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.

Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders

“…This suggests that in dystrophic or regenerating (DiMario and Funk, 1999) muscles, changes in expression of proteins that are speci®c to ®bre type, the sarcolemma and the neuromuscular junction proteins may go in parallel. Similarly, in the AChR de®ciency syndrome caused by AChR e-subunit mutations (Engel et al, 1999;Croxen et al, 2001), the AChR g-subunit is thought to be crucial for maintaining neuromuscular transmission, but the present study suggests that its expression might be restricted to type 1 ®bres. A systematic study of expression of the factors involved in controlling expression of all these proteins could lead to a better understanding of the pathogenesis of the associated disorders.…”

Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders

“…This suggests that in dystrophic or regenerating (DiMario and Funk, 1999) muscles, changes in expression of proteins that are speci®c to ®bre type, the sarcolemma and the neuromuscular junction proteins may go in parallel. Similarly, in the AChR de®ciency syndrome caused by AChR e-subunit mutations (Engel et al, 1999;Croxen et al, 2001), the AChR g-subunit is thought to be crucial for maintaining neuromuscular transmission, but the present study suggests that its expression might be restricted to type 1 ®bres. A systematic study of expression of the factors involved in controlling expression of all these proteins could lead to a better understanding of the pathogenesis of the associated disorders.…”

Choline acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine resynthesis

“…An apparent mild reduction of the EPP quantal content was also seen in the patients reported by Ohno et al17 However, in their study, the findings were not statistically significant, probably because the quantal content was calculated by the indirect method, which usually tends to overestimate quantal release 4. A practical point is that the findings of the microelectrode and ultrastructural studies in this syndrome overlap those encountered in other described presynaptic CMS, such as the quantal release deficiency syndrome15 or the congenital myasthenic syndrome resembling Lambert–Eaton myasthenic syndrome 5, 7…”

High Throughput Random Mutagenesis and Single Molecule Real Time Sequencing of the Muscle Nicotinic Acetylcholine Receptor

“…This valine (13’ in transmembrane domain 2 (TM2)) is part of the hydrophobic girdle that starts at leucine 9’. Mutations in the equivalent position in the human β1 (V266M, V266A) as well as the ε subunit (V265A) give rise to a slow channel form of congenital myasthenia, displaying slower closing rates, spontaneous openings and an increase in apparent acetylcholine affinity [ 24 , 25 ]. Recently published further analysis of such β1 and ε subunit mutants revealed an increase in gating efficiency, due to increased opening rate and decreased closing rate.…”

Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders

“…This suggests that in dystrophic or regenerating (DiMario and Funk, 1999) muscles, changes in expression of proteins that are speci®c to ®bre type, the sarcolemma and the neuromuscular junction proteins may go in parallel. Similarly, in the AChR de®ciency syndrome caused by AChR e-subunit mutations (Engel et al, 1999;Croxen et al, 2001), the AChR g-subunit is thought to be crucial for maintaining neuromuscular transmission, but the present study suggests that its expression might be restricted to type 1 ®bres. A systematic study of expression of the factors involved in controlling expression of all these proteins could lead to a better understanding of the pathogenesis of the associated disorders.…”

Choline acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine resynthesis

“…An apparent mild reduction of the EPP quantal content was also seen in the patients reported by Ohno et al17 However, in their study, the findings were not statistically significant, probably because the quantal content was calculated by the indirect method, which usually tends to overestimate quantal release 4. A practical point is that the findings of the microelectrode and ultrastructural studies in this syndrome overlap those encountered in other described presynaptic CMS, such as the quantal release deficiency syndrome15 or the congenital myasthenic syndrome resembling Lambert–Eaton myasthenic syndrome 5, 7…”

High Throughput Random Mutagenesis and Single Molecule Real Time Sequencing of the Muscle Nicotinic Acetylcholine Receptor

“…This valine (13’ in transmembrane domain 2 (TM2)) is part of the hydrophobic girdle that starts at leucine 9’. Mutations in the equivalent position in the human β1 (V266M, V266A) as well as the ε subunit (V265A) give rise to a slow channel form of congenital myasthenia, displaying slower closing rates, spontaneous openings and an increase in apparent acetylcholine affinity [ 24 , 25 ]. Recently published further analysis of such β1 and ε subunit mutants revealed an increase in gating efficiency, due to increased opening rate and decreased closing rate.…”

Expression of foetal type acetylcholine receptor is restricted to type 1 muscle fibres in human neuromuscular disorders

“…This suggests that in dystrophic or regenerating (DiMario and Funk, 1999) muscles, changes in expression of proteins that are speci®c to ®bre type, the sarcolemma and the neuromuscular junction proteins may go in parallel. Similarly, in the AChR de®ciency syndrome caused by AChR e-subunit mutations (Engel et al, 1999;Croxen et al, 2001), the AChR g-subunit is thought to be crucial for maintaining neuromuscular transmission, but the present study suggests that its expression might be restricted to type 1 ®bres. A systematic study of expression of the factors involved in controlling expression of all these proteins could lead to a better understanding of the pathogenesis of the associated disorders.…”

Choline acetyltransferase mutations in myasthenic syndrome due to deficient acetylcholine resynthesis

“…An apparent mild reduction of the EPP quantal content was also seen in the patients reported by Ohno et al17 However, in their study, the findings were not statistically significant, probably because the quantal content was calculated by the indirect method, which usually tends to overestimate quantal release 4. A practical point is that the findings of the microelectrode and ultrastructural studies in this syndrome overlap those encountered in other described presynaptic CMS, such as the quantal release deficiency syndrome15 or the congenital myasthenic syndrome resembling Lambert–Eaton myasthenic syndrome 5, 7…”

High Throughput Random Mutagenesis and Single Molecule Real Time Sequencing of the Muscle Nicotinic Acetylcholine Receptor

“…This valine (13’ in transmembrane domain 2 (TM2)) is part of the hydrophobic girdle that starts at leucine 9’. Mutations in the equivalent position in the human β1 (V266M, V266A) as well as the ε subunit (V265A) give rise to a slow channel form of congenital myasthenia, displaying slower closing rates, spontaneous openings and an increase in apparent acetylcholine affinity [ 24 , 25 ]. Recently published further analysis of such β1 and ε subunit mutants revealed an increase in gating efficiency, due to increased opening rate and decreased closing rate.…”