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      Congenital myasthenic syndrome: phenotypic variability in patients harbouring p.T159P mutation in CHRNE gene

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          Abstract

          Congenital myasthenic syndromes (CMS) are rare and heterogeneous genetic diseases characterized by compromised neuromuscular transmission and clinical features of fatigable weakness; age at onset, presenting symptoms, distribution of weakness, and response to treatment differ depending on the underlying molecular defect. Mutations in one of the multiple genes, encoding proteins expressed at the neuromuscular junction, are currently known to be associated with subtypes of CMS. The most common CMS syndrome identified is associated with mutation in the CHRNE gene, causing principally muscle nicotinic acetylcholine receptor deficiency, that results in reduced receptor density on the postsynaptic membrane.

          We describe the clinical, neurophysiological and molecular features of two unrelated CMS Italian families with marked phenotypic variability, carrying the already reported p.T159P mutation in the CHRNE gene. Our report highlights clinical heterogeneity, intrafamily variability in spite of the same genotype and a possible gender effect; it confirms the efficacy and safety of salbutamol in patients who harbor mutations in the epsilon subunit of acetylcholine receptor.

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          Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor epsilon subunit.

          We describe the genetic and kinetic defects for a low-affinity fast channel disease of the acetylcholine receptor (AChR) that causes a myasthenic syndrome. In two unrelated patients with very small miniature end plate (EP) potentials, but with normal EP AChR density and normal EP ultrastructure, patch-clamp studies demonstrated infrequent AChR channel events, diminished channel reopenings during ACh occupancy, and resistance to desensitization by ACh. Each patient had two heteroallelic AChR epsilon subunit gene mutations: a common epsilon P121L mutation, a signal peptide mutation (epsilon G-8R) (patient 1), and a glycosylation consensus site mutation (epsilon S143L) (patient 2). AChR expression in HEK fibroblasts was normal with epsilon P121L but was markedly reduced with the other mutations. Therefore, epsilon P121L defines the clinical phenotype. Studies of the engineered epsilon P121L AChR revealed a markedly decreased rate of channel opening, little change in affinity of the resting state for ACh, but reduced affinity of the open channel and desensitized states.
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            Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea.

            The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
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              Identification of mutations in the MYO9A gene in patients with congenital myasthenic syndrome

              Congenital myasthenic syndromes result from defects in the neuromuscular junction. Using whole exome sequencing, O'Connor et al. identify mutations in a novel candidate gene, MYO9A, which encodes an unconventional myosin. They provide preliminary evidence that MYO9A contributes to formation of the neuromuscular junction via effects on the presynaptic motor axon.
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                Author and article information

                Journal
                Acta Myol
                Acta Myol
                Pacini
                Acta Myologica
                Pacini Editore SRL
                1128-2460
                March 2017
                : 36
                : 1
                : 28-32
                Affiliations
                [1 ] Child Neurology Unit, Foundation IRCCS Neurological Institute "Carlo Besta, Milan, Italy;
                [2 ] Neurology IV - Neuroimmunology and Neuromuscular Diseases Unit, Foundation IRCCS Neurological Institute "Carlo Besta", Milan, Italy
                Author notes
                Address for correspondence: Dr Raffaella Brugnoni, Neurology IV, Neuroimmunology and Neuromuscular Diseases Unit, Foundation IRCCS Neurological Institute "Carlo Besta", via Celoria 11, 20133 Milan, Italy. Tel. +39 02 23944652. Fax +39 02 70633874. E-mail: Raffaella.Brugnoni@ 123456istituto-besta.it
                Article
                Pacini
                5479107
                cf834503-e6cc-46c8-a8c4-5320f7d86515
                The journal and the individual contributions contained in it are protected by the copyright of Gaetano Conte Academy, Naples, Italy

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License, which permits for noncommercial use, distribution, and reproduction in any digital medium, provided the original work is properly cited and is not altered in any way. For details, please refer to http://creativecommons.org/licenses/by-nc-nd/3.0/

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                Case Reports

                Plant science & Botany
                congenital myasthenic syndromes,chrne gene,phenotype variability
                Plant science & Botany
                congenital myasthenic syndromes, chrne gene, phenotype variability

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