Response to creatine analogs in fibroblasts and patients with creatine transporter deficiency

Abstract:  Creatine transporter (CRTR) deficiency is one of the most frequent causes of X-linked mental retardation. The lack of an effective treatment for this disease, in contrast to creatine (Cr) biosynthesis disorders that respond to Cr monohydrate (CM), led us to analyze the efficacy of a lipophilic molecule derived from Cr, creatine ethyl ester (CEE), in fibroblasts and patients with CRTR deficiency. CM and CEE uptake studies were performed in six controls and four fibroblast cell lines from patients. We found a significant increase in Cr uptake after 72 h of incubation with CEE (500 lmol/L) in patients and control fibroblasts compared to incubation with CM. Subsequently, we assayed the clinical effect of CEE administration in four patients with CRTR deficiency. After 1 year of treatment, a lack of significant improvement in neuropsychological assessment or changes in Cr level in brain 1H MRS was observed, and CEE was discontinued. In conclusion, this 12-month trial with CEE did not increase the brain concentration of Cr. Our in vitro data lend support to the idea of a certain passive transport of CEE in both pathological and control cells, although more lipophilic molecules or other cell systems that mimic the BBB should be used for a better approach to the in vivo system.

Parent Summary: In this study, the authors studied whether dietary supplementation with creatine monohydrate (CM) or creatine ethyl ester (CEE) (both of which can be purchased commerically in powder form) had clinical benefits. First, the researchers showed that CEE crossed the plasma membrane of fibroblasts (which are types of cells that help connect the body’s tissue together). Thus, they explored whether CEE supplementation would have benefits in patients with CTD. However, after 1 year of treatment with CEE supplementation, while there were no adverse effects, there were also no improvements in communication, daily living skills, socialization, or motor skills in these patients; also, there was not an increase in creatine in the brain. Because there were positive results with the fibroblast cells, there is reason for future research exploring mechanisms of cellular transport of CEE, but these authors do not recommend CEE treatment for patients with CTD.

Link to Article: https://www.sciencedirect.com/science/article/abs/pii/S109671920900479X

PubMed:  https://pubmed.ncbi.nlm.nih.gov/19955008/

Authors: C. Fons, A. Arias, A. Sempere, P. Póo, M. Pineda, A. Mas, A. López-Sala, J. Garcia-Villoria, M.A. Vilaseca, L. Ozaez, M. Lluch, R. Artuch, J. Campistol, & A. Ribes

Key Terms: CTD, Small Molecule Therapy, Therapeutics, Supplements, In vitro, MRS, Clinical Study, Basic Science, Pediatric Patient