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Congenital myasthenic syndrome

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https://www.readbyqxmd.com/read/29671051/update-on-muscle-disease
#1
J Witherick, S Brady
In this article, we highlight some of the most important developments from the last few years in the field of muscle diseases, including new additions to the congenital myasthenic syndromes (CMS) and limb-girdle muscular dystrophies (LGMD), advances in our understanding of the pathophysiology of certain muscle disorders and progress in diagnostics and therapeutics. Unsurprisingly, the most prominent developments have come from the field of genetics, with significant advances in diagnosis and gene therapy giving hope to those with hitherto untreatable conditions...
April 18, 2018: Journal of Neurology
https://www.readbyqxmd.com/read/29663639/a-novel-ecel1-mutation-expands-the-phenotype-of-distal-arthrogryposis-multiplex-congenita-type-5d-to-include-pretibial-vertical-skin-creases
#2
Eva-Lena Stattin, Josefin Johansson, Sanna Gudmundsson, Adam Ameur, Staffan Lundberg, Marie-Louise Bondeson, Maria Wilbe
Arthrogryposis multiplex congenita (AMC) is a heterogeneous disorder characterized by multiple joint contractures often in association with other congenital abnormalities. Pretibial linear vertical creases are a rare finding associated with arthrogryposis, and the etiology of the specific condition is unknown. We aimed to genetically and clinically characterize a boy from a consanguineous family, presenting with AMC and pretibial vertical linear creases on the shins. Whole exome sequencing and variant analysis revealed homozygous novel missense variants of ECEL1 (c...
April 16, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29655455/congenital-myasthenic-syndromes
#3
REVIEW
Perry B Shieh, Shin J Oh
The congenital myasthenic syndromes (CMS) are a group of rare genetic conditions characterized by abnormal neuromuscular transmission. Typically, these conditions have been the result of a dysfunctional protein that is present in the presynaptic terminal, the synaptic cleft, or the postsynaptic terminal. Many of these syndromes present within the first few years of life with fluctuating and fatiguable weakness in a distribution similar to myasthenia gravis, although a limb-girdle distribution and late onset are also seen in certain specific types of CMS...
May 2018: Neurologic Clinics
https://www.readbyqxmd.com/read/29626165/collagen-xiii-is-required-for-neuromuscular-synapse-regeneration-and-functional-recovery-after-peripheral-nerve-injury
#4
Zarin Zainul, Anne Heikkinen, Hennariikka Koivisto, Iina Rautalahti, Mika Kallio, Shuo Lin, Heli Härönen, Oula Norman, Markus A Rüegg, Heikki Tanila, Taina Pihlajaniemi
Collagen XIII occurs as both a transmembrane-bound and a shed extracellular protein, and is able to regulate the formation and function of neuromuscular synapses. Its absence results in myasthenia, i.e. pre-and postsynaptic defects at the neuromuscular junction (NMJ), leading to destabilization of the motor nerves, muscle regeneration and atrophy. Mutations in COL13A1 have recently been found to cause congenital myasthenic syndrome (CMS), characterized by fatigue and chronic muscle weakness, which may be lethal...
April 6, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29605429/dysfunction-of-nav1-4-a-skeletal-muscle-voltage-gated-sodium-channel-in-sudden-infant-death-syndrome-a-case-control-study
#5
Roope Männikkö, Leonie Wong, David J Tester, Michael G Thor, Richa Sud, Dimitri M Kullmann, Mary G Sweeney, Costin Leu, Sanjay M Sisodiya, David R FitzPatrick, Margaret J Evans, Iona J M Jeffrey, Jacob Tfelt-Hansen, Marta C Cohen, Peter J Fleming, Amie Jaye, Michael A Simpson, Michael J Ackerman, Michael G Hanna, Elijah R Behr, Emma Matthews
BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome...
March 28, 2018: Lancet
https://www.readbyqxmd.com/read/29597332/makaluvamine-g-from-the-marine-sponge-zyzzia-fuliginosa-inhibits-muscle-nachr-by-binding-at-the-orthosteric-and-allosteric-sites
#6
Denis S Kudryavtsev, Ekaterina N Spirova, Irina V Shelukhina, Lina V Son, Yana V Makarova, Natalia K Utkina, Igor E Kasheverov, Victor I Tsetlin
Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We found that pyrroloiminoquinone alkaloid Makaluvamine G (MG) inhibits several subtypes of nicotinic receptors and ionotropic γ-aminobutiric acid receptors, showing a higher affinity and moderate selectivity toward muscle nAChR. The action of MG on the latter was studied by a combination of electrophysiology, radioligand assay, fluorescent microscopy, and computer modeling...
March 28, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29497086/an-allosteric-link-connecting-the-lipid-protein-interface-to-the-gating-of-the-nicotinic-acetylcholine-receptor
#7
Jaimee A Domville, John E Baenziger
The mechanisms underlying lipid-sensing by membrane proteins is of considerable biological importance. A unifying mechanistic question is how a change in structure at the lipid-protein interface is translated through the transmembrane domain to influence structures critical to protein function. Gating of the nicotinic acetylcholine receptor (nAChR) is sensitive to its lipid environment. To understand how changes at the lipid-protein interface influence gating, we examined how a mutation at position 418 on the lipid-facing surface of the outer most M4 transmembrane α-helix alters the energetic couplings between M4 and the remainder of the transmembrane domain...
March 1, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29483676/the-second-point-mutation-in-prepl-a-case-report-and-literature-review
#8
Sebastian Silva, Noriko Miyake, Carolina Tapia, Naomichi Matsumoto
Prolyl endopeptidase-like (PREPL) deficiency (MIM# 616224) is a rare autosomal recessive inherited congenital myasthenic syndrome characterized by neonatal hypotonia, feeding problems, mild dysmorphism, and neuromuscular symptoms, followed by hyperphagia and obesity in later childhood. Some patients also exhibit growth deficits, sexual hormone deficiency, and cognitive impairments. This syndrome is caused by biallelic mutations in PREPL. To date, only one nucleotide deletion and seven small microdeletions in PREPL have been reported...
February 26, 2018: Journal of Human Genetics
https://www.readbyqxmd.com/read/29478601/genetic-basis-and-phenotypic-features-of-congenital-myasthenic-syndromes
#9
Andrew G Engel
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. No fewer than 20 disease genes have been recognized to date...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29475025/protein-anchoring-therapy-to-target-extracellular-matrix-proteins-to-their-physiological-destinations
#10
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
#11
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
#12
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
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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