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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. 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. 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. [ABSTRACT FROM AUTHOR]

Highlights • Of a cohort of 61 Brazilian patients, 5% harbored the RAPSN p.N88K mutation. • The p.N88K mutation may be an important cause of RAPSN cases, even in non-European populations. • Early-onset RAPSN congenital myasthenic syndrome may present favorable long-term outcomes. • The p.N88K RAPSN mutation can be related to early-onset phenotype with or without apneic crisis. Abstract 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. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMS) are a heterogeneous group of genetic disorders, all of which impair neuromuscular transmission. Epidemiological data and frequencies of gene mutations are scarce in the literature. Here we describe the molecular genetic and clinical findings of sixty-four genetically confirmed CMS patients from Spain. Thirty-six mutations in the CHRNE, RAPSN, COLQ, GFPT1, DOK7, CHRNG, GMPPB, CHAT, CHRNA1, and CHRNB1 genes were identified in our patients, with five of them not reported so far. These data provide an overview on the relative frequencies of the different CMS subtypes in a large Spanish population. CHRNE mutations are the most common cause of CMS in Spain, accounting for 27% of the total. The second most common are RAPSN mutations. We found a higher rate of GFPT1 mutations in comparison with other populations. Remarkably, several founder mutations made a large contribution to CMS in Spain: RAPSN c.264C > A (p.Asn88Lys), CHRNE c.130insG (Glu44Glyfs*3), CHRNE c.1353insG (p.Asn542Gluf*4), DOK7 c.1124_1127dup (p.Ala378Serfs*30), and particularly frequent in Spain in comparison with other populations, COLQ c.1289A > C (p.Tyr430Ser). Furthermore, we describe phenotypes and distinguishing clinical signs associated with the various CMS genes which might help to identify specific CMS subtypes to guide diagnosis and management. [ABSTRACT FROM AUTHOR]

Introduction Fetal akinesia deformation sequence (FADS) or arthrogryposis multiplex congenita (AMC) is characterized by clinical ambiguity and genetic heterogeneity, hampering genetic diagnosis via traditional sequencing methods. Next generation sequencing (NGS) of all known disease-causing genes offers an elegant solution to identify the genetic etiology of AMC/FADS in a diagnostic setting. Methods An in-house developed disease-associated gene panel was conducted in two unrelated fetuses with FADS. First, a de novo analysis was performed on the entire disease-associated gene panel. If no pathogenic mutation was identified, analysis of variants retained in a specific subpanel with arthrogryposis/fetal akinesia-causing genes was performed. Results In the first family, FADS relates to a homozygous c.484G > A (p.Glu162Lys) mutation in the gene RAPSN . The second case concerns a sporadic patient with brain anomalies and arthrogryposis due to a de novo hemizygous c.498C > T splice-site mutation in the pyruvate dehydrogenase-alpha 1 ( PDHA1 ) gene. Discussion NGS facilitated genetic diagnosis, and hence genetic counseling, for both families with AMC/FADS. Biallelic RAPSN mutations typically result in congenital myasthenia syndrome, or occasionally in FADS. This is the first report attributing the RAPSN mutation c.484G > A, identified in a homozygous state in patient 1, to FADS. The second patient represents the first case of AMC due to a PDHA1 mutation, advocating that pyruvate dehydrogenase deficiency should be considered in the differential diagnosis of fetal akinesia. This study illustrates the relevance of a disease-associated-gene panel as a diagnostic tool in pregnancies complicated by this genetically heterogeneous condition. [ABSTRACT FROM AUTHOR]

The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified. Mutations in RAPSN were identified in 13 kinships in Israel. The most common mutation was c.-38A>G detected in 8 patients of Iranian and/or Iraqi Jewish origin. Four different recessive mutations in COLQ were identified in 11 kinships, 10 of which were of Muslim-Arab descent. Mutations in CHRNE were identified in 7 kinships. Less commonly detected mutations were in CHRND , CHAT , GFPT1 and DOK7. In conclusion, mutations in RAPSN and COLQ are the most common causes of CMS in our cohort. Specific mutations in COLQ , RAPSN , and CHRNE occur in specific ethnic populations and should be taken into account when the diagnosis of a CMS is suspected. [ABSTRACT FROM AUTHOR]