Abstract 17231: Sodium Channel Blockers Shorten Prolonged QTC in Patients With Rett Syndrome

Abstract

Introduction: Rett syndrome (RTT) is an X-linked disorder caused by mutations in the MECP2 gene resulting in various neurological, respiratory, and gastrointestinal symptoms. Up to 25% of deaths in RTT are sudden. Prolonged corrected QT (QTc) has also been reported and thought to be a cause of sudden death in RTT. Previous studies in mice with RTT showed that MECP2 mutations lead to persistent increased cardiac sodium current causing prolonged QTc and increasing risks of ventricular tachycardia. The aim of this study was to determine whether sodium channel blockers lidocaine (acutely) and mexiletine (chronically) shorten QTc in RTT patients. Hypothesis: Sodium channel blockers such as lidocaine (acutely) and mexiletine (chronically) significantly shorten QTc (≥ 30ms from baseline) in RTT patients with prolonged QTc. Methods: RTT patients with prolonged QTc were prospectively enrolled to receive a lidocaine attenuation test. The test consisted of a loading dose of 1 mg/kg intravenous lidocaine followed by a continuous infusion at 50 μg / (kg·min). Patients were deemed responders should their QTc shorten by 30 ms or more. These patients were then prescribed mexiletine for chronic therapy. Results: A total of 6 patients (all females) were given lidocaine and mexiletine. The median age of the cohort at the time of testing was 12 years (8-19 years), and the median QTc before therapy was 480.5 ms (476-506 ms). All 6 patients responded positively to lidocaine with median QTc shortening of 44.5 ms (33-54 ms, P = 0.018). The median daily dose of mexiletine was 8.75 mg/kg. The median duration of therapy was 5 months (4-12 months). Mexiletine shortened QTc by an average of 47 ms at latest follow-up ( P = 0.016). One patient developed whole-body tremors as a side effect of mexiletine, which was stopped. Conclusions: Sodium channel blockers that target late sodium channels were effective in shortening QTc thereby confirming the presence of late sodium current causing prolonged QTc in RTT. Therefore mexiletine could be used clinically in RTT patients with long QTc. Larger and longer studies are needed to confirm these drugs’ positive effects in shortening the QTc and reducing arrhythmic events in RTT patients.