Congenital myasthenic syndromes Daniel Hantaı¨ , …

1 Congenital myasthenic syndromesDaniel Hanta a, Pascale Richardb, Jeanine Koenigaand Bruno EymardaPurpose of reviewCongenital myasthenic syndromes are a heterogeneous groupof diseases caused by genetic defects affecting neuromusculartransmission. In this article, a strategy that leads to thediagnosis of Congenital myasthenic syndromes is presented,and recent advances in the clinical, genetic and molecularaspects of Congenital myasthenic syndrome are findingsBesides the identification of new mutations in genes alreadyknown to be implicated in Congenital myasthenic syndromes (genes for the acetylcholine receptor subunits and the collagentail of acetylcholinesterase)

2 , mutations in other genes have morerecently been discovered and characterized (genes for cholineacetyltransferase, rapsyn, and the muscle sodium channelSCN4A). Fluoxetine has recently been proposed as analternative treatment for slow channel Congenital characterization of Congenital myasthenic syndromescomprises two complementary steps: establishing the diagnosisand identifying the pathophysiological type of congenitalmyasthenic syndrome. Characterization of the type of congenitalmyasthenic syndrome has allowed it to be classified as causedby presynaptic, synaptic and postsynaptic defects.

3 A clinicallyand muscle histopathologically oriented genetic study hasidentified several genes in which mutations cause the comprehensive characterization, the phenotypicexpression of one given gene involved is variable, and theaetiology of many Congenital myasthenic syndromes remains tobe , genetic diagnosis, microelectrophysiology,neuromuscular junction molecules, neuromuscular transmission,treatmentCurr Opin Neurol 17:539 551.#2004 Lippincott Williams & U582 and Unite Clinique de Pathologie Neuromusculaire, Institut deMyologie, andbUnite Fonctionnelle de Cardioge ne tique et Myoge ne tique, Ho pital dela Salpe trie` re, Paris, FranceCorrespondence to Daniel Hanta , Inserm U582, Institut de Myologie, Ho pital de laSalpe trie` re, 47 Boulevard de l Ho pital, 75651 Paris Cedex 13, FranceTel: +33 1 42165706; fax: +33 1 42165700.

4 E-mail: Opinion in Neurology2004, 17:539 551 AbbreviationsChATcholine acetyltransferaseCMAP compound muscle action potentialCMScongenital myasthenic syndrome#2004 Lippincott Williams & Wilkins1350-7540 IntroductionCongenital myasthenic syndromes (CMSs) form aheterogeneous group of genetic diseases characterizedby a dysfunction of neuromuscular transmission. Thisdysfunction causes muscle weakness, which is increasedby exertion and usually starts during childhood. Theprevalence of CMS is estimated at one in 500 000 inEurope, and CMSs are much more uncommon thanautoimmune myasthenia [1].

5 Knowledge of the mechanisms underlying CMS hasincreased considerably in the past 25 years, because ofthe pioneering work undertaken by the group of Engeletal. [2]. Acetylcholinesterase deficiency was the first CMSidentified, based on the lack of the enzyme atneuromuscular junctions [2]. Progressively, the patho-physiological heterogeneity of CMS was demonstrated:besides synaptic CMS caused by acetylcholinesterasedeficiency, pre- and postsynaptic CMS were described,the latter including quantitative deficiency or kineticanomalies of the acetylcholine receptor. In the past 15years, many gene mutations responsible for CMS wereidentified, affecting the different acetylcholine receptorsubunits and the collagenic tail of acetylcholinesterase[3, ].

6 Mutations in the genes for choline acetyltrans-ferase (ChAT) [5], rapsyn [6], and more recently thesodium channel SCN4A have been reported to causeCMS [7.].Several reviews have been devoted to CMS, one of themore recent being that of Engelet al.[ ]. Theobjectives of the present review are to highlight theprincipal phenotypical and pathophysiological character-istics of CMS, to pinpoint the more recent advances inthe field, and to propose a strategy for the accuratecharacterization of these of Congenital myasthenicsyndromes and recent findingsThe current classification of CMS is based on patho-physiology, on the precise identification of theneuromuscular transmission anomaly.

7 The location ofthe dysfunction of neuromuscular transmission (Fig. 1)[9], which is specific to the different CMSs, is eitherpresynaptic (generally caused by an anomaly of ChAT),synaptic (corresponding to an anomaly of the acetylcho-linesterase collagen tail), or postsynaptic (secondary to ananomaly of acetylcholine receptor or rapsyn). In theexperience of Engel s group, postsynaptic CMSs arethree times more frequent than acetylcholinesterasedeficiency and 10 times more frequent than presynaptic539 CMS [ ]. The different classes and subclasses of CMSwill be described below with reminders of their firstdescriptions and main characteristics and with anemphasis on the latest Congenital myasthenic syndromesAmong the presynaptic CMSs, only those caused bymutations in the ChAT gene have been fully character-ized, the others remain to be defined at the myasthenic syndromes caused by ChAT mutationsThese CMSs usually manifest at birth or in the neonatalperiod with bulbar disorders and respiratory insufficiencywith apnoea [10,11] or even sudden death [11,12].

8 Theseepisodes are triggered by fever, fatigue and from these bouts, the myasthenic signs are oftenmodest or not present. Cholinesterase inhibitors areeffective. Microelectrophysiology shows, after prolonged10 Hz repetitive stimulation, a reduction in amplitude ofthe miniature endplate potentials. These anomalies arecharacteristic of a defect in the resynthesis of acetylcho-line or in the filling of synaptic vesicles [10]. Ultra-structural examination shows that, when muscle is atrest, the synaptic vesicles are of reduced and collaborators [5] described the first mutationsinCHAT, the gene encoding ChAT and located ChAT is a presynaptic protein localized in thenerve terminals, where it catalyses acetylcholine produc-tion.

9 As shown in knockout mice, ChAT affectssynaptogenesis and coordinates synaptic maturation[13]. Mutations lead to a reduction or even abolition ofthe catalytic capacity of the enzyme [5]. Fourteenmutations have been reported to date, mostly of themissense type [5,14.,15.]. Recent structural studiesindicate that whereas half of the missense mutationsare positioned in the molecule such that they affectenzyme activity directly, the remaining mutations aredistant from the active site and must exert indirectFigure 1. Pathophysiological classification of Congenital myasthenic syndromesaxon terminalbasal laminaAChRrapsynmuscle fibreNa+ channelAChChATAChE Q, TPresynaptic defectsDefects in ACh resynthesis (AR) CHATP aucity of synaptic vesiclesLambert-Eaton like CMSS ynaptic defectsEndplate AChE deficiency (AR) COLQCOLQCHATP ostsynaptic defectsAChR kinetic anomalies slow channel syndrome (AD) >.

10 Fast channel syndrome (AR)AChR deficiency (AR) AChR > , . rapsyn (AR) RAPSNA nomaly of muscle Na+ channel -subunit SCN4 ARAPSNSCN4A > , , > , , Incompletely characterized CMSCMS with plectin deficiencyFamilial limb girdle myastheniaCMS with tubular aggregatesNo identified defectsCHRNB1 CHRNDCHRNA1 CHRNE The eight genes involved in Congenital myasthenic syndromes (CMSs) are namedCHRNA1,CHRNB1,CHRND,CHRNE,COLQ,CHAT , coded protein and the gene location are, respectively, as follows: (1)a(2q24 q32),b(17p11 p12),d(2q33 q34),e(17p13)subunits of acetylcholine receptor (AChR).