Treatment of X-linked creatine transporter (SLC6A8) deficiency: systematic review of the literature and three new cases

Mol Genet Metab. 2014 Aug;112(4):259-74. doi: 10.1016/j.ymgme.2014.05.011. Epub 2014 May 29.


Background: Creatine transporter deficiency (CTD) is an X-linked inborn error of creatine metabolism characterized by reduced intra-cerebral creatine, developmental delay/intellectual disability, (ID), behavioral disturbance, seizures, and hypotonia in individuals harboring mutations in the SLC6A8 gene. Treatment for CTD includes supplementation with creatine, either alone or in combination with creatine precursors (arginine or glycine). Unlike other disorders of creatine metabolism, the efficacy of its treatment remains controversial.

Methods: We present our systematic literature review (2001-2013) comprising 7 publications (case series/reports), collectively describing 25 patients who met the inclusion criteria, and 3 additional cases treated at our institution. Definitions were established and extracted data analyzed for cognitive ability, psychiatric and behavioral disturbances, epilepsy, and cerebral proton magnetic resonance spectroscopy measurements at pre- and post-treatment.

Results: Treatment regimens varied among the 28 cases: 2 patients received creatine-monohydrate supplementation; 7 patients received L-arginine; 2 patients received creatine-monohydrate and L-arginine; and 17 patients received a combination of creatine-monohydrate, L-arginine and glycine. Median treatment duration was 34.6 months (range 3 months-5 years). Level of evidence was IV. A total of 10 patients (36%) demonstrated response to treatment, manifested by either an increase in cerebral creatine, or improved clinical parameters. Seven of the 28 patients had quantified pre- and post-treatment creatine, and it was significantly increased post-treatment. All of the patients with increased cerebral creatine also experienced clinical improvement. In addition, the majority of patients with clinical improvement had detectable cerebral creatine prior to treatment. 90% of the patients who improved were initiated on treatment before nine years of age.

Conclusions: Acknowledging the limitations of this systematic review, we conclude that a proportion of CTD patients show amenability to treatment-particularly milder cases with residual brain creatine, and therefore probable residual protein function. We propose systematic screening for CTD in patients with ID, to allow early initiation of treatment, which currently comprises oral creatine, arginine and/or glycine supplementation. Standardized monitoring for safety and evaluation of treatment effects are required in all patients. This study provides effectiveness on currently available treatment, which can be used to discern effectiveness of future interventions (e.g. cyclocreatine).

Keywords: Creatine deficiency; Developmental delay; Intellectual disability; MR spectroscopy; Outcomes; Treatment.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Adolescent
  • Brain Diseases, Metabolic, Inborn / drug therapy*
  • Child
  • Child, Preschool
  • Creatine / deficiency*
  • Creatine / therapeutic use
  • Female
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Membrane Transport Proteins / deficiency*
  • Mental Retardation, X-Linked / drug therapy*
  • Plasma Membrane Neurotransmitter Transport Proteins / deficiency*
  • Treatment Outcome


  • Membrane Transport Proteins
  • Plasma Membrane Neurotransmitter Transport Proteins
  • creatine transporter
  • Creatine

Supplementary concepts

  • Creatine deficiency, X-linked