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

Abstract

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.

Keywords: amifampridine; cholinesterase inhibitors; congenital myasthenic syndromes; ephedrine; muscle nicotinic acetylcholine receptor; neuromuscular junction; salbutamol (albuterol).

Figure 1

Thirty-five genes (red letters) causing CMS.

Figure 2

Crystal structure of AChR viewed from the extracellular side (PDB 2BG9) [87]. (A) Extracellular domains of AChR subunits. Other domains are shown in gray. (B) Transmembrane domains of AChR subunits. αM4 domains are not indicated.

Figure 3

Representative molecules at the nerve terminal and the agrin-LPR4-MuSK signaling pathway to induce AChR clustering. Interactions between binding domains are indicated by double headed arrows [71,98,100,101,102]. Broken arrows in the muscle indicate that the exact signaling molecules are not shown. Diseases other than CMS and toxins affecting the NMJ are indicated in red letters. βCAT, β-catenin; BPD, β-propeller domain; C6, six-cysteine-box; Ctgf, connective tissue growth factor; Fz-CRD, frizzled-like cysteine-rich domain; Ig, immunoglobulin-like domain; LDLR-A, low-density lipoprotein receptor class A repeat; Lgr5, leucine-rich repeat-containing G-protein coupled receptor 5; and Rspo2, R-spondin 2.

Figure 4

Hexosamine biosynthesis pathway to make UDP-GlcNAc and N-glycosylation pathway. Genes causing CMS are shown in red. Figure 4 is shown as an inset in Figure 1.