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



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.

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Fig. 1: Human and mouse electrocardiogram (ECGs) demonstrate prolonged QTc and echocardiographic data consistent with cardiomyopathy.
Fig. 2: Slc68a−/y mouse model echocardiographic data 3 and 9 months demonstrates preserved systolic function, LV chamber dilation, and increased LV was thickness.
Fig. 3: Three-month Slc6a8−/y mice show increased VO2, diminished exercise capacity, and shorter time to exhaustion.
Fig. 4: Slc6a8−/y mice show significantly diminished survival probability and increased unexpected death incidence when compared to controls.

Data availability

Data will be made available upon request to first, corresponding, or senior authors. Genomic data will be made available provided related NIH and NICHD privacy guidelines can be fully met. De-identified genomic data will be provided upon request.


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The National Center for Advancing Translational Sciences (NCATS), NICHD, National Institute of Mental Health (NIMH), and National Heart, Lung, and Blood Institute (NHLBI) intramural programs funded this work. We express our sincere gratitude to the subjects and their families for supporting this work. We also thank the Association for Creatine Deficiencies. The Slc6a8−/y mice were provided by Laura Baroncelli (Italian National Research Council). We acknowledge support by Lumos Pharmaceuticals and Ultragenyx. We also acknowledge the NHLBI pathology and mouse phenotyping cores for their assistance in data collection and data analysis. Each author has reviewed the manuscript and has agreed to its submission.

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Conceptualization: M.D.L., S.B., F.D.P. Data curation: M.D.L., S.B., A.S.M., N.X.C., A.D.D., D.H., J.F.G., A.T., J.M., J.P., N.G., D.S., C.F.S., C.A.W., Z.X.Y., A.S.C., F.D.P., F.H.S. Formal analysis: M.D.L., S.B., A.S.M. N.X.C., A.D.D., J.F.G., A.T., J.M., N.G., D.S., B.K., C.F.S., C.A.W., Z.X.Y., A.S.C., F.D.P., F.H.S. Funding acquisition: F.D.P. Investigation: M.D.L., S.B., A.S.M. N.X.C., A.D.D., J.F.G., N.G., D.S., Z.X.Y., C.A.W., F.D.P., F.H.S. Methodology: M.D.L., S.B., A.D.D., FDP, Z.X.Y., F.H.S. Supervision: M.D.L., S.B., F.D.P., F.H.S. Visualization: M.D.L., Z.X.Y., A.S.M., F.H.S. Writing & editing: M.D.L., S.B., A.S.M., N.X.C., A.D.D., D.H., J.F.G., A.T., J.M., J.P., N.G., D.S., C.F.S., C.A.W., Z.X.Y., B.K., A.S.C., F.D.P., F.H.S.

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Correspondence to Mark D. Levin.

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Study approval was obtained from the IRB at the National Institute of Child Health and Human Development (NICHD), NIH. All guidelines for good clinical practice were followed. Guardians provided written consent. Assent was obtained when possible. Animal studies: All studied experiments performed had prior approval from NICHD animal studies committee and were carried out in strict compliance with all NIH guidelines and ethical regulations.

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The authors declare no competing interests.

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Levin, M.D., Bianconi, S., Smith, A. et al. X-linked creatine transporter deficiency results in prolonged QTc and increased sudden death risk in humans and disease model. Genet Med (2021).

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