CLCN1 and Myotonia: Combined GOF mutations in SCN4A and LOF mutations in CLCN1 are known to synergistically aggravate the severity of myotonia.18,19 The LOF defects for R1460W channels were more severe than those of R1460Q (smaller amplitude, figure 2; greater left shift of inactivation, figure 3), which may explain why the parents shown to be p.R1460W carriers did not have myotonia.