Sodium channelopathy of peripheral nerve: tightening the genotype-phenotype relationship.

Among proteins involved in neurological disease ion channels are amenable to the most detailed characterisation: patch-clamp methods allow the opening and closing of individual channels to be documented at millisecond resolution in response to precisely delivered stimuli (whether electrical or pharmacological). In theory, therefore, inherited disorders of ion channels should be ideal candidates to link the functional consequences of individual mutations at the molecular level to their clinical manifestations. Disappointingly, it has been difficult to ‘explain’ the phenotype of many CNS channelopathies: even where diseaseassociated mutations exert robust effects on ion channel properties studied in vitro, a full account of the occurrence of hemiplegic migraine, seizures, ataxia or paroxysmal dyskinesias remains frustratingly out of reach. More success has been encountered in the muscle channelopathies: myotonic discharges are explained by disruption of the normal membrane-potential stabilising function of mutated chloride channels, or gain-of-function mutations of sodium channels. And if sufficiently severe, impaired inactivation of sodium channels predisposes to persistent depolarisation and inexcitability, accounting for attacks of periodic paralysis. Nevertheless, even among the muscle channelopathies many puzzles remain, not least how mutations that affect voltage-sensing amino acids of sodium or calcium channels lead to hypokalaemic periodic paralysis. In contrast to the patchy success in explaining genotype-phenotype correlations in most CNS and muscle channelopathies, those caused by mutations of the peripheral nerve sodium channel NaV1.7 are showing a remarkable degree of consistency, as illustrated by the elegant study of Han and co-workers in this issue (Han et al., 2009).