Genetics in medicine : official journal of the American College of Medical Genetics · 2021
X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод пока не подготовлен
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Levin Mark D, Bianconi Simona, Smith Andrew, Cawley Niamh X, Do An Dang, Hammond Dylan, Grafstein Julia F, Thurm Audrey, Miller Judith, Perreault John, Noguchi Audrey, Springer Danielle, Kozel Beth A, Spurney Christopher F, Wassif Christopher A, Yu Zu-Xi, Schulze Andreas, Porter Forbes D, Hannah-Shmouni Fady
Аннотация
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 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.
RESULTS: 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%).
CONCLUSION: 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.
METHODS: 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.
RESULTS: 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%).
CONCLUSION: 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.