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

Abstract: 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. We performed a cross-sectional analysis of CTD males between 2017 and 2020. Subjects underwent evaluation with electrocardiogram (ECG), echocardiography, and ambulatory ECG with comparable analysis in creatine transporter deficient mice (Slc6a8−/y) using ECG, echocardiography, exercise testing, and indirect calorimetry. Eighteen subjects with CTD (18 males, age 7.4 [3.8] years) were evaluated: seven subjects (39%) had QTc ≥ 470 milliseconds: 510.3 ± 29.0 vs. 448.3 ± 15.9, P < 0.0001. The QTc ≥ 470 milliseconds 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%). 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.

Parent Summary: These authors studied the cardiac profile of 18 boys with CTD. To do so, they analyzed the QTc interval, which reflects heart rhythm. Long QTc intervals (and long QT syndrome) may lead to heart conditions, like arrhythmia. One common designation for what counts as a long QTc interval is 450 milliseconds. Here, of the 18 patients with CTD, 7 of them had QTc intervals greater than 470 milliseconds (i.e., prolonged QTc intervals). Similar results were observed in an animal model of CTD. These authors recommend that newly diagnosed CTD patients have an electrocardiogram and an echocardiogram to measure heart rhythm (and to avoid medications that may lead to prolonged QTc intervals).

Link to article:  https://www.sciencedirect.com/science/article/pii/S1098360021051352

Link to PubMed:  https://pubmed.ncbi.nlm.nih.gov/34050321/

Authors: Mark D. Levin, Simona Bianconi, Andrew Smith, Niamh X. Cawley, An Dang Do, Dylan Hammond, Julia F. Grafstein, Audrey Thurm, Judith Miller, John Perreault, Audrey Noguchi, Danielle Springer, Beth A. Kozel, Christopher F. Spurney, Christopher A. Wassif, Zu-Xi Yu, Andreas Schulze, Forbes D. Porter, & Fady Hannah-Shmouni

Key Terms: CTD, Cardiovascular symptoms (QTc), clinical study, diagnostic, basic science, pediatric patient, male patient