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Congenital myasthenic syndrome

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https://www.readbyqxmd.com/read/28544784/presynaptic-congenital-myasthenic-syndrome-with-a-homozygous-sequence-variant-in-lama5-combines-myopia-facial-tics-and-failure-of-neuromuscular-transmission
#1
Ricardo A Maselli, Juan Arredondo, Jessica Vázquez, Jessica X Chong, Michael J Bamshad, Deborah A Nickerson, Marian Lara, Fiona Ng, Victoria L Lo, Peter Pytel, Craig M McDonald
Defects in genes encoding the isoforms of the laminin alpha subunit have been linked to various phenotypic manifestations, including brain malformations, muscular dystrophy, ocular defects, cardiomyopathy, and skin abnormalities. We report here a severe defect of neuromuscular transmission in a consanguineous patient with a homozygous variant in the laminin alpha-5 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 muscle weakness, myopia, and facial tics...
May 25, 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28508085/intragenic-dok7-deletion-detected-by-whole-genome-sequencing-in-congenital-myasthenic-syndromes
#2
Yoshiteru Azuma, Ana Töpf, Teresinha Evangelista, Paulo José Lorenzoni, Andreas Roos, Pedro Viana, Hidehito Inagaki, Hiroki Kurahashi, Hanns Lochmüller
OBJECTIVE: To identify the genetic cause in a patient affected by ptosis and exercise-induced muscle weakness and diagnosed with congenital myasthenic syndromes (CMS) using whole-genome sequencing (WGS). METHODS: Candidate gene screening and WGS analysis were performed in the case. Allele-specific PCR was subsequently performed to confirm the copy number variation (CNV) that was suspected from the WGS results. RESULTS: In addition to the previously reported frameshift mutation c...
June 2017: Neurology. Genetics
https://www.readbyqxmd.com/read/28505670/the-increasing-genetic-and-phenotypical-diversity-of-congenital-myasthenic-syndromes
#3
Grace McMacken, Angela Abicht, Teresinha Evangelista, Sally Spendiff, Hanns Lochmüller
No abstract text is available yet for this article.
May 15, 2017: Neuropediatrics
https://www.readbyqxmd.com/read/28478914/late-onset-limb-girdle-muscular-dystrophy-caused-by-gmppb-mutations
#4
Hasan Balcin, Johanna Palmio, Sini Penttilä, Inger Nennesmo, Mikaela Lindfors, Göran Solders, Bjarne Udd
Mutations in GMPPB gene have been reported in patients with early-onset disease ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy (LGMD) with mental retardation. More recently mutations in GMPPB have been identified with congenital myasthenic syndromes as well as milder phenotypes. We report two unrelated cases with LGMD that underwent clinical, histopathological and genetic studies. In both cases, we found identical compound heterozygous GMPPB mutations c.79G>C p.D27H and c...
April 18, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28464723/genetic-landscape-of-congenital-myasthenic-syndromes-from-turkey-novel-mutations-and-clinical-insights
#5
Uluç Yiş, Kerstin Becker, Semra Hız Kurul, Gökhan Uyanik, Erhan Bayram, Göknur Haliloğlu, Ayşe İpek Polat, Müge Ayanoğlu, Derya Okur, Ayşe Fahriye Tosun, Gül Serdaroğlu, Sanem Yilmaz, Haluk Topaloğlu, Banu Anlar, Sebahattin Cirak, Andrew G Engel
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. Here, the authors report on cases with genetically proven congenital myasthenic syndromes from Turkey. The authors retrospectively reviewed their experience of all patients with congenital myasthenic syndromes, referred over a 5-year period (2011-2016) to the Child Neurology Department of Dokuz Eylül University, Izmir, Turkey...
January 1, 2017: Journal of Child Neurology
https://www.readbyqxmd.com/read/28433477/novel-mutations-in-the-c-terminal-region-of-gmppb-causing-limb-girdle-muscular-dystrophy-overlapping-with-congenital-myasthenic-syndrome
#6
Sushan Luo, Shuang Cai, Susan Maxwell, Dongyue Yue, Wenhua Zhu, Kai Qiao, Zhen Zhu, Lei Zhou, Jianying Xi, Jiahong Lu, David Beeson, Chongbo Zhao
Mutations in the GMPPB gene may underlie both limb girdle muscular dystrophy (LGMD) and congenital myasthenic syndrome (CMS). Forty-one cases have been reported to date and hotspot mutations are emerging in the Caucasian population. Clinical and pathological features of 5 patients with compound heterozygous GMPPB mutations were collected and retrospectively reviewed. In vitro functional analysis was performed to investigate the pathogeneity of GMPPB variants. The patients presented with proximal limb weakness in their first to second decades...
March 10, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28369367/collagen-xiii-secures-pre-and-postsynaptic-integrity-of-the-neuromuscular-synapse
#7
Heli Härönen, Zarin Zainul, Hongmin Tu, Nikolay Naumenko, Raija Sormunen, Ilkka Miinalainen, Anastasia Shakirzyanova, Tuomo Oikarainen, Azat Abdullin, Paula Martin, Sabrina Santoleri, Jari Koistinaho, Israel Silman, Rashid Giniatullin, Michael A Fox, Anne Heikkinen, Taina Pihlajaniemi
Both transmembrane and extracellular cues, one of which is collagen XIII, regulate the formation and function of the neuromuscular synapse, and their absence results in myasthenia. We show that the phenotypical changes in collagen XIII knock-out mice are milder than symptoms in human patients, but the Col13a1-/- mice recapitulate major muscle findings of congenital myasthenic syndrome type 19 and serve as a disease model. In the lack of collagen XIII neuromuscular synapses do not reach full size, alignment, complexity and function resulting in reduced muscle strength...
June 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28253535/homozygous-mutations-in-vamp1-cause-a-presynaptic-congenital-myasthenic-syndrome
#8
Vincenzo Salpietro, Weichun Lin, Andrea Delle Vedove, Markus Storbeck, Yun Liu, Stephanie Efthymiou, Andreea Manole, Sarah Wiethoff, Qiaohong Ye, Anand Saggar, Kenneth McElreavey, Shyam S Krishnakumar, Matthew Pitt, Oscar D Bello, James E Rothman, Lina Basel-Vanagaite, Monika Weisz Hubshman, Sharon Aharoni, Adnan Y Manzur, Brunhilde Wirth, Henry Houlden
We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1(lew/lew) mice, observing neurophysiological features of presynaptic impairment, similar to the patients...
April 2017: Annals of Neurology
https://www.readbyqxmd.com/read/28221312/what-s-in-the-literature
#9
David Lacomis, Nicholas J Silvestri, Edward J Fine, Gil I Wolfe
In this edition of this column, we review new studies concerning the pathophysiology, treatment, and outcomes of patients with necrotizing myopathy, genetic testing in congenital myopathies, and limb girdle muscular dystrophies, and the incidence of polyneuropathy in the myotonic dystrophies. Various studies in myasthenia gravis, including those concerning antibody testing, clinical features, and quality of life are also reviewed as are recent findings in congenital myasthenic syndromes. Finally, 2 studies concerning polyneuropathy are discussed, including one on the association of polyneuropathy in patients with the metabolic syndrome and one on laboratory testing in patients with otherwise idiopathic small fiber polyneuropathy...
March 2017: Journal of Clinical Neuromuscular Disease
https://www.readbyqxmd.com/read/28221310/colq-related-congenital-myasthenic-syndrome-and-response-to-salbutamol-therapy
#10
LETTER
Hansashree Padmanabha, Arushi G Saini, Naveen Sankhyan, Pratibha Singhi
No abstract text is available yet for this article.
March 2017: Journal of Clinical Neuromuscular Disease
https://www.readbyqxmd.com/read/28221305/a-novel-missense-variant-in-the-agrn-gene-congenital-myasthenic-syndrome-presenting-with-head-drop
#11
Mert Karakaya, Ozge Ceyhan-Birsoy, Alan H Beggs, Haluk Topaloglu
Congenital myasthenic syndromes (CMS) are a heterogeneous group of diseases of the neuromuscular junction caused by compromised synaptic transmission. Clinical features include early-onset weakness of limbs and oculobulbar muscles resulting in hypotonia, bulbar paresis, ptosis, and hypoventilation. The first dropped head syndrome in children were detected in 2 patients with LMNA and SEPN1 mutations. We report a 17-month-old boy with dropped head and limb-girdle weakness, who had no ptosis or ophthalmoplegia at presentation...
March 2017: Journal of Clinical Neuromuscular Disease
https://www.readbyqxmd.com/read/28188302/vesicular-acetylcholine-transporter-defect-underlies-devastating-congenital-myasthenia-syndrome
#12
Adi Aran, Reeval Segel, Kota Kaneshige, Suleyman Gulsuner, Paul Renbaum, Scott Oliphant, Tomer Meirson, Ariella Weinberg-Shukron, Yair Hershkovitz, Sharon Zeligson, Ming K Lee, Abraham O Samson, Stanley M Parsons, Mary-Claire King, Ephrat Levy-Lahad, Tom Walsh
OBJECTIVE: To identify the genetic basis of a recessive congenital neurologic syndrome characterized by severe hypotonia, arthrogryposis, and respiratory failure. METHODS: Identification of the responsible gene by exome sequencing and assessment of the effect of the mutation on protein stability in transfected rat neuronal-like PC12(A123.7) cells. RESULTS: Two brothers from a nonconsanguineous Yemeni Jewish family manifested at birth with severe hypotonia and arthrogryposis...
March 14, 2017: Neurology
https://www.readbyqxmd.com/read/28168212/novel-synaptobrevin-1-mutation-causes-fatal-congenital-myasthenic-syndrome
#13
Xin-Ming Shen, Rosana H Scola, Paulo J Lorenzoni, Cláudia S K Kay, Lineu C Werneck, Joan Brengman, Duygu Selcen, Andrew G Engel
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...
February 2017: Annals of Clinical and Translational Neurology
https://www.readbyqxmd.com/read/28072465/splicing-regulation-and-dysregulation-of-cholinergic-genes-expressed-at-the-neuromuscular-junction
#14
REVIEW
Kinji Ohno, Mohammad Alinoor Rahman, Mohammad Nazim, Farhana Nasrin, Yingni Lin, Jun-Ichi Takeda, Akio Masuda
We humans have evolved by acquiring diversity of alternative RNA metabolisms including alternative means of splicing and transcribing non-coding genes, and not by acquiring new coding genes. Tissue-specific and developmental stage-specific alternative RNA splicing is achieved by tightly regulated spatiotemporal regulation of expressions and activations of RNA-binding proteins that recognize their cognate splicing cis-elements on nascent RNA transcripts. Genes expressed at the neuromuscular junction (NMJ) are also alternatively spliced...
January 10, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28042994/assessing-neuromuscular-junction-stability-from-stimulated-emg-in-children
#15
Matthew C Pitt, John C Mchugh, Jacquie Deeb, Ralph A Smith
OBJECTIVE: We present our 9-year experience of stimulated EMG potential analysis using concentric electrodes (SPACE) to evaluate neuromuscular junction (NMJ) disorders in awake children. The technique uses high frequency filtration of stimulated motor unit potentials and applies peak detection software to estimate mean consecutive difference (MCD). METHODS: SPACE was carried out in orbicularis oculi of 878 children (377 girls; median age 47months) between 2007 and 2015, stimulating the facial nerve with a monopolar cathode...
February 2017: Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology
https://www.readbyqxmd.com/read/28024842/congenital-myasthenic-syndrome-in-israel-genetic-and-clinical-characterization
#16
Sharon Aharoni, Menachem Sadeh, Yehuda Shapira, Simon Edvardson, Muhannad Daana, Talia Dor-Wollman, Aviva Mimouni-Bloch, Ayelet Halevy, Rony Cohen, Liora Sagie, Zohar Argov, Malcolm Rabie, Ronen Spiegel, Ilana Chervinsky, Naama Orenstein, Andrew G Engel, Yoram Nevo
The objective of the study was to evaluate the epidemiology of patients with congenital myasthenic syndrome (CMS) in Israel. Targeted mutation analysis was performed based on the clinical symptoms and electrophysiological findings for known CMS. Additional specific tests were performed in patients of Iranian and/or Iraqi Jewish origin. All medical records were reviewed and clinical data, genetic mutations and outcomes were recorded. Forty-five patients with genetic mutations in known CMS genes from 35 families were identified...
February 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/27966543/limb-girdle-myasthenia-with-digenic-rapsn-and-a-novel-disease-gene-ak9-mutations
#17
Ching-Wan Lam, Ka-Sing Wong, Ho-Wan Leung, Chun-Yiu Law
Though dysfunction of neuromuscular junction (NMJ) is associated with congenital myasthenic syndrome (CMS), the proteins involved in neuromuscular transmission have not been completely identified. In this study, we aimed to identify a novel CMS gene in a consanguineous family with limb-girdle type CMS. Homozygosity mapping of the novel CMS gene was performed using high-density single-nucleotide polymorphism microarrays. The variants in CMS gene were identified by whole-exome sequencing (WES) and Sanger sequencing...
February 2017: European Journal of Human Genetics: EJHG
https://www.readbyqxmd.com/read/27941137/tubular-aggregates-and-cylindrical-spirals-have-distinct-immunohistochemical-signatures
#18
Stefen Brady, Estelle G Healy, Qiang Gang, Matt Parton, Ros Quinlivan, Saiju Jacob, Elizabeth Curtis, Safa Al-Sarraj, Caroline A Sewry, Michael G Hanna, Henry Houlden, David Beeson, Janice L Holton
Tubular aggregates and cylindrical spirals are 2 distinct ultrastructural abnormalities observed in muscle biopsies that have similar histochemical staining characteristics on light microscopy. Both are found in a wide range of disorders. Recently, a number of genetic mutations have been reported in conditions with tubular aggregates in skeletal muscle. It is widely accepted that tubular aggregates arise from the sarcoplasmic reticulum, but the origin of cylindrical spirals has been less clearly defined. We describe the histopathological features of myopathies with tubular aggregates, including a detailed immunohistochemical analysis of congenital myasthenic syndromes with tubular aggregates due to mutations in GFPT1 and DPAGT1, and myopathies with cylindrical spirals...
December 2016: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/27874200/two-patients-with-gmppb-mutation-the-overlapping-phenotypes-of-limb-girdle-myasthenic-syndrome-and-lgmd2t-dystroglycanopathy
#19
Federica Montagnese, Elisabeth Klupp, Dimitrios C Karampinos, Saskia Biskup, Dieter Gläser, Jan S Kirschke, Benedikt Schoser
INTRODUCTION: Mutations in the GDP-mannose pyrophosphorylase-B gene (GMPPB) have been identified in congenital muscular dystrophies (CMDs), limb-girdle muscular dystrophy (LGMD2T), and congenital myasthenic syndromes (CMSs); overall, 41 patients have been described. METHODS: Two patients presented with a myasthenic syndrome (patient 1, 74-year-old) and rhabdomyolysis (patient 2, 23-year-old). Examinations included repetitive nerve stimulation, muscle biopsy and whole-body MRI (WBMRI); next generation sequencing facilitated diagnosis...
November 22, 2016: Muscle & Nerve
https://www.readbyqxmd.com/read/27830186/copy-number-analysis-reveals-a-novel-multiexon-deletion-of-the-colq-gene-in-congenital-myasthenia
#20
Wei Wang, Yanhong Wu, Chen Wang, Jinsong Jiao, Christopher J Klein
Congenital myasthenic syndrome (CMS) is genetically and clinically heterogeneous.(1) Despite a considerable number of causal genes discovered, many patients are left without a specific diagnosis after genetic testing. The presumption is that novel genes yet to be discovered will account for the majority of such patients. However, it is also possible that we are neglecting a type of genetic variation: copy number changes (>50 bp) as causal for some of these patients. Next-generation sequencing (NGS) can simultaneously screen all known causal genes(2) and is increasingly being validated to have a potential to identify copy number changes...
December 2016: Neurology. Genetics
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