Current understanding of congenital myasthenic syndromes Andrew G Engel 1 and Steven M Sine 2 Investigation of congenital myasthenic syndromes (CMSs) disclosed a diverse array of molecular targets at the motor endplate. Clinical, electrophysiologic and morphologic studies paved the way for detecting CMS-related mutations in proteins such as the acetylcholine receptor, acetylcholinesterase, choline acetyltransferase, rapsyn, MuSK and Na v 1.4. Analysis of electrophysiologic and biochemical properties of mutant proteins expressed in heterologous systems contributed crucially to defining the molecular consequences of the observed mutations and resulted in improved therapy of different CMSs. Recent crystallography studies of choline acetyltransferase and homology structural models of the acetylcholine receptor are providing further clues to how point mutations alter protein function. Addresses 1 Department of Neurology and Neuromuscular Research Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA 2 Physiology and Biomedical Engineering and Receptor Biology Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA Corresponding authors: Engel, Andrew G (age@mayo.edu); Sine, Steven M (sine@mayo.edu) Current Opinion in Pharmacology 2005, 5:308–321 This review comes from a themed issue on Musculoskeletal Edited by Daniel Bertrand and Ronald Hogg Available online 20th April 2005 1471-4892/$ – see front matter # 2004 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2004.12.007 Introduction Congenital myasthenic syndromes (CMSs) are a hetero- geneous group of disorders in which the safety margin of neuromuscular transmission is compromised by one or more specific mechanisms. At the normal neuromuscular junction, activation of acetylcholine receptors (AChRs) by acetylcholine (ACh) triggers an endplate potential (EPP) that activates voltage-dependent sodium channels of Na v 1.4 type, giving rise to a propagated action poten- tial. A high concentration of AChRs on crests of the synaptic folds [1] and of Na v 1.4 in the depth of the folds [2,3] ensures that excitation is propagated beyond the endplate (EP) [4]. The safety margin of neuromuscular transmission is a function of the difference between the depolarization caused by the EPP and the depolarization required to activate Na v 1.4 channels. All CMSs identified so far have been traced to one or more factors that render the EPP subthreshold for activating Na v 1.4 channels or a mutation involving Na v 1.4 itself [5]. Factors determining the safety margin can be resolved into those that govern the number of ACh molecules per synaptic vesicle, those that affect quantal release of ACh, and those that determine the efficacy of individual quanta. Quantal efficacy, in turn, depends upon geometry of the synaptic space, density of acetylcholinesterase (AChE) in the synaptic basal lamina, density and distribu- tion of AChRs on the postsynaptic junctional folds, and properties of the AChR ion channel. Combined electro- myographic, morphologic and in vitro electrophysiologic studies of the neuromuscular junction identified factors that compromise the safety margin in different CMSs and pointed to candidate gene products. This candidate gene approach proved to be a powerful means of discovering diverse molecular targets in identified CMSs. Current classification of CMSs CMSs are conveniently classified according to their target as presynaptic, synaptic basal lamina-associated or post- synaptic (Table 1). The frequencies of the different types of CMS shown in Table 1 are based on 205 index patients investigated at the Mayo Clinic, US. Intercostal muscle specimens, intact from origin to insertion, were obtained from 108 patients for correlative studies of in vitro para- meters of neuromuscular transmission, ultrastructural and cytochemical studies of EPs, and genetic analysis; 97 patients were investigated using DNA isolated from blood. Table 1 indicates that postsynaptic CMSs are the most frequent and presynaptic CMS the least fre- quent. This classification is useful but still incomplete because additional types of CMS probably exist and, in a CMS that involves limb-girdle muscles but spares cranial muscles, the site of the defect remains elusive. This review focuses primarily on CMSs in which the under- lying genetic defects have been identified. CMS caused by defects in choline acetyltransferase Combined clinical and electrophysiologic clues led to discovery of this type of CMS [6]. Affected patients have sudden episodes of respiratory embarrassment and bulbar paralysis, culminating in apnea against a background of variable or no myasthenic symptoms. Between crises, the electromyographic hallmark of impaired neuromuscular transmission — a decremental response of the compound muscle action potential (CMAP) on 2 Hz stimulation — is usually absent but appears after a conditioning train of 10 Hz stimuli for 5 min. During the 10 Hz volley, CMAP decreases abnormally and then recovers slowly over the Current Opinion in Pharmacology 2005, 5:308–321 www.sciencedirect.com