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Congenital myasthenic syndrome

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https://www.readbyqxmd.com/read/29475025/protein-anchoring-therapy-to-target-extracellular-matrix-proteins-to-their-physiological-destinations
#1
REVIEW
Mikako Ito, Kinji Ohno
Endplate acetylcholinesterase (AChE) deficiency is a form of congenital myasthenic syndrome (CMS) caused by mutations in COLQ, which encodes collagen Q (ColQ). ColQ is an extracellular matrix (ECM) protein that anchors AChE to the synaptic basal lamina. Biglycan, encoded by BGN, is another ECM protein that binds to the dystrophin-associated protein complex (DAPC) on skeletal muscle, which links the actin cytoskeleton and ECM proteins to stabilize the sarcolemma during repeated muscle contractions. Upregulation of biglycan stabilizes the DPAC...
February 20, 2018: Matrix Biology: Journal of the International Society for Matrix Biology
https://www.readbyqxmd.com/read/29462491/the-beta-adrenergic-agonist-salbutamol-modulates-neuromuscular-junction-formation-in-zebrafish-models-of-human-myasthenic-syndromes
#2
Grace McMacken, Dan Cox, Andreas Roos, Juliane Müller, Roger Whittaker, Hanns Lochmüller
Inherited defects of the neuromuscular junction (NMJ) comprise an increasingly diverse range of disorders, termed congenital myasthenic syndromes (CMS). Therapies acting on the sympathetic nervous system, including the selective β2 adrenergic agonist salbutamol and the α and β adrenergic agonist ephedrine, have become standard treatment for several types of CMS. However, the mechanism of the therapeutic effect of sympathomimetics in these disorders is not understood. Here, we examined the effect of salbutamol on NMJ development using zebrafish with deficiency of the key postsynaptic proteins Dok-7 and MuSK...
February 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29462312/myo9a-deficiency-in-motor-neurons-is-associated-with-reduced-neuromuscular-agrin-secretion
#3
Emily O'Connor, Vietxuan Phan, Isabell Cordts, George Cairns, Stefan Hettwer, Daniel Cox, Hanns Lochmüller, Andreas Roos
Congenital myasthenic syndromes (CMS) are a group of rare, inherited disorders characterised by compromised function of the neuromuscular junction, manifesting with fatigable muscle weakness. Mutations in MYO9A were previously identified as causative for CMS but the precise pathomechanism remained to be characterised. Based on the role of MYO9A as an actin-based molecular motor and as a negative regulator of RhoA, we hypothesised that loss of MYO9A may affect the neuronal cytoskeleton, leading to impaired intracellular transport...
February 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29441694/presynaptic-congenital-myasthenic-syndrome-with-altered-synaptic-vesicle-homeostasis-linked-to-compound-heterozygous-sequence-variants-in-rph3a
#4
Ricardo A Maselli, Jessica Vázquez, Leah Schrumpf, Juan Arredondo, Marian Lara, Jonathan B Strober, Peter Pytel, Robert L Wollmann, Michael Ferns
BACKGROUND: Monogenic defects of synaptic vesicle (SV) homeostasis have been implicated in many neurologic diseases, including autism, epilepsy, and movement disorders. In addition, abnormal vesicle exocytosis has been associated with several endocrine dysfunctions. METHODS: We report an 11 year old girl with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate. Failure of neuromuscular transmission was confirmed by single fiber electromyography...
February 14, 2018: Molecular Genetics & Genomic Medicine
https://www.readbyqxmd.com/read/29405353/congenital-myasthenic-syndromes-with-acetylcholinesterase-deficiency-the-pathophysiological-mechanisms
#5
REVIEW
Claire Legay
The neuromuscular junction (NMJ) is a cholinergic synapse in vertebrates. This synapse connects motoneurons to muscles and is responsible for muscle contraction, a physiological process that is essential for survival. A key factor for the normal functioning of this synapse is the regulation of acetylcholine (ACh) levels in the synaptic cleft. This is ensured by acetylcholinesterase (AChE), which degrades ACh. A number of mutations in synaptic genes expressed in motoneurons or muscle cells have been identified and are causative for a class of neuromuscular diseases called congenital myasthenic syndromes (CMSs)...
February 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29395675/congenital-myasthenic-syndromes-in-turkey-clinical-clues-and-prognosis-with-long-term-follow-up
#6
Hacer Durmus, Xin-Ming Shen, Piraye Serdaroglu-Oflazer, Bulent Kara, Yesim Parman-Gulsen, Coskun Ozdemir, Joan Brengman, Feza Deymeer, Andrew G Engel
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. Median follow-up time was 9.8 years (range 1-22 years). The most common CMS was primary acetylcholine receptor (AChR) deficiency (31/51) and the most common mutations in AChR were c.1219 + 2T > G (12/51) and c...
November 28, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29395672/dok7-myasthenic-syndrome-with-subacute-adult-onset-during-pregnancy-and-partial-response-to-fluoxetine
#7
Mariana Santos, Simão Cruz, João Peres, Luís Santos, Purificação Tavares, Jorge Pinto Basto, Vasco Salgado, Ana Herrero Valverde
DOK7 congenital myasthenic syndrome (DOK7-CMS) generally presents early in life and is treated with salbutamol or ephedrine. This report describes an atypical case of a 39-year-old woman who presented with proximal upper limb weakness in the third trimester of pregnancy and was initially diagnosed with seronegative myasthenia gravis. Dramatic clinical worsening under pyridostigmine and further inefficacy of steroids, intravenous human immunoglobulin (IVIG) and plasma exchange (PLEX) led to the presumptive diagnosis of a CMS...
December 13, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29390429/new-compound-heterozygous-variants-of-the-cholinergic-receptor-nicotinic-delta-subunit-gene-in-a-chinese-male-with-congenital-myasthenic-syndrome-a-case-report
#8
Huiru Feng, Hongyu Zhou
INTRODUCTION: Congenital myasthenic syndromes (CMS) are a group of genetic disorders that stem mostly from molecular defects in nicotinic acetylcholine receptors (AChRs). Defects in the cholinergic receptor nicotinic delta subunit (CHRND) gene can cause a series of myasthenic syndromes. Here, we report 2 new compound heterozygous variants of the CHRND gene in a Chinese male with CMS. CASE PRESENTATION: A 43-year-old Chinese male presented with progressive muscle weakness, difficulty chewing, and an inability to lift his head from the time he was 8 years old...
December 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/29383513/a-common-chrne-mutation-in-brazilian-patients-with-congenital-myasthenic-syndrome
#9
Eduardo de Paula Estephan, Cláudia Ferreira da Rosa Sobreira, André Clériston José Dos Santos, Pedro José Tomaselli, Wilson Marques, Roberta Paiva Magalhães Ortega, Marcela Câmara Machado Costa, André Macedo Serafim da Silva, Rodrigo Holanda Mendonça, Vitor Marques Caldas, Antonio Alberto Zambon, Osório Abath Neto, Paulo Eurípedes Marchiori, Carlos Otto Heise, Umbertina Conti Reed, Yoshiteru Azuma, Ana Töpf, Hanns Lochmüller, Edmar Zanoteli
The most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE...
January 30, 2018: Journal of Neurology
https://www.readbyqxmd.com/read/29381222/therapeutic-strategies-for-congenital-myasthenic-syndromes
#10
REVIEW
Manon Lee, David Beeson, Jacqueline Palace
To date, more than 25 genes have been implicated in the etiology of the congenital myasthenic syndromes (CMS), and an ever-growing phenotypic landscape is now encountered in the CMS clinic. Unlike the autoimmune form of myasthenia, there is no role for immunomodulatory agents in the treatment of CMS. The present-day drug repertoire comprises acetylcholinesterase inhibitors (mainly pyridostigmine), 3,4-diaminopyridine (3,4-DAP), ephedrine, salbutamol/albuterol, open-channel blockers (fluoxetine, quinidine), or a combination of these...
January 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29377152/a-presynaptic-congenital-myasthenic-syndrome-attributed-to-a-homozygous-sequence-variant-in-lama5
#11
REVIEW
Ricardo A Maselli, Juan Arredondo, Jessica Vázquez, Jessica X Chong, Michael J Bamshad, Deborah A Nickerson, Marian Lara, Fiona Ng, Victoria Lee Lo, Peter Pytel, Craig M McDonald
We report a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin α5 subunit gene (LAMA5). The variant c.8046C > T (p.Arg2659Trp) is rare and has a predicted deleterious effect. The affected individual, who also carries a rare homozygous sequence variant in LAMA1, had normal cognitive function, but magnetic resonance brain imaging showed mild volume loss and periventricular T2 prolongation. Repetitive nerve stimulation at 2 Hz showed 50% decrement of compound muscle action potential amplitudes but 250% facilitation immediately after exercise, similar to that seen in Lambert-Eaton myasthenic syndrome...
January 28, 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29363764/myasthenic-syndromes-due-to-defects-in-col13a1-and-in-the-n-linked-glycosylation-pathway
#12
David Beeson, Judith Cossins, Pedro Rodriguez-Cruz, Susan Maxwell, Wei-Wei Liu, Jacqueline Palace
The congenital myasthenic syndromes (CMS) are hereditary disorders of neuromuscular transmission. The number of cases recognized, at around 1:100,000 in the United Kingdom, is increasing with improved diagnosis. The advent of next-generation sequencing has facilitated the discovery of many genes that harbor CMS-associated mutations. An emerging group of CMS, characterized by a limb-girdle pattern of muscle weakness, is caused by mutations in genes that encode proteins involved in the initial steps of the N-linked glycosylation pathway, which is surprising, since this pathway is found in all mammalian cells...
January 24, 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29355968/the-unfolding-landscape-of-the-congenital-myasthenic-syndromes
#13
REVIEW
Andrew G Engel, Xin-Ming Shen, Duygu Selcen
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. Defects in LRP4 hinder synaptic development and maintenance; the defects in PREPL are predicted to diminish filling of the synaptic vesicle with acetylcholine; and defects in SNAP25, Munc13-1, and synaptotbrevin-1 impede synaptic vesicle exocytosis...
January 21, 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29315608/clinical-and-research-strategies-for-limb-girdle-congenital-myasthenic-syndromes
#14
REVIEW
Emily O'Connor, Ana Töpf, René Zahedi, Sally Spendiff, Daniel Cox, Andreas Roos, Hanns Lochmüller
Congenital myasthenic syndromes (CMS) are a group of rare disorders that cause fatigable muscle weakness due to defective signal transmission at the neuromuscular junction, a specialized synapse between peripheral motor neurons and their target muscle fibers. There are now over 30 causative genes that have been reported for CMS. Of these, there are 10 that are associated with a limb-girdle pattern of muscle weakness and are thus classed as LG-CMS. Next-generation sequencing and advanced methods of data sharing are likely to uncover further genes that are associated with similar clinical phenotypes, contributing to better diagnosis and effective treatment of LG-CMS patients...
January 5, 2018: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/29311015/tubular-aggregates-in-congenital-myasthenic-syndrome
#15
Amalia Feresiadou, Olivera Casar-Borota, Anca Dragomir, Carola Hedberg Oldfors, Erik Stålberg, Anders Oldfors
No abstract text is available yet for this article.
November 24, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/29195055/neuromuscular-junction-formation-aging-and-disorders
#16
Lei Li, Wen-Cheng Xiong, Lin Mei
Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. NMJ formation requires intimate interactions among motoneurons, muscles, and SCs. Deficits in NMJ formation and maintenance cause neuromuscular disorders, including congenital myasthenic syndrome and myasthenia gravis...
February 10, 2018: Annual Review of Physiology
https://www.readbyqxmd.com/read/29189923/congenital-myasthenic-syndrome-with-episodic-apnoea-clinical-neurophysiological-and-genetic-features-in-the-long-term-follow-up-of-19-patients
#17
Grace McMacken, Roger G Whittaker, Teresinha Evangelista, Angela Abicht, Marina Dusl, Hanns Lochmüller
BACKGROUND: Congenital myasthenic syndrome with episodic apnoea (CMS-EA) is a rare but potentially treatable cause of apparent life-threatening events in infancy. The underlying mechanisms for sudden and recurrent episodes of respiratory arrest in these patients are unclear. Whilst CMS-EA is most commonly caused by mutations in CHAT, the list of associated genotypes is expanding. METHODS: We reviewed clinical information from 19 patients with CMS-EA, including patients with mutations in CHAT, SLC5A7 and RAPSN, and patients lacking a genetic diagnosis...
November 30, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/29150079/mechanism-hypotheses-for-the-electrophysiological-manifestations-of-two-cases-of-endplate-acetylcholinesterase-deficiency-related-congenital-myasthenic-syndrome
#18
Qingyun Ding, Dongchao Shen, Yi Dai, Youfang Hu, Yuzhou Guan, Mingsheng Liu, Liying Cui
OBJECTIVE: To summarize the electrophysiological characteristics of two cases of endplate acetylcholinesterase deficiency (EAD) related congenital myasthenic syndrome (CMS) caused by COLQ mutation and to discuss the possible mechanism of these electrophysiological phenomena. METHODS: Electrophysiological examinations were conducted including nerve conduction studies, routine electromyography (EMG), repetitive nerve stimulation (RNS) and single fiber EMG (SFEMG)...
November 14, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/29130637/how-chromosomal-deletions-can-unmask-recessive-mutations-deletions-in-10q11-2-associated-with-chat-or-slc18a3-mutations-lead-to-congenital-myasthenic-syndrome
#19
Mathias Schwartz, Damien Sternberg, Sandra Whalen, Alexandra Afenjar, Arnaud Isapof, Brigitte Chabrol, Marie-France Portnoï, Solveig Heide, Boris Keren, Sandra Chantot-Bastaraud, Jean-Pierre Siffroi
A congenital myasthenia was suspected in two unrelated children with very similar phenotypes including several episodes of severe dyspnea. Both children had a 10q11.2 deletion revealed by Single Nucleotide Polymorphisms array or by Next Generation Sequencing analysis. The deletion was inherited from the healthy mother in the first case. These deletions unmasked a recessive mutation at the same locus in both cases, but in two different genes: CHAT and SLC18A3.
November 12, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29125502/congenital-myasthenic-syndromes-or%C3%A2-inherited-disorders-of-neuromuscular-transmission-recent-discoveries-and%C3%A2-open%C3%A2-questions
#20
Sophie Nicole, Yoshiteru Azuma, Stéphanie Bauché, Bruno Eymard, Hanns Lochmüller, Clarke Slater
Congenital myasthenic syndromes (CMS) form a heterogeneous group of rare diseases characterized by fatigable muscle weakness. They are genetically-inherited and caused by defective synaptic transmission at the cholinergic neuromuscular junction (NMJ). The number of genes known to cause CMS when mutated is currently 30, and the relationship between fatigable muscle weakness and defective functions is quite well-understood for many of them. However, some of the most recent discoveries in individuals with CMS challenge our knowledge of the NMJ, where the basis of the pathology has mostly been investigated in animal models...
November 8, 2017: Journal of Neuromuscular Diseases
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