Background And Objectives: To provide real-word clinical follow-up data on patients carrying variations of congenital myasthenic syndromes (CMS) and who respond to some innovative drugs.
Methods: Patients recruited from the Neurology Department of the Mustapha Bacha university hospital in Algiers. Treated with innovative drugs, they were monitored and their clinical progress was evaluated on the basis of clinical arguments suggestive of CMSs, but also para clinical arguments (electromyography and genetic study).
Objective: The objective of this study was to evaluate the implementation of NGS within the French mitochondrial network, MitoDiag, from targeted gene panels to whole exome sequencing (WES) or whole genome sequencing (WGS) focusing on mitochondrial nuclear-encoded genes.
Methods: Over 2000 patients suspected of Primary Mitochondrial Diseases (PMD) were sequenced by either targeted gene panels, WES or WGS within MitoDiag. We described the clinical, biochemical, and molecular data of 397 genetically confirmed patients, comprising 294 children and 103 adults, carrying pathogenic or likely pathogenic variants in nuclear-encoded genes.
Objectives: Heterozygous missense variants in have been recently identified in 13 patients from 6 families with congenital myopathy with tremor. All the patients had mild skeletal myopathy invariably associated with a distinctive myogenic tremor and hypotonia with gradual clinical improvement. However, no phenotypic description has been reported for the neonatal respiratory impairment that patients may suffer.
View Article and Find Full Text PDFAims: Limb-girdle congenital myasthenic syndrome (LG-CMS) is a genetically heterogeneous disorder characterized by muscle weakness and fatigability. The LG-CMS gene DPAGT1 codes for an essential enzyme of the glycosylation pathway, a posttranslational modification mechanism shaping the structure and function of proteins. In DPAGT1-related LG-CMS, reduced glycosylation of the acetylcholine receptor (AChR) reduces its localization at the neuromuscular junction (NMJ), and results in diminished neuromuscular transmission.
View Article and Find Full Text PDFCongenital Myasthenic Syndromes (CMSs) are rare inherited diseases of the neuromuscular junction characterized by muscle weakness. CMSs with acetylcholinesterase deficiency are due to pathogenic variants in COLQ, a collagen that anchors the enzyme at the synapse. The two COLQ N-terminal domains have been characterized as being biochemical and functional.
View Article and Find Full Text PDFCongenital myasthenic syndromes (CMS) are genetically and phenotypically very heterogeneous conditions resulting in a defect in the neuromuscular transmission. Post-synaptic forms are the most frequent CMSs, and acetyl choline receptor (low expressor) deficiency is the most commonly involved pathophysiological mechanism. CMS with kinetic abnormalities of the acetylcholine receptor (AChr) are much rarer and can give rise to potentially life-threatening phenotypes.
View Article and Find Full Text PDFCongenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far.
View Article and Find Full Text PDFThe RYR1 gene encodes the ryanodine-receptor 1, a key protein in the excitation-contraction coupling that takes place in muscle fibers. This receptor is the main channel responsible for calcium release from the endoplasmic reticulum [1]. A number of clinical phenotypes are linked to various mutations in this large gene as shown in a compilation established by ORPHANET (see table).
View Article and Find Full Text PDFCongenital myasthenic syndromes (CMS) are a group of heterogeneous diseases of the neuromuscular junction. We report electrodiagnostic testing (EDX) and genetic findings in a series of 120 CMS patients tested with a simple non-invasive EDX workup with surface recording of CMAPs and 3Hz repetitive nerve stimulation of accessory, radial and deep fibular nerves. Five ENMG phenotypes were retrieved based on the presence or not of R-CMAPs and the distribution pattern of decremental CMAP responses which significantly correlated with genetic findings (p <0.
View Article and Find Full Text PDFThe implementation of high-throughput diagnostic sequencing has led to the generation of large amounts of mutational data, making their interpretation more complex and responsible for long delays. It has been important to prioritize certain analyses, particularly those of "actionable" genes in diagnostic situations, involving specific treatment and/or management. In our project, we carried out an objective assessment of the clinical actionability of genes involved in myopathies, for which only few data obtained methodologically exist to date.
View Article and Find Full Text PDFCongenital myasthenic syndromes (CMS) are predominantly characterized by muscle weakness and fatigability and can be caused by a variety of mutations in genes required for neuromuscular junction formation and maintenance. Among them, AGRN encodes agrin, an essential synaptic protein secreted by motoneurons. We have identified severe CMS patients with uncharacterized p.
View Article and Find Full Text PDFBackground And Purpose: Andersen-Tawil syndrome (ATS) is a skeletal muscle channelopathy caused by KCNJ2 mutations, characterized by a clinical triad of periodic paralysis, cardiac arrhythmias and dysmorphism. The muscle phenotype, particularly the atypical forms with prominent permanent weakness or predominantly painful symptoms, remains incompletely characterized.
Methods: A retrospective clinical, histological, electroneuromyography (ENMG) and genetic analysis of molecularly confirmed ATS patients, diagnosed and followed up at neuromuscular reference centers in France, was conducted.
Background: Congenital myasthenic syndromes caused by mutations in the COL13A1 gene are very rare and have a phenotype described as severe. We present the first case of congenital myasthenic syndrome described in Algeria and the Maghreb with a new mutation of this gene.
Case Presentation: We present an 8-year-old Algerian female patient, who presented with a moderate phenotype with bilateral ptosis that fluctuates during the day and has occurred since birth.
Rare pathogenic variants in TOR1AIP1 (OMIM 614512), coding the inner nuclear membrane protein lamin-associated protein 1 (LAP1), have been associated with a spectrum of disorders including limb girdle muscular dystrophy with cardiac involvement and a severe multisystem phenotype. Recently, Cossins et al reported two siblings with limb girdle muscular dystrophy and impaired transmission of the neuromuscular synapse, demonstrating that defective LAP1 may lead to a congenital myasthenic syndrome. Herein, we describe the association of TOR1AIP1 deficiency with congenital myasthenic syndrome in three siblings.
View Article and Find Full Text PDFObjective: To report the identification of 2 new homozygous recessive mutations in the synaptotagmin 2 () gene as the genetic cause of severe and early presynaptic forms of congenital myasthenic syndromes (CMSs).
Methods: Next-generation sequencing identified new homozygous intronic and frameshift mutations in the gene as a likely cause of presynaptic CMS. We describe the clinical and electromyographic patient phenotypes, perform ex vivo splicing analyses to characterize the effect of the intronic mutation on exon splicing, and analyze the functional impact of this variation at the neuromuscular junction (NMJ).
Familial hypokalaemic periodic paralysis is a rare skeletal muscle disease caused by the dysregulation of sarcolemmal excitability. Hypokalaemic periodic paralysis is characterized by repeated episodes of paralytic attacks with hypokalaemia, and several variants in coding for Ca1.1 and coding for Na1.
View Article and Find Full Text PDFNon-dystrophic myotonias are a group of rare neuromuscular diseases linked to SCN4A or CLCN1. Among the subtypes, myotonia permanens, associated with the Gly1306Glu variant of SCN4A, is a relatively less frequent but more severe form. Most reports of non-dystrophic myotonias describe European populations.
View Article and Find Full Text PDFIntroduction: Brody myopathy (BM) is a recessive condition caused by mutations in the ATP2A1 gene and usually induces impaired muscle relaxation during and after exercise. Diagnosis relies on needle electromyography showing electrical silence, muscle biopsy with decreased sarcoplasmic reticulum calcium adenosine triphosphatase activity, and genetic analysis. Electrodiagnostic functional analyses are useful in the diagnosis of channelopathies, and thus may be impaired in BM.
View Article and Find Full Text PDFSodium channel myotonia and paramyotonia congenita are caused by gain-of-function mutations in the skeletal muscle voltage-gated sodium channel hNav1.4. The first-line drug is the sodium channel blocker mexiletine; however, some patients show side effects or limited responses.
View Article and Find Full Text PDFNext-generation sequencing (NGS) gene-panel-based analyses constitute diagnosis strategies which are adapted to the genetic heterogeneity within the field of myopathies, including more than 200 implicated genes to date. Nonetheless, important inter-laboratory diversity of gene panels exists at national and international levels, complicating the exchange of data and the visibility of the diagnostic offers available for referring neurologists. To address this issue, we here describe the initiative of the genetic diagnosis section of the French National Network for Rare Neuromuscular Diseases (Filière Nationale des Maladies Rares Neuromusculaires, FILNEMUS), which led to set up a consensual nationwide diagnostic strategy among the nine French genetic diagnosis laboratories using NGS for myopathies.
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