Congenital myasthenic syndrome due to novel <i>CHAT</i> mutations in an ethnic kadazandusun family

Tan, Jully; Ambang, T.; Ahmad‐Annuar, Azlina; Rajahram, Giri Shan; Wong, Kum Thong; Goh, Khean Jin

doi:10.1002/mus.25037

Cited by 9 publications

(13 citation statements)

References 23 publications

(56 reference statements)

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“…In-vitro microelectrode studies performed in biopsied muscle may show moderate reduction of quantal release [22]. AchEI may be beneficial for mild symptoms [27] but may not prevent the occurrence of apneic episodes [23]. Some patients may require permanent ventilation [25].…”

Section: Resultsmentioning

confidence: 99%

“…Single patients present with a fluctuating course [57]. Single patients develop severe scoliosis [27]. RNS may be decremental [27] or may be normal [64].…”

Section: Resultsmentioning

confidence: 99%

“…Single patients develop severe scoliosis [27]. RNS may be decremental [27] or may be normal [64]. Single-fiber EMG (SF-EMG) may reveal an increased jitter [64].…”

Section: Resultsmentioning

confidence: 99%

“…Single-fiber EMG (SF-EMG) may reveal an increased jitter [64]. Some patients may show repetitive CMAPs [27]. Most patients respond favourably to AchEI [61].…”

Section: Resultsmentioning

confidence: 99%

“…Hyperlordosis or hyperkyphosis were reported in patients carrying SCN4A [97], RAPSN [101], or SYB1 [7] mutations. Scoliosis may occur in CHRNE -related CMS [27] but also in COLQ -related CMS [43]. Foot deformities include pes cavus (hollow foot), pes planus, or hammertoes ( SYT2 -related CMS [127], SLC25A1 ).…”

Section: Resultsmentioning

confidence: 99%

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Congenital myasthenic syndromes

Finsterer

2019

Orphanet J Rare Dis

146

154

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Objectives Congenital myasthenic syndromes (CMSs) are a genotypically and phenotypically heterogeneous group of neuromuscular disorders, which have in common an impaired neuromuscular transmission. Since the field of CMSs is steadily expanding, the present review aimed at summarizing and discussing current knowledge and recent advances concerning the etiology, clinical presentation, diagnosis, and treatment of CMSs. Methods Systematic literature review. Results Currently, mutations in 32 genes are made responsible for autosomal dominant or autosomal recessive CMSs. These mutations concern 8 presynaptic, 4 synaptic, 15 post-synaptic, and 5 glycosilation proteins. These proteins function as ion-channels, enzymes, or structural, signalling, sensor, or transporter proteins. The most common causative genes are CHAT, COLQ, RAPSN, CHRNE, DOK7, and GFPT1. Phenotypically, these mutations manifest as abnormal fatigability or permanent or fluctuating weakness of extra-ocular, facial, bulbar, axial, respiratory, or limb muscles, hypotonia, or developmental delay. Cognitive disability, dysmorphism, neuropathy, or epilepsy are rare. Low- or high-frequency repetitive nerve stimulation may show an abnormal increment or decrement, and SF-EMG an increased jitter or blockings. Most CMSs respond favourably to acetylcholine-esterase inhibitors, 3,4-diamino-pyridine, salbutamol, albuterol, ephedrine, fluoxetine, or atracurium. Conclusions CMSs are an increasingly recognised group of genetically transmitted defects, which usually respond favorably to drugs enhancing the neuromuscular transmission. CMSs need to be differentiated from neuromuscular disorders due to muscle or nerve dysfunction.

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Section: Resultsmentioning

confidence: 99%

“…Single patients present with a fluctuating course [57]. Single patients develop severe scoliosis [27]. RNS may be decremental [27] or may be normal [64].…”

Section: Resultsmentioning

confidence: 99%

“…Single patients develop severe scoliosis [27]. RNS may be decremental [27] or may be normal [64]. Single-fiber EMG (SF-EMG) may reveal an increased jitter [64].…”

Section: Resultsmentioning

confidence: 99%

“…Single-fiber EMG (SF-EMG) may reveal an increased jitter [64]. Some patients may show repetitive CMAPs [27]. Most patients respond favourably to AchEI [61].…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Congenital myasthenic syndromes

Finsterer

2019

Orphanet J Rare Dis

146

154

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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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Significance of Choline Acetyltransferase Enzyme in Tackling Neurodegenerative Diseases

Bagwe

Sathaye

2022

Curr Mol Bio Rep

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Congenital myasthenic syndrome due to novel CHAT mutations in an ethnic kadazandusun family

Abstract: Differences in survival demonstrate phenotypic variability within the same family and a relatively good long-term outcome of the surviving siblings.

Cited by 9 publications

References 23 publications

Congenital myasthenic syndromes

Congenital myasthenic syndromes

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

Significance of Choline Acetyltransferase Enzyme in Tackling Neurodegenerative Diseases

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