Advancing the Understanding of Vesicle-Associated Membrane Protein 1-Related Congenital Myasthenic Syndrome: Phenotypic Insights, Favorable Response to 3,4-Diaminopyridine, and Clinical Characterization of Five New Cases.

Background: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular junction (NMJ) disorders arising from gene variants encoding diverse NMJ proteins. Recently, the VAMP1 gene, responsible for encoding the vesicle-associated membrane protein 1 (VAMP1), has been associated with CMS.

Methods: This study presents a characterization of five new individuals with VAMP1-related CMS, providing insights into the phenotype.

Impaired gating of γ- and ε-AChR respectively causes Escobar syndrome and fast-channel myasthenia.

Objective: To dissect the kinetic defects of acetylcholine receptor (AChR) γ subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR ε subunit in a congenital myasthenic syndrome (CMS).

Methods: Whole exome sequencing, α-bungarotoxin binding assay, single channel patch-clamp recordings, and maximum likelihood analysis of channel kinetics.

Results: We identified compound heterozygous variants in AChR γ and ε subunits in three Escobar syndrome (1-3) and three CMS patients (4-6), respectively.

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.

Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients.

Treatment of slow-channel congenital myasthenic syndrome in a Thai family with fluoxetine.

The slow-channel congenital myasthenic syndrome is an autosomal dominant neuromuscular disorder caused by mutations in different subunits of the acetylcholine receptor. Fluoxetine, a common antidepressant and long-lived open-channel blocker of acetylcholine receptor, has been reported to be beneficial in the slow-channel congenital myasthenic syndrome. Here we report a prospective open label study of fluoxetine treatment in some affected members of a Thai family with slow-channel congenital myasthenic syndrome caused by a novel p.

Determinants of the repetitive-CMAP occurrence and therapy efficacy in slow-channel myasthenia.

Objective: To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and to assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS).

Methods: Neurologic examination, EMG study, laboratory test, muscle biopsy, and next-generation and Sanger sequencing; literature review of reported patients with SCCMS, including EMG, kinetics of mutant acetylcholine receptors (AChRs), and response to therapy; and simulation of the decay phase of endplate potential (EPP) were performed.

Results: Three newly characterized and 57 reported patients with SCCMS with mutations of AChR subunits were included.

A novel fast-channel myasthenia caused by mutation in β subunit of AChR reveals subunit-specific contribution of the intracellular M1-M2 linker to channel gating.

Genetic variants causing the fast-channel congenital myasthenic syndrome (CMS) have been identified in the α, δ, and ε but not the β subunit of acetylcholine receptor (AChR). A 16-year-old girl with severe myasthenia had low-amplitude and fast-decaying miniature endplate potentials. Mutation analysis revealed two heteroallelic variants in CHRNB1 encoding the AChR β subunit: a novel c.

Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner.

Congenital myasthenic syndromes (CMS) are caused by mutations in molecules expressed at the neuromuscular junction. We report clinical, structural, ultrastructural, and electrophysiologic features of 4 CMS patients with 6 heteroallelic variants in AGRN, encoding agrin. One was a 7.

A novel heterozygous mutation in the C-terminal region of HSPB8 leads to limb-girdle rimmed vacuolar myopathy.

Mutations in heat shock protein B8 were initially identified in inherited neuropathies and were more recently found to cause a predominantly distal myopathy with myofibrillar pathology and rimmed vacuoles. Rare patients also had proximal weakness. Only very few pathogenic variants have been identified in HSPB8.

Slow-channel myasthenia due to novel mutation in M2 domain of AChR delta subunit.

Objective: To characterize the molecular and phenotypic basis of a severe slow-channel congenital myasthenic syndrome (SCCMS).

Methods: Intracellular and single-channel recordings from patient endplates; alpha-bungarotoxin binding studies; direct sequencing of AChR genes; microsatellite analysis; kinetic analysis of AChR activation; homology modeling of adult human AChR structure.

Results: Among 24 variants reported to cause SCCMS only two appear in the AChR δ-subunit.

A homozygous mutation in GMPPB leads to centronuclear myopathy with combined pre- and postsynaptic defects of neuromuscular transmission.

Mutations in GMPPB cause a wide spectrum of neuromuscular syndromes, including muscular dystrophies and congenital myasthenic syndrome. The mechanisms by which GMPPB mutations impair neuromuscular transmission however remain incompletely understood. We expand here upon a previous report of one such patient presenting with a myopathy-congenital myasthenic syndrome overlap phenotype.

Congenital myasthenic syndrome due to rapsyn deficiency: A case report with a new mutation and compound heterozygosity.

Introduction: The congenital myasthenic syndromes are a heterogeneous group of genetic disorders characterized by an abnormal synaptic transmission in the neuromuscular plate.

Report: We present a two-year-old patient, male, with hypotonia, palpebral ptosis, and proximal symmetric weakness with a neonatal onset that motivated several and prolonged hospitalizations for pneumonia and respiratory failure. From two years of age, the parents noticed that the facial and general weakness worsened in the afternoons and with repeated or prolonged physical activity.

A nomenclature and classification for the congenital myasthenic syndromes: preparing for FAIR data in the genomic era.

Background: Congenital myasthenic syndromes (CMS) are a heterogeneous group of inherited neuromuscular disorders sharing the common feature of fatigable weakness due to defective neuromuscular transmission. Despite rapidly increasing knowledge about the genetic origins, specific features and potential treatments for the known CMS entities, the lack of standardized classification at the most granular level has hindered the implementation of computer-based systems for knowledge capture and reuse. Where individual clinical or genetic entities do not exist in disease coding systems, they are often invisible in clinical records and inadequately annotated in information systems, and features that apply to one disease but not another cannot be adequately differentiated.

Correction to: The Therapy of Congenital Myasthenic Syndromes.

The third paragraph in the left column of page 256 of the article pertaining to the treatment of congenital choline acetyl transferase (ChAT) deficiency states that "Because apneic attacks occur suddenly in infants and children, the parents should be provided with an inflatable rescue bag."

Congenital myasthenic syndromes in adult neurology clinic: A long road to diagnosis and therapy.

Objective: To investigate the diagnostic challenges of congenital myasthenic syndromes (CMS) in adult neuromuscular practice.

Methods: We searched the Mayo Clinic database for patients with CMS diagnosed in adulthood in the neuromuscular clinic between 2000 and 2016. Clinical, laboratory, and electrodiagnostic data were reviewed.

Congenital Myasthenic Syndromes in 2018.

Purpose Of Review: Summarize features of the currently recognized congenital myasthenic syndromes (CMS) with emphasis on novel findings identified in the past 6 years.

Recent Findings: Since the last review of the CMS in this journal in 2012, several novel CMS were identified. The identified disease proteins are SNAP25B, synaptotagmin 2, Munc13-1, synaptobrevin-1, GFPT1, DPAGT1, ALG2, ALG14, Agrin, GMPPB, LRP4, myosin 9A, collagen 13A1, the mitochondrial citrate carrier, PREPL, LAMA5, the vesicular ACh transporter, and the high-affinity presynaptic choline transporter.

Myopathy With and Variants: Clinical and Pathological Features.

Objective: The aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.

Patients And Methods: Clinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.

Genetic basis and phenotypic features of congenital myasthenic syndromes.

The congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. The disease proteins reside in the nerve terminal, the synaptic basal lamina, or in the postsynaptic region, or at multiple sites at the neuromuscular junction as well as in other tissues. Targeted mutation analysis by Sanger or exome sequencing has been facilitated by characteristic phenotypic features of some CMS.

Congenital myasthenic syndromes in Turkey: Clinical clues and prognosis with long term follow-up.

Congenital myasthenic syndromes (CMS) are a group of hereditary disorders affecting the neuromuscular junction. Here, we present clinical, electrophysiological and genetic findings of 69 patients from 51 unrelated kinships from Turkey. Genetic tests of 60 patients were performed at Mayo Clinic.

Mutations causing congenital myasthenia reveal principal coupling pathway in the acetylcholine receptor ε-subunit.

We identify 2 homozygous mutations in the ε-subunit of the muscle acetylcholine receptor (AChR) in 3 patients with severe congenital myasthenia: εR218W in the pre-M1 region in 2 patients and εE184K in the β8-β9 linker in 1 patient. Arg218 is conserved in all eukaryotic members of the Cys-loop receptor superfamily, while Glu184 is conserved in the α-, δ-, and ε-subunits of AChRs from all species. εR218W reduces channel gating efficiency 338-fold and AChR expression on the cell surface 5-fold, whereas εE184K reduces channel gating efficiency 11-fold but does not alter AChR cell surface expression.

The unfolding landscape of the congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are heterogeneous disorders in which the safety margin of neuromuscular transmission is impaired by one or more specific mechanisms. Since the advent of next-generation sequencing methods, the discovery of novel CMS targets and phenotypes has proceeded at an accelerated rate. Here, we review the current classification of CMS and describe our findings in five of these targets identified and investigated in our laboratory in the past 5 years.

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights.

Congenital myasthenic syndromes are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. This underlines the importance of genetic diagnosis.

Congenital myopathy associated with the triadin knockout syndrome.

Objective: Triadin is a component of the calcium release complex of cardiac and skeletal muscle. Our objective was to analyze the skeletal muscle phenotype of the triadin knockout syndrome.

Methods: We performed clinical evaluation, analyzed morphologic features by light and electron microscopy, and immunolocalized triadin in skeletal muscle.

Novel synaptobrevin-1 mutation causes fatal congenital myasthenic syndrome.

Objective: To identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome.

Methods: We performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation.

Results: Clinical electrophysiology studies of the patient revealed several-fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect.