Treatment outcome of creatine transporter deficiency: international retrospective cohort study
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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.
KeywordsCreatine transporter deficiency SLC6A8 Arginine and glycine treatment Creatine treatment Epilepsy Intellectual disability
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.
Institutional Research Ethics Board approved the study (Approval#1000045872).
- Betsalel OT, Pop A, Rosenberg EH, Fernandez-Ojeda M, Creatine Transporter Research, Group, Jakobs C, Salomons GS (2012) Detection of variants in SLC6A8 and functional analysis of unclassified missense variants. Mol Genet Metab 105(4):596–601. https://doi.org/10.1016/j.ymgme.2011.12.022 CrossRefPubMedGoogle Scholar
- Chilosi A, Leuzzi V, Battini R, Tosetti M, Ferretti G, Comparini A, Casarano M, Moretti E, Alessandrì MG, Bianchi MC, Cioni G (2008) Treatment with L-arginine improves neuropsychological disorders in a child with creatine transporter defect. Neurocase 14(2):151–161. https://doi.org/10.1080/13554790802060821 CrossRefPubMedGoogle Scholar
- Fons C, Sempere A, Arias A, López-Sala A, Póo P, Pineda M, Mas A, Vilaseca MA, Salomons GS, Ribes A, Artuch R, Campistol J (2008) Arginine supplementation in four patients with X-linked creatine transporter defect. J Inherit Metab Dis 31(6):724–728. https://doi.org/10.1007/s10545-008-0902-1 CrossRefPubMedGoogle Scholar
- Garcia P, Rodrigues F, Valongo C, Salomons GS, Diogo L (2012) Phenotypic variability in a Portuguese family with x-linked creatine transport deficiency. Pediatr Neurol 46(1):39–41. https://doi.org/10.1016/j.pediatrneurol.2011.10.005 CrossRefPubMedGoogle Scholar
- Kleefstra T, Rosenberg EH, Salomons GS, Stroink H, van Bokhoven H, Hamel BCJ, de Vries BBA (2005) Progressive intestinal, neurological and psychiatric problems in two adult males with cerebral creatine deficiency caused by an SLC6A8 mutation. Clin Genet 68(4):379–381. https://doi.org/10.1111/j.1399-0004.2005.00489.x CrossRefPubMedGoogle Scholar
- Malheiro R, Diogo L, Garcia P, Fineza I, Oliviera G (2012) Cerebral creatine deficiency syndromes. Acta Medica Port 25(6):389–398Google Scholar
- Mercimek-Mahmutoglu S, Salomons GS (2009) [updated 2015] Creatine deficiency syndromes. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong CT, Stephens K (eds) GeneReviews® [internet]. Seattle: University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK3794/. Accessed Nov 2016
- Mercimek-Mahmutoglu S, Connolly MB, Poskitt KJ, Horvath GA, Lowry N, Salomons GS, Casey B, Sinclair G, Davis C, Jakobs C, Stockler-Ipsiroglu S (2010) Treatment of intractable epilepsy in a female with SLC6A8 deficiency. Mol Genet Metab 101(4):409–412. https://doi.org/10.1016/j.ymgme.2010.08.016 CrossRefPubMedGoogle Scholar
- Valayannopoulos V, Boddaert N, Chabli A, Barbier V, Desguerre I, Philippe A, Afenjar A, Mazzuca M, Cheillan D, Munnich A, de Keyzer Y, Jakobs C, Salomons GS, de Lonlay P (2012) Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect. J Inherit Metab Dis 35(1):151–157. https://doi.org/10.1007/s10545-011-9358-9 CrossRefPubMedGoogle Scholar