Determinants of the repetitive-CMAP occurrence and therapy efficacy in slow-channel myasthenia

Objective: To find determinants of the occurrence of repetitive compound muscle action potential (R-CMAP) and assess the efficacy of channel blocker therapy in slow-channel congenital myasthenic syndrome (SCCMS). Methods: Neurological examination, EMG study, lab test, muscle biopsy, and next generation and Sanger sequencing; literature review of reported SCCMS patients including EMG, kinetics of mutant AChRs, and response to therapy; simulation of decay phase of end plate potential (EPP). Results: Three newly characterized and 57 reported SCCMS patients with mutations of AChR subunits were included. In patients with R-CMAP, the length of channel opening bursts of mutant AChR was increased 8.68(mean) ± 2.82(SD)-fold compared to wild-type; in patients without R-CMAP the length was increased 3.84 ± 0.65-fold (95%CI[3.18, 6.50], P = 0.000014). The EPP amplitude after refractory period of action potential in muscle fiber is above the threshold in patients with R-CMAP, but below the threshold in patients without R-CMAP. In patients with good results from channel blocker therapy, treatment was initiated 11.60 ± 5.17 years after onset of symptoms; in patients with no to moderate benefit from channel blocker therapy, treatment was initiated 30.70 ± 12.72 years after onset (95%CI[-28.57, -9.63], P = 0.00089). Conclusions: In SCCMS the R-CMAP occurrence is related to the extent of prolongation of the opening episodes of mutant AChR channel. Channel blocker treatment is more effective the sooner it is started after the onset of symptoms. Classification of Evidence: This study provides Class IV evidence that channel blocker therapy in SCCMS patients improves symptoms.