Congenital myasthenic syndromes

Andrew G Engel MD (Dr. Engel of the Mayo Clinic College of Medicine has no relevant financial relationships to disclose.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released November 3, 2006; last updated December 7, 2016; expires December 7, 2019

This article includes discussion of congenital myasthenic syndromes, agrin deficiency, ALG2 and ALG14 deficiency, choline acetyltransferase deficiency, collagen 13A1 related myasthenia, congenital myopathies with myasthenic features, defects in endplate development and maintenance (agrin myasthenia, LRP4 myasthenia, MuSK myasthenia, Dok-7 myasthenia), defects in glycosylation of endplate associated proteins (GFPT1 myasthenia, DPAGT1 myasthenia, ALG2 and ALG14 myasthenias, GMPPB myasthenia), endplate acetylcholinesterase (AChE) deficiency, endplate choline acetyltransferase deficiency, escobar syndrome, fast-channel congenital myasthenic syndrome, GFPT1 myasthenia, GMPPB deficiency, high-affinity presynaptic choline transporter deficiency, laminin beta2 deficiency, mitochondrial citrate carrier deficiency, Munc13-1 deficiency, MuSK deficiency, Myosin 9A deficiency, paucity of synaptic vesicles and reduced quantal release, plectin deficiency, PREPL deletion syndrome, presynaptic high-affinity choline transporter deficiency, primary AChR deficiency, rapsyn deficiency, slow-channel congenital myasthenic syndrome, SNAP25B myasthenia, sodium channel myasthenia, synaptotagmin 2 deficiency, and vesicular ACh transporter deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Congenital myasthenic syndromes (CMS) are inherited disorders in which the safety margin of neuromuscular transmission is compromised by 1 or more specific mechanisms. The defective proteins reside in the nerve terminal, the synaptic basal lamina, or in the postsynaptic region of the neuromuscular junction, or at more than 1 of these sites. Because the congenital myasthenic syndromes 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 no fewer 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 1 type of congenital myasthenic syndrome can be harmful in another type. This article provides an overview of the clinical aspects of the congenital myasthenic syndromes. It describes the historical aspects and current classification of the congenital myasthenic syndromes, summarizes the 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 the congenital myasthenic syndromes is relevant to diagnosis, prevention, and therapy.

 

• No fewer than 30 genetically distinct congenital myasthenic syndromes have been recognized to date. 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.

 

• Cholinergic agonists are harmful in the congenital myasthenic syndromes caused by slow-channel mutations of AChR, ColQ, Dok7, laminin beta2, agrin, MuSK, and LRP4.

 

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

 

• 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.

 

• Medications that befit 1 type of congenital myasthenic syndrome can worsen another type. Therefore, 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

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 congenital myasthenic 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 syndromes mutations were also observed in MuSK that activates rapsyn (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).

In the past 5 years, an increasing number of congenital myasthenic syndromes disease genes and proteins were identified by whole exome sequencing. The identified disease proteins include SNAP25B (Shen et al 2014), synaptotagmin 2 (Herrmann et al 2014), and Munc13-1 (Engel et al 2016), all essential for synaptic vesicle exocytosis; DPAGT1 (Belaya et al 2012), ALG2 and ALG14 (Cossins et al 2013), and GMPPB (Belaya et al 2015), subserving glycosylation of synaptic proteins; LRP4 (Ohkawara et al 2014; Selcen et al 2015) required for activating MUSK; Myosin 9A (O'Connor et al 2016) required for normal endplate development; and collagen 13A1, which promotes AChR clustering (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), and the high-affinity presynaptic choline transporter (Bauche et al 2016) are all required for ACh resynthesis.

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