日本小児循環器学会雑誌 Pediatric Cardiology and Cardiac Surgery

Long QT syndrome (LQTS) type 8 is known as Timothy syndrome. It is a multi-systemic disorder involving QT prolongation on electrocardiogram, syndactyly, congenital heart disease, and mental retardation. Herein, we report a case of LQTS type 8 without multi-systemic disorders with a CACNA1C variant identified on whole-exome analysis. An 18-year-old male patient presented with LQTS (QTc＝500 msc) at the age of 6 years based on a school health examination. He had been asymptomatic but underwent genetic testing at the age of 9 years. However, via a conventional Sanger screening, no mutations were identified in the following genes: KCNQ1 (LQT1), KCNH2 (LQT2), and SCN5A (LQT3). During follow-up at the age of 18 years, an exercise stress test induced functional 2 : 1 atrioventricular (AV) block with a significant QT prolongation. Whole-exome analysis identified Pro857Arg, a pathogenic variant of the CACNA1C gene, in this patient (proband) and his father. We further performed a drug-provocation study using propranolol, mexiletine, and verapamil, and only mexiletine infusion (2 mg/kg) reduced the QTc interval. In conclusion, when a patient with an unidentified genotype in the major three LQTS genes present with a functional 2 : 1 AV block or T-wave alternans, further genetic screening for the CACNA1C gene might be required. There are no established guidelines on the medical treatment of LQT8. However, our findings showed that propranolol and mexiletine can be effective for the management of LQT8.