Epilepsy and the long QT syndrome: Is there a link?—Commentary on Hindocha et al.

To the Editors: In the last 20 years, the role of ion channels in electrophysiology has been clearly established. Ion channels are involved in the control of cardiac, muscular, and central nervous system activity. Mutations of genes encoding for ion channels, which result in alterations of channel functions, the so-called “channelopathies,” have been found in a variety of inherited cardiac, muscular, or neurological diseases. Among the cardiac channelopathies, the long QT syndrome (LQTS), one of the leading causes of death under 20 years of age, is a disease due to mutations of genes, which encode for ionic channels responsible for the control of ventricular repolarization (Schwartz, 2006). The most frequent forms of LQTS are due to mutations of genes encoding for the potassium channels Iks (KCNQ1), Ikr (KCNH2), and the sodium channel (SCN5A). Also, an increasing number of epileptic syndromes belongs to the group of channelopathies, such as benign familial neonatal convulsions due to mutations of potassium channels genes (KCNQ2, KCNQ3) or generalized epilepsy with febrile seizures (GEFS+) due to mutations of the sodium channel genes (SCN1B, SCN1A). Sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death (Nashef et al., 2007), and it has been suggested that some of these deaths may be due to cardiac arrhythmias. The report by Hidocha et al. (2007) in this issue of Epilepsia describes two cases of probable SUDEP in a GEFS+ family in which the authors identified a novel mutation of SCN1A. Unfortunately, DNA was not available from these two SUDEP cases. Screening of LQTS gene mutations was also performed in two members of this family who acted as surrogates for the SUDEP cases, in one case the father and in the other a sibling. None of the LQTS mutations were found in these family members. However, disease-causing mutations are found in only 70% of LQTS families. Furthermore, in LQTS approximately 35% are de novo mutations, that is, not inherited from any of the parents. As SUDEP occurred in two members of the same family, the involvement of de novo LQTS mutations is unlikely, but cannot be completely ruled out. The authors do not report whether an ECG had been performed in their patients or family members, and data on QT interval duration are not available. We cannot exclude that the novel mutation in the sodium channel gene responsible of GEFS+ might be also associated with QT interval prolongation, leading to a higher susceptibility to arrhythmias and sudden cardiac death in some affected individuals. Interestingly, it has been observed that the sodium channel blocker phenytoin, utilized for epilepsy therapy, is able to shorten QT interval in LQTS patients. The typical symptom of LQTS is a syncopal episode that sometimes may be associated with seizures. Cases of LQTS have been erroneously diagnosed as affected by epilepsy in the past. However, it is now recognized that in some cases, epilepsy may indeed coexist with LQTS. The effort of Hidocha et al. is meritorious for having raised the possibility of a link between neural and cardiac channelopathies. However, further research is necessary to elucidate this difficult but intriguing issue, which might have relevant clinical implications.