X-linked Creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model

PURPOSE: Creatine transporter deficiency (CTD) is a rare X-linked disorder of creatine transport caused by pathogenic variants in SLC6A8 (Xq28). CTD features include developmental delay, seizures and autism spectrum disorder. This study was designed to investigate CTD cardiac phenotype and sudden death risk. METHODS: We performed a cross-sectional analysis of CTD males between 2017–2020. Subjects underwent evaluation with ECG, echocardiography and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8(−/y)) using ECG, echocardiography, exercise testing and indirect calorimetry. RESULTS: Eighteen subjects with CTD [18 males, age 7.4 (3.8) years] were evaluated: seven subjects (39%) had QTc≥470msec: 510.3±29.0 vs. 448.3±15.9, P<0.0001. The QTc≥470msec cohort had increased left ventricular internal dimension(diastole) ((LVIDd) Z-score: 0.22±0.74, n=7 vs. −0.93±1.0, n=11, P=0.0059), and diminished left ventricular posterior wall dimension(diastole)((LVPWDd, in mm): 5.0±0.6, n=7 vs. 5.7±0.8, n=11, P=0.0183), when compared to subjects with normal or borderline QTc prolongation. Similar ECG and echocardiographic abnormalities were seen in Slc6a8(−/y) mice. Additionally, Slc6a8(−/y) mice had diminished survival (65%). CONCLUSIONS: Prolonged QTc and abnormal echocardiographic parameters consistent with developing cardiomyopathy are seen in some male subjects with CTD. Slc6a8(−/y) mice recapitulated these cardiac abnormalities. Male CTD subjects may be at increased risk for cardiac dysfunction and sudden death.