Congenital Myasthenic Syndrome Caused by a Novel Hemizygous CHAT Mutation

Zhang, Yixia; Cheng, Xinru; Luo, Chenghan; Lei, Mengyuan; Mao, Fengxia; Shi, Zhang; Cao, Wenjun; Zhang, Jingdi; Zhang, Qian

doi:10.3389/fped.2020.00185

Cited by 12 publications

(13 citation statements)

References 30 publications

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“…Presynaptic CMS types usually present with dyspnea, apnea, arthrogryposis, ventilator dependence, fatigue, ptosis, and bulbar paralysis. [13] In our study, our patients with CHAT mutation had a severe weakness, ptosis, bulbar findings, and arthrogryposis. One of our patients was connected to a mechanical ventilator.…”

Section: Discussionsupporting

confidence: 45%

Different Faces of Congenital Myasthenic Syndromes in Childhood

Kırık¹

2022

South Clin Ist Euras

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Objective: Congenital myasthenic syndrome (CMS) is a heterogeneous group of diseases that are not immune-mediated. It is caused by structural defects in different synaptic proteins of neuromuscular transmission as a result of different mutations. CMS is classified according to the location of the mutant protein as presynaptic, synaptic basal lamina-associated, or postsynaptic. In this study, we aimed to help further the knowledge of this issue by analyzing the clinical features and treatment responses of patients with an extremely rare condition of CMS. Methods:The clinical information of 13 patients who attended the CMS clinic at Mersin City Training and Research Hospital and Aydın Maternity and Child Hospital were reviewed. After considering the clinical diagnosis in all our cases, we performed a genetic diagnosis with whole exon sequencing or a CMS panel. Results:Of the 13 patients included in this study, 11 (84.6%) were males and 2 (15.4%) were females. The mean age of our patients was 73.30±60.56 months, and the mean age at the time of diagnosis was 44±49.15 months. In our patients diagnosed with CMS, 9 (69.2%) COLQ mutations, 2 (15.4%) CHAT mutations, 1 (7.7%) RAPSN mutation, and 1 (7.7%) SCN4A mutation were observed. Ephedrine was started in 8 of the 9 patients with COLQ mutations, and a good response was obtained. A good response to treatment was not observed in those patients who were started on pyridostigmine. Conclusion:CMS can often be confused with other neuromuscular diseases. In patients presenting with ptosis, bulbar findings, apnea, and muscle weakness, CMS should be prediagnosed, and a genetic examination should be performed on these patients.

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Section: Discussionsupporting

confidence: 45%

Different Faces of Congenital Myasthenic Syndromes in Childhood

Kırık¹

2022

South Clin Ist Euras

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“…We sought to evaluate our sifting criteria before proceeding further. To do so, we collected all 36 CHAT SNPs associated with CMS that have been reported so far 9‐14,16‐20,49,50,52‐54 and subjected them to our filtering process. In the first step, 89% (32) mutations were predicted to be deleterious, which is much higher than the 26% we obtained when filtering the 334 unassigned missense mutations.…”

Section: Resultsmentioning

confidence: 99%

A multidimensional computational exploration of congenital myasthenic syndrome causing mutations in human choline acetyltransferase

Janežič

Dileep

Zhang

2021

J of Cellular Biochemistry

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Missense mutations of human choline acetyltransferase (CHAT) are mainly associated with congenital myasthenic syndrome (CMS). To date, several pathogenic mutations have been reported, but due to the rarity and genetic complexity of CMS and difficult genotype–phenotype correlations, the CHAT mutations, and their consequences are underexplored. In this study, we systematically sift through the available genetic data in search of previously unreported pathogenic mutations and use a dynamic in silico model to provide structural explanations for the pathogenicity of the reported deleterious and undetermined variants. Through rigorous multiparameter analyses, we conclude that mutations can affect CHAT through a variety of different mechanisms: by disrupting the secondary structure, by perturbing the P‐loop through long‐range allosteric interactions, by disrupting the domain connecting loop, and by affecting the phosphorylation process. This study provides the first dynamic look at how mutations affect the structure and catalytic activity in CHAT and highlights the need for further genomic research to better understand the pathology of CHAT.

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“…CHAT -CMS has been reported in 19 original articles since 2001 [ 45 , 140 , 141 , 142 , 340 , 343 , 353 , 354 , 355 , 356 , 357 , 358 , 359 , 360 , 361 , 362 , 363 , 364 ]. A follow-up study of 11 patients with CHAT -CMS for maximum of 12 years showed two forms of disease [ 358 ].…”

Section: Thirty-five Genes In 14 Groups Of Cmsmentioning

confidence: 99%

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

Ohno

Ohkawara

Shen

et al. 2023

IJMS

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Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders characterized by impaired neuromuscular signal transmission due to germline pathogenic variants in genes expressed at the neuromuscular junction (NMJ). A total of 35 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT, CHD8, CHRNA1, CHRNB1, CHRND, CHRNE, CHRNG, COL13A1, COLQ, DOK7, DPAGT1, GFPT1, GMPPB, LAMA5, LAMB2, LRP4, MUSK, MYO9A, PLEC, PREPL, PURA, RAPSN, RPH3A, SCN4A, SLC18A3, SLC25A1, SLC5A7, SNAP25, SYT2, TOR1AIP1, UNC13A, VAMP1). The 35 genes can be classified into 14 groups according to the pathomechanical, clinical, and therapeutic features of CMS patients. Measurement of compound muscle action potentials elicited by repetitive nerve stimulation is required to diagnose CMS. Clinical and electrophysiological features are not sufficient to identify a defective molecule, and genetic studies are always required for accurate diagnosis. From a pharmacological point of view, cholinesterase inhibitors are effective in most groups of CMS, but are contraindicated in some groups of CMS. Similarly, ephedrine, salbutamol (albuterol), amifampridine are effective in most but not all groups of CMS. This review extensively covers pathomechanical and clinical features of CMS by citing 442 relevant articles.

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Congenital Myasthenic Syndrome Caused by a Novel Hemizygous CHAT Mutation

Cited by 12 publications

References 30 publications

Different Faces of Congenital Myasthenic Syndromes in Childhood

Different Faces of Congenital Myasthenic Syndromes in Childhood

A multidimensional computational exploration of congenital myasthenic syndrome causing mutations in human choline acetyltransferase

Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes—A Comprehensive Review

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