identified in several CMS patients with AChR deficiency. In most patients, RAPSN N88K was identified, either homozygously or heteroallelic to a second missense mutation. A sporadic CMS patient from Germany was analyzed for RAPSN mutations by RFLP, long-range PCR and sequence analysis. Clinically, the patient presents with an early onset CMS, associated with arthrogryposis multiplex congenita, recurrent episodes of respiratory insufficiency provoked by infections, and a moderate general weakness, responsive to anticholinesterase treatment. The mutation RAPSN N88K was found heterozygously to a large deletion of about 4.5 kb disrupting the RAPSN gene. Interestingly, an Alu-mediated unequal homologous recombination may have caused the deletion. We hypothesize that numerous interspersed Alu elements may predispose the RAPSN locus for genetic rearrangements.

Introduction Congenital myasthenic syndromes (CMS) are rare genetic syndromes resulting from presynaptic, synaptic or postsynaptic defects of the neuromuscular junction. In 2006 mutations in DOK7, a gene encoding a muscle-intrinsic activator of MUSK, were proven a postsynaptic cause of CMS. Until today 65 DOK7 mutations have been described. Case report A 16 year old girl, daughter to healthy, non-consanguineous parents has been followed up at our clinic since birth. History includes decreased fetal movements, hypotonia at birth and slightly delayed motor milestones with sitting at 8 months and walking at 15 months. Neurological examination discloses facial and proximal muscle weakness, bulbar and respiratory weakness, ptosis, joint laxity, massive kyphoscoliosis, feeding difficulty and failure to thrive. The patient is currently ambulant, able to climb stairs and walk approximately 50 meters, before getting tired. Under nocturnal noninvasive ventilation (BiPAP) she maintains oxygen saturation levels >98%. Creatin kinase is 200 U/l (normal: 150 U/l). Electrophysiologic studies revealed normal NCV's and a mildly myopathic EMG. Repetitive nerve stimulation demonstrated mild decrement at infancy, but now is normal. Muscle biopsy showed predominance of type 1 fibers and decreased oxidative activity. Since the clinical features were consistent with CMS, molecular analysis of CHAT, RAPSN, CHRNE and DOK7 was undertaken, which in turn revealed a compound heterozygous mutation in the DOK7 gene. Conclusion To the best of our knowledge this is the first Greek patient with confirmed DOK7 myasthenic syndrome. One of the mutations, the c.472C>T (p.Arg158Trp) has not been previously described. Accurate diagnosis of DOK7 myasthenic syndromes bears important clinical implications, since ephedrine or salbutamol rather than acetylcholinesterase inhibitors are the treatment of choice.

Objective Congenital myasthenic syndromes (CMS) are a rare heterogeneous group of inherited neuromuscular disorders associated with distinctive clinical, electrophysiological and genetic abnormalities. Mutations in various genes of the neuromuscular junction may cause presynaptic, synaptic or postsynaptic defects. In this study, the genetic and clinical characteristics of Israeli patients with CMS were evaluated. Methods Twentysix patients with CMS from 16 independent families in whom genetic mutation was detected were diagnosed in two Israeli medical centers. Genetic evaluation was initially performed depending on patients' clinical symptoms and known CMS genes were sequenced. Patients of Jewish Iranian or Iraqi ethnic origin were screened directly for a known 38 A-G mutation in RAPSYN. In two patients, whole exome sequencing was analyzed. All patients' medical records were reviewed and their clinical data, electrophysiological studies and outcome were recorded. Results The diagnosis of CMS was confirmed in 26 patients of 16 families. Among these patients, 8 patients of 4 families had recessive mutations in COLQ, eight patients of 5 families, mutations in CHRNE, and eight patients of 5 families, mutations in RAPSN. CHRND was diagnosed in 2 patients from one family. The mean age of onset of clinical symptoms was 6 months. Ptosis, ophthalmoplegia and feeding problems were the most common symptoms. Conclusions RAPSYN and CHRNE are the most common causes of CMS in our cohort. The second most common cause is COLQ. Specific mutations in RAPSYN, CHRNE and COLQ are detected in unique ethnic populations in Israel.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders caused by genetic defects affecting neuromuscular transmission and leading to muscle weakness accentuated by exertion. Three different aspects have been investigated by the members of the French CMS network: the difficulties to make a proper diagnosis, the course and long term prognosis, and the response to therapy, especially for the CMS that do not respond to cholinesterase inhibitors. CMS diagnosis was late in most cases due to confusion with other entities: congenital myopathies, due to the frequent myopathic presentation of patients including permanent weakness, atrophy, scoliosis, and biopsy often showing abnormalities of internal structure, diameter and distribution of fibers (type I predominance, type II atrophy); seronegative autoimmune myasthenia gravis when CMS was late onset; metabolic myopathy, with presence of lipidosis in muscle. We studied long term prognosis of CMS in a series of 81 patients recruited with the following mutated genes: CHRNA, CHRNE, DOK7, COLQ, RAPSN, AGRN, MUSK. Course pattern (progressive worsening, exacerbation, stability, improvement) could be variable along the life in one single patient. DOK7 patients had the most severe course with progressive worsening: among the 8 wheel-chair bound and ventilated, 6 were mutated for this gene. Pregnancy was a frequent cause of exacerbation. Anticholinesterase agents are the first line therapy for CMS patients, except for Slow-Channel, COLQ and DOK7. In our experience, 3,4-DAP was a useful complement for several patients harboring CMS with AChR loss CMS or RAPSN gene mutations. Ephedrine was given to 18 patients (8 DOK7, 5 COLQ, 4 AGRN, 1 RAPSN). Tolerance was good. Therapeutic response was encouraging even in the most severely affected patients, particularly with DOK7 and COLQ. Salbutamol was a good alternative in one patient, allergic to Ephedrine.