Prominent U-waves without QT prolongation in X-linked creatine transporter deficiency caused by SLC6A8 variants

Creatine transporter deficiency (CTD) is a rare X-linked disease caused by SLC6A8 variants, which impair ATP-dependent energy metabolism in neurons and myocytes. Although the neurologic and muscular manifestations are well characterized, the cardiac phenotype remains poorly understood. Early clinical reports and a transgenic mouse model have raised concerns about possible associations with corrected QT (QTc) interval prolongation and dilated cardiomyopathy.

This study aimed to characterize the cardiac phenotype of male patients with CTD.

This cross-sectional study prospectively included male patients with CTD with confirmed SLC6A8 pathogenic variants. A systematic cardiological evaluation was performed, including 12-lead resting electrocardiogram (ECG), ambulatory ECG (Holter monitoring), transthoracic echocardiography, and biological analysis.

23 male patients with CTD (median [interquartile range] age 17.1 years [13.5-20.5]) with 20 distinct SLC6A8 variants were included. Prominent U-waves were observed in 82.6% of resting ECGs and 95% of ambulatory ECGs, and biphasic T-waves in 30.4% and 90%, respectively. No patient had a prolonged QTc interval (median [interquartile range] QTc interval 431 ms [411-443]) when the U-waves were excluded. Repolarization abnormalities were not secondary to electrolyte disorders. No sustained arrhythmias or conduction disorders were observed. No patient reported syncope or cardiac arrest. Transthoracic echocardiography revealed no cardiomyopathy or congenital heart defects. 2 patients had mildly elevated N-terminal pro-brain natriuretic peptide with no clinical or imaging abnormalities.

This study highlighted an atypical ventricular repolarization pattern in patients with CTD (prominent U-waves and biphasic T-waves) without QTc interval prolongation. Long-term follow-up data are needed to establish its prognosis, but it must be distinguished from long-QT syndrome. No patient met diagnostic criteria for cardiomyopathy or congenital heart defect.