Congenital Myasthenic Syndromes

Abstract

Congenital myasthenic syndromes (CMS) can arise from presynaptic, synaptic, or postsynaptic defects. Mutations of the acetylcholine receptor (AChR) that increase or decrease the synaptic response to acetylcholine (ACh) are a common cause of the postsynaptic CMS. An increased response occurs in the slow-channel syndromes. Here, dominant mutations in different AChR subunits and in different domains of the subunits prolong the activation episodes of AChR by either delaying channel closure or increasing the affinity of AChR for ACh. A decreased synaptic response to ACh occurs with recessive, loss-of-function mutations. Missense mutations in the low-affinity, fast-channel syndrome and in a disorder associated with mode-switching kinetics of AChR result in brief activation episodes and reduce the probability of channel opening. Mutations causing premature termination of the translational chain or missense mutations preventing the assembly or glycosylation of AChR curtail the expression of AChR. These mutations are concentrated in the epsilon subunit, probably because substitution of the fetal gamma for the adult epsilon subunit can rescue humans from fatal null mutations in epsilon. Recent molecular genetic studies have also elucidated the pathogenesis of the CMS caused by absence of the asymmetric form of acetylcholinesterase from the synaptic basal lamina. Endplate acetylcholinesterase deficiency is now known to be caused by mutations in the collagenic tail subunit of the asymmetric enzyme that prevents the association of the collagenic tail subunit with the catalytic subunit or its insertion into the basal lamina.

Autoimmune diseases involving nicotinic receptors

“…They might also resemble phenotypes resulting from knock in of excitotoxic AChR subunit mutations, if cytotoxic autoimmune responses were to destroy AChR-expressing cells. Muscle fibers seem relatively resistant to death from excitotoxic CMS, and damage is confined to the neuromuscular junction, perhaps because these are large multinuclear cells accustomed to dealing with large calcium ion fluxes and because AChRs are confined to a tiny fraction of the muscle cell surface (Engel et al, 1999(Engel et al, , 2002a. Many small neurons are killed by similar excitotoxic M2 mutations in ␣4 or ␣7 AChRs, resulting in neonatal lethality Labarca et al, 2001).…”

“…Nicotinic acetylcholine receptors (AChRs) are the targets of both autoimmune and genetic diseases (Drachman, 1994;Lindstrom, 2000aLindstrom, , 2002aVernino et al, 2000;Grando, 2000;Engel et al, 1999Engel et al, , 2002aSteinlein, 2000;Kuryatov et al, 1997;De Fusco et al, 2000;Phillips et al, 2001). For both types of pathologies, initially myasthenias rather than neuronal AChR diseases were discovered because we better understand the functional role of muscle AChRs and most easily recognized the effects on neuromuscular transmission of pathologies resulting from decreasing or increasing AChR function.…”

“…For example, discovery that myasthenia gravis (MG) is caused by an antibody-mediated autoimmune response to muscle AChRs (Drachman, 1994;Lindstrom, 2000aLindstrom, , 2002a laid the conceptual and methodological groundwork for discoveries that: first, Lambert-Eaton myasthenic syndrome (LEMS) is caused by an antibody-mediated autoimmune response to presynaptic active zone voltage-gated calcium channels (Newsom-Davis, 1998;Lang and Vincent, 2002); second, that autoimmune myasthenia lacking antibodies to AChRs or calcium channels have autoantibodies to a receptor tyrosine kinase (Hoch et al, 2001); and, most recently, that autoantibodies to potassium channels can cause peripheral nerve hyperactivity syndromes (Hart et al, 2002). Similarly, studies of the genetic bases of congenital myasthenic syndromes (CMSs) have revealed not only more than 60 mutations in AChR subunits, but also mutations in the collagen tail of the muscle form of acetylcholinesterase, the muscle AChR binding protein rapsyn, choline acetyltransferase, plectin, and other synaptic proteins yet to be identified (Engel et al, 1999(Engel et al, , 2002a.…”

Miastenia gravis congênita e oftalmoplegia externa

“…Não existe nenhuma evidência histopatológica ou sorológica de processo imune contra o receptor de acetilcolina, assim como não há sinais de doença na mãe (3) . Os sintomas manifestam-se tipicamente ao nascimento ou nos primeiros anos de vida e constituem-se de dificuldades para a alimentação, sucção e deglutição, hipotonia, fraqueza muscular, ptose palpebral, oftalmoplegia externa, diminuição da expressão facial e envolvimento principalmente dos grupos musculares cervicais e do dorso, podendo as manifestações oculares ser as primeiras a se manifestar (8)(9) . Em alguns casos, existe severo acometimento extra-ocular na infância com fraqueza generalizada leve, a qual pode desenvolver-se concomitantemente ou anos mais tarde (10) .…”

“…As mutações no receptor de acetilcolina, que aumentam ou diminuem a resposta à acetilcolina, são causa comum de miastenia gravis congênita pós-sináptica. Também são descritas ausência da forma assimétrica de acetilcolinesterase na lâmina basal sináptica e deficiência de receptores de acetilcolina (8)(9)(10) .…”