Slow‐channel myasthenia due to novel mutation in M2 domain of AChR delta subunit

Shen, Xiaowen; Milone, Margherita; Wang, Hang Long; Banwell, Brenda; Selcen, Duygu; Sine, Steven M.; Engel, Andrew G.

doi:10.1002/acn3.50902

Cited by 8 publications

(3 citation statements)

References 38 publications

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“…SCCMS has been reported in 34 original articles since 1995 [ 27 , 31 , 162 , 163 , 165 , 168 , 177 , 178 , 179 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 , 203 , 204 ]. As observed in other autosomal dominant disorders, the onset of SCCMS can be in adolescence or adulthood.…”

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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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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“…Analysis of pathogenic εAChR variants in CMS provided insights into structure–function relationships and mechanisms governing the postsynaptic response of the NMJ 7 , 17 , 18 , 19 , 20 , 21 that led to precise treatment of CMS patients. Patients with mutations causing slow‐channel kinetics usually respond well to long‐lived channel blockers of AChR, 22 , 23 , 24 , 25 whereas patients with fast‐channel CMS are treated with an AChE inhibitor or combined with 3,4‐DAP.…”

Section: Introductionmentioning

confidence: 99%

Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia

Shen

Nakata

Mizuno

et al. 2023

Ann Clin Transl Neurol

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Objective: To dissect the kinetic defects of acetylcholine receptor (AChR) c subunit variant in an incomplete form of the Escobar syndrome without pterygium and compare it with those of a variant of corresponding residue in the AChR e subunit in a congenital myasthenic syndrome (CMS). Methods: Whole exome sequencing, a-bungarotoxin binding assay, single channel patch-clamp recordings, and maximum likelihood analysis of channel kinetics. Results: We identified compound heterozygous variants in AChR c and e subunits in three Escobar syndrome (1-3) and three CMS patients (4-6), respectively. Each Escobar syndrome patient carries cP121R along with cV221Afs*44 in patients 1 and 2, and cY63* in patient 3. Three CMS patients share eP121T along with eR20W, eG-8R, and eY15H in patients 4, 5, and 6, respectively. Surface expressions of cP121Rand eP121T-AChR were 80% and 138% of the corresponding wild-type AChR, whereas eR20W, eG-8R, and eY15H reduced receptor expression to 27%, 35%, and 30% of wild-type eAChR, respectively. cV221Afs*44 and cY63* are null variants. Thus, cP121R and eP121T determine the phenotype. cP121R and eP121T shorten channel opening burst duration to 28% and 18% of corresponding wild-type AChR by reducing the channel gating equilibrium constant 44-and 63-fold, respectively. Interpretation: Similar impairment of channel gating efficiency of a corresponding P121 residue in the acetylcholine-binding site of the AChR c and e subunits causes Escobar syndrome without pterygium and fast-channel CMS, respectively, suggesting that therapy for the fast-channel CMS will benefit Escobar syndrome.

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“…The NMJ acetylcholine receptor (AChR) is a pentameric ligand-gated ion channel composed of four different subunits 2(␣ 1 ), ␤ 1 , δ, . Slow channel syndrome (SCS) is caused by many different variants (currently 26 known) in the genes encoding any of the four subunits of the AChR [4][5][6][7][8]. It usually presents with autosomal dominant inheritance, although recessive patterns and de novo variants have been described [9,10].…”

Section: Introductionmentioning

confidence: 99%

Slow Channel Syndrome Revisited: 40 Years Clinical Follow-Up and Genetic Characterization of Two Cases

Boon

Jacobs

Wouter

et al. 2022

JND

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Background: The slow channel syndrome is a rare hereditary disorder caused by a dominant gain-of-function variant in one of the subunits of the acetylcholine receptor at the neuromuscular junction. Patients typically experience axial, limb and particularly extensor finger muscle weakness. Objective: Age at diagnosis is variable and although the long-term prognosis is important for newly diagnosed patients, extensive follow-up studies are rare. We aim to provide answers and perspective for this patient group by presenting an elaborate description of the lifetime follow-up of two slow channel syndrome patients. Methods: We describe 40 years follow-up in two, genetically confirmed cases (CHRNA1; c.866G > T p.(Ser289Ile)(legacy Ser269Ile) and CHRNE; c.721C > T p.(Leu241Phe)(legacy Leu221Phe) variants). Results: We find that the disease course has a fluctuating pattern and is only mildly progressive. However, hormonal imbalances, (psychological) stress or excessive hot or cold environments are often aggravating factors. Quinidine and fluoxetine are helpful, but ephedrine and salbutamol may also improve symptoms. Conclusion: Slow channel syndrome is mildly progressive with a fluctuating pattern. The observations reported here provide a lifespan perspective and answers to the most pressing questions about prognosis and treatment options for newly diagnosed patients.

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Slow‐channel myasthenia due to novel mutation in M2 domain of AChR delta subunit

Cited by 8 publications

References 38 publications

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

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

Impaired gating of γ‐ and ε‐AChR respectively causes Escobar syndrome and fast‐channel myasthenia

Slow Channel Syndrome Revisited: 40 Years Clinical Follow-Up and Genetic Characterization of Two Cases

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