Congenital myasthenic syndromes

Andrew G Engel MD (Dr. Engel of the Mayo Clinic College of Medicine has no relevant financial relationships to disclose.)
Emma Ciafaloni MD, editor. (

Dr. Ciafaloni of the University of Rochester received personal compensation for serving on advisory boards and/or as a consultant for Avexis, Biogen, Pfizer, PTC Therapeutics, Sarepta, Ra pharma, Wave, and Strongbridge Biopharma; and for serving on a speaker’s bureau for Biogen. Dr Ciafaloni also received research and/or grant support from Orphazyme, PTC Therapeutics, Santhera, and Sarepta.

)
Originally released November 3, 2006; last updated October 13, 2020; expires October 13, 2023

Overview

Congenital myasthenic syndromes are inherited disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. Because they are relatively infrequent, they often go undiagnosed or misdiagnosed. Some congenital myasthenic syndromes can be diagnosed by clinical clues; others require special laboratory studies that define parameters of neuromuscular transmission and analyze the structure of the endplate. The genetic basis of more than 30 congenital myasthenic disorders has now been identified, with 4 novel syndromes recognized since the last review. Most congenital myasthenic syndromes are treatable but therapy has to be tailored for the underlying molecular defect because therapies beneficial in some congenital myasthenic syndromes can be harmful in another type. This article provides an overview of the clinical aspects of the congenital myasthenic syndromes, describes their historical aspects and current classification, summarizes general and specific features of the different disorders, and considers their pathophysiology, pathogenesis, and prognosis.

Key points

 

• The congenital myasthenic syndromes are not uncommon, but are commonly misdiagnosed.

 

• Identification of the clinical, physiologic, and molecular features of the congenital myasthenic syndromes is relevant to diagnosis, prevention, and therapy.

 

• To date, no fewer than 30 genetically distinct congenital myasthenic syndromes have been recognized. In the Mayo cohort of congenital myasthenic syndromes patients, molecular defects in AChR subunits, rapsyn, ColQ, Dok7, and ChAT account for 51%, 15%, 13%, 10%, and 5%, or a total of 93% of the congenital myasthenic syndromes.

 

• Cholinergic agonists benefit the congenital myasthenic syndromes caused by low expressor and fast-channel mutations in AChR subunits, rapsyn, choline acetyltransferase, glutamine-fructose-6- phosphate transaminase 1 (GFPT1), and are of variable benefit in congenital myasthenic syndromes caused by mutations in DPAGT1.

 

• Cholinergic agonists can also improve the myasthenic features associated with some congenital myopathies.

 

• The slow-channel syndrome responds to the long-lived open-channel blockers of AChR, like fluoxetine, quinine, or quinidine.

 

• The congenital myasthenic syndromes caused by defects in Dok7, LRP4, and ColQ respond to ephedrine or albuterol. Albuterol is also beneficial as an adjuvant to cholinergic agonists in congenital myasthenic syndromes caused by defects in rapsyn and by low-expressor mutations in AChR subunits.

 

• Because medications that benefit one type of syndrome can worsen another type, a correct genetic diagnosis is essential before treatment is initiated.

 

• Most congenital myasthenic syndromes disease proteins reside in the nerve terminal, the synaptic space, or in the postsynaptic region, but some are also expressed in the central nervous system and other tissues.

Historical note and terminology

The congenital myasthenic syndromes were described as early as 1937 (Rothbart 1937) but received little attention until after the autoimmune origin of acquired myasthenia gravis was discovered. In the late 1970s and early 1980s, 3 different syndromes were delineated by clinical, electromyographic, conventional microelectrode, cytochemical, and ultrastructural criteria: congenital endplate acetylcholinesterase deficiency (Engel et al 1977), the slow-channel myasthenic syndrome (Engel et al 1982), and a disorder attributed to reduced synthesis or vesicular packaging of acetylcholine (Engel and Lambert 1987; Mora et al 1987). From the early 1990s, single-channel recordings have been used to analyze the kinetic properties of AChR channels at intercostal muscle endplates of congenital myasthenic syndrome patients (Milone et al 1994). The data derived from a combination of the above studies enabled the candidate gene approach and led to discovery of mutations in endplate associated proteins, namely mutations in AChR that cause slow- and fast-channel syndromes or endplate AChR deficiency; in ColQ that result in endplate acetylcholinesterase deficiency; in choline acetyltransferase that impair ACh synthesis and cause frequent episodes of apnea; in rapsyn that impair anchoring of AChR in the postsynaptic membrane; and in Nav1.4, the voltage-gated sodium channel of skeletal muscle, that inhibit generation of the muscle action potential (Engel et al 2003; Engel and Sine 2005).

Between 2005 and 2011, congenital myasthenic syndrome mutations were also observed in MuSK, which is required for postsynaptic development (Chevessier et al 2004); in Dok-7 (Beeson et al 2006), a muscle intrinsic activator of MuSK required for maintaining the structural integrity of the neuromuscular junction (Selcen et al 2008); in agrin (Huze et al 2009), an activator of LRP4; in laminin beta2 that alters the endplate geometry (Maselli et al 2009); in plectin, an intermediate filament linker essential for cytoskeletal support (Selcen et al 2011); and in GFPT1 (Senderek et al 2011).

Since 2012, an increasing number of congenital myasthenic syndromes disease genes and proteins were identified by whole exome sequencing (Vanhaesebrouck and Beeson 2019). The identified disease proteins include SNAP25B (Shen et al 2014), synaptotagmin 2 (Herrmann et al 2014; Whittaker et al 2015), Munc13-1 (Engel et al 2016), and synaptobrevin-1 (Engel et al 2017; Salpietro et al 2017), all essential for synaptic vesicle exocytosis; DPAGT1 (Belaya et al 2012), ALG2, ALG14 (Cossins et al 2013), and GMPPB (Belaya et al 2015); LRP4 (Ohkawara et al 2014; Selcen et al 2015); Myosin 9A (O'Connor et al 2016); collagen 13A1 (Logan et al 2015); the mitochondrial citrate carrier (Chaouch et al 2014); PREPL (Regal et al 2014); the vesicular ACh transporter (O'Grady et al 2016); the high-affinity presynaptic choline transporter (Bauche et al 2016; Aran et al 2017); laminin 5A (Maselli et al 2017); and agrin (Ohkawara et al 2020; Wang et al 2020). A study describes clinical and genetic features of patients in Turkey with long-term followup (Mert et al 2019).

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