Treatment outcome of creatine transporter deficiency: international retrospective cohort study

  • Theodora U. J. Bruun
  • Sarah Sidky
  • Anabela O. Bandeira
  • Francoise-Guillaume Debray
  • Can Ficicioglu
  • Jennifer Goldstein
  • Kairit Joost
  • Dwight D. Koeberl
  • Diogo Luísa
  • Marie-Cecile Nassogne
  • Siobhan O’Sullivan
  • Katrin Õunap
  • Andreas Schulze
  • Lionel van Maldergem
  • Gajja S. Salomons
  • Saadet Mercimek-Andrews
Original Article
  • 32 Downloads

Abstract

To evaluate the outcome of current treatment for creatine transporter (CRTR) deficiency, we developed a clinical severity score and initiated an international treatment registry. An online questionnaire was completed by physicians following patients with CRTR deficiency on a treatment, including creatine and/or arginine, and/or glycine. Clinical severity score included 1) global developmental delay/intellectual disability; 2) seizures; 3) behavioural disorder. Phenotype scored 1–3 = mild; 4–6 = moderate; and 7–9 = severe. We applied the clinical severity score pre- and on-treatment. Seventeen patients, 14 males and 3 females, from 16 families were included. Four patients had severe, 6 patients had moderate, and 7 patients had a mild phenotype. The phenotype ranged from mild to severe in patients diagnosed at or before 2 years of age or older than 6 years of age. The phenotype ranged from mild to severe in patients with mildly elevated urine creatine to creatinine ratio. Fourteen patients were on the combined creatine, arginine and glycine therapy. On the combined treatment with creatine, arginine and glycine, none of the males showed either deterioration or improvements in their clinical severity score, whereas two females showed improvements in the clinical severity score. Creatine monotherapy resulted in deterioration of the clinical severity score in one male. There seems to be no correlation between phenotype and degree of elevation in urine creatine to creatinine ratio, genotype, or age at diagnosis. Combined creatine, arginine and glycine therapy might have stopped disease progression in males and improved phenotype in females.

Keywords

Creatine transporter deficiency SLC6A8 Arginine and glycine treatment Creatine treatment Epilepsy Intellectual disability 

Notes

Acknowledgments

We would like to thank the families for the excellent care of their children and allowing us to present their children’s results and treatment outcome. We would like to thank Mr. Evan Munro for his help performing statistical analysis for the results. Dr. Mercimek-Andrews (principal author) was funded through the Department of Pediatrics, University of Toronto (New Investigator start-up funding), and would like to thank them for this support.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.

Ethical approval

Institutional Research Ethics Board approved the study (Approval#1000045872).

Supplementary material

11011_2018_197_MOESM1_ESM.docx (27 kb)
ESM 1 (DOCX 27 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Theodora U. J. Bruun
    • 1
    • 2
    • 3
  • Sarah Sidky
    • 2
  • Anabela O. Bandeira
    • 4
  • Francoise-Guillaume Debray
    • 5
  • Can Ficicioglu
    • 6
  • Jennifer Goldstein
    • 7
  • Kairit Joost
    • 8
  • Dwight D. Koeberl
    • 7
  • Diogo Luísa
    • 9
  • Marie-Cecile Nassogne
    • 10
  • Siobhan O’Sullivan
    • 11
  • Katrin Õunap
    • 8
    • 12
  • Andreas Schulze
    • 1
    • 2
    • 13
  • Lionel van Maldergem
    • 14
  • Gajja S. Salomons
    • 15
  • Saadet Mercimek-Andrews
    • 1
    • 2
    • 16
  1. 1.Genetics and Genome Biology Program, Research InstituteThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Division of Clinical and Metabolic Genetics, Department of PaediatricsUniversity of Toronto, The Hospital for Sick ChildrenTorontoCanada
  3. 3.Department of BiochemistryUniversity of OxfordOxfordUK
  4. 4.Pediatrics, Metabolic UnitCentro Materno Infantil do Norte, Centro Hospitalar do PortoPortoPortugal
  5. 5.Service of Human GeneticsCHU Liège, University of LiègeLiègeBelgium
  6. 6.Department of Pediatrics, Division of Human Genetics, The Children’s Hospital of PhiladelphiaPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  7. 7.Department of Pediatrics, Division of Medical GeneticsDuke University Medical CenterNorthUSA
  8. 8.Department of Clinical Genetics, United LaboratoriesTartu University HospitalTartuEstonia
  9. 9.Metabolic Unit - Child Development Center, Hospital PediátricoCentro Hospitalar e Universitário de Coimbra (CHUC)CoimbraPortugal
  10. 10.Cliniques Universitaires Saint-LucUniversité Catholique de LouvainWoluwe-Saint-LambertBelgium
  11. 11.Department of Metabolic PaediatricsRoyal Hospital for Sick ChildrenBelfastUK
  12. 12.Department of Clinical Genetics, Institute of Clinical MedicineUniversity of TartuTartuEstonia
  13. 13.Departments of Paediatrics and BiochemistryUniversity of TorontoTorontoCanada
  14. 14.Center for Human GeneticsFranche-Comté UniversityBesançonFrance
  15. 15.Metabolic Unit, Department of Clinical ChemistryVU University Medical Center, Amsterdam NeuroscienceAmsterdamThe Netherlands
  16. 16.Institute of Medical SciencesUniversity of Toronto, The Hospital for Sick ChildrenTorontoCanada

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