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Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome.

ABSTRACT: Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., Lancet Neurol 14: 420 [2015]; Finsterer, Orphanet J Rare Dis 14: 57 [2019]; Prior and Ghosh, J Child Neurol 36: 610 [2021]). The SNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novo SNAP25 c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported SNAP25 variant phenotype, and paves a foundation for personalized management for CMS18.

SUBMITTER: Reynolds HM

PROVIDER: S-EPMC9808558 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome.

Reynolds Hayley M HM Wen Ting T Farrell Andrew A Mao Rong R Moore Barry B Boyden Steven E SE Bayrak-Toydemir Pinar P Nicholas Thomas J TJ Rynearson Shawn S Holt Carson C Miller Christine C Noble Katherine K Bentley Dawn D Palmquist Rachel R Ostrander Betsy B Manberg Stephanie S Bonkowsky Joshua L JL Shayota Brian J BJ Jenkins Sabrina Malone SM

Cold Spring Harbor molecular case studies 20221228 7

Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., Lancet Neurol 14: 420 [2015]; Finsterer, Orphanet J Rare Dis 14: 57 [2019]; Prior and Ghosh, J Child Neurol 36: 610 [20 ...[more]

PMID: 36379720

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Project description:BackgroundMyasthenia is a condition in which neuromuscular transmission is affected by antibodies against neuromuscular junction components (autoimmune myasthenia gravis, MG; and neonatal myasthenia gravis, NMG) or by defects in genes for neuromuscular junction proteins (congenital myasthenic syndromes, CMSs). Clinically, some individuals seem to benefit from treatment with ephedrine, but its effects and adverse effects have not been systematically evaluated.ObjectivesTo assess the effects and adverse effects of ephedrine in people with autoimmune MG, transient neonatal MG, and the congenital myasthenic syndromes.Search methodsOn 17 November 2014, we searched the Cochrane Neuromuscular Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE. We also searched reference lists of articles, conference proceedings of relevant conferences, and prospective trial registers. In addition, we contacted manufacturers and researchers in the field.Selection criteriaWe considered randomised controlled trials (RCTs) and quasi-RCTs comparing ephedrine as a single or add-on treatment with any other active treatment, placebo, or no treatment in adults or children with autoimmune MG, NMG, or CMSs.Data collection and analysisTwo review authors independently assessed study design and quality, and extracted data. We contacted study authors for additional information. We collected information on adverse effects from included articles, and contacted authors.Main resultsWe found no RCTs or quasi-RCTs, and therefore could not establish the effect of ephedrine on MG, NMG and CMSs. We describe the results of 53 non-randomised studies narratively in the Discussion section, including observations of endurance, muscle strength and quality of life. Effects may differ depending on the type of myasthenia. Thirty-seven studies were in participants with CMS, five in participants with MG, and in 11 the precise form of myasthenia was unknown. We found no studies for NMG. Reported adverse effects included tachycardia, sleep disturbances, nervousness, and withdrawal symptoms.Authors' conclusionsThere was no evidence available from RCTs or quasi-RCTs, but some observations from non-randomised studies are available. There is a need for more evidence from suitable forms of prospective RCTs, such as series of n-of-one RCTs, that use appropriate and validated outcome measures.

Dataset Information

Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome.

Publications

Rapid genome sequencing identifies a novel de novo <i>SNAP25</i> variant for neonatal congenital myasthenic syndrome.

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