Response to creatine analogs in fibroblasts and patients with creatine transporter deficiency.
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 micromol/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 (1)H 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.
Fons
C
C
Department of Child Neurology, Hospital Universitari Sant Joan de Déu, Centre for Research on Rare Diseases, CIBERER, Barcelona, Spain. cfons@hsjdbcn.org
Arias
A
A
Sempere
A
A
Póo
P
P
Pineda
M
M
Mas
A
A
López-Sala
A
A
Garcia-Villoria
J
J
Vilaseca
M A
MA
Ozaez
L
L
Lluch
M
M
Artuch
R
R
Campistol
J
J
Ribes
A
A
D001921:Brain / Q000378:metabolism; D002460:Cell Line; D003401:Creatine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D026901:Membrane Transport Proteins / Q000172:deficiency*; D038901:X-Linked Intellectual Disability / Q000188:drug therapy*; D016896:Treatment Outcome
D026901:Membrane Transport Proteins; C080679:creatine transporter; C542315:creatine ethyl ester; D003401:Creatine