Glycine and l-Arginine Treatment Causes Hyperhomocysteinemia in Cerebral Creatine Transporter Deficiency Patients

Abstract

Our aim was to monitor folate status in five creatine transporter deficient (CRTR) patients undergoing glycine/L-arginine (Gly/Arg) therapy after the finding of severe hyperhomocysteinemia in one of these cases.Five male patients (age range: 12-20; median ¼ 13 years) genetically confirmed of CRTR deficiency, who were treated with oral glycine (200 mg/kg/day) and L-arginine (400 mg/kg/day) twice a day for 9 months. Clinical followup was done at baseline and every 3 months after the start of the therapy. Serum folate was assayed by automated procedures, and plasma total homocysteine (tHcys) by HPLC with fluorescence detection. The 677C!T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene was analyzed by PCR.Case 1 presented severe hyperhomocysteinemia (81 mmol/L; control values < 10.8) 3 months after Gly/ Arg therapy. Three out of the other four cases disclosed mildly increased plasma tHcys values. Serum folate was normal in all cases before therapy, but 3 months after, a deficient status was detected in two cases and a clear decrement in the others when compared with baseline conditions. Two cases were homozygous for the 677C!T polymorphism of the MTHFR, presenting the highest plasma tHcys values. In all cases, after 3 months of folate supplementation (5 mg/day), both serum folate and tHcys concentrations returned to normal values.In conclusion, prior to the start of long-term Gly/Arg therapy, the monitoring of folate and plasma tHcys values, together with study of the 677C!T polymorphism of the MTHFR gene, seems necessary in order to correct hyperhomocysteinemia by means of folate supplementation.

X‐linked creatine transporter deficiency: clinical aspects and pathophysiology

“…Arginine supplementation might have an effect outside the brain, for instance on the muscle function. Increased urinary guanidinoacetate excretion in several patients during arginine supplementation suggests increased peripheral synthesis (Fons et al 2008;Villar et al 2012). Increased methylation demands of the GAMT reaction might explain the increased homocysteine and decreased folate levels found during arginine and glycine supplementation in CRTR-D patients (Villar et al 2012).…”

“…Increased urinary guanidinoacetate excretion in several patients during arginine supplementation suggests increased peripheral synthesis (Fons et al 2008;Villar et al 2012). Increased methylation demands of the GAMT reaction might explain the increased homocysteine and decreased folate levels found during arginine and glycine supplementation in CRTR-D patients (Villar et al 2012). Therefore, folate supplementation seems advisable to prevent hyperhomocysteinemia but also to enhance creatine synthesis (Villar et al 2012).…”

“…Increased methylation demands of the GAMT reaction might explain the increased homocysteine and decreased folate levels found during arginine and glycine supplementation in CRTR-D patients (Villar et al 2012). Therefore, folate supplementation seems advisable to prevent hyperhomocysteinemia but also to enhance creatine synthesis (Villar et al 2012). SAM supplementation might also strengthen the cerebral creatine synthesis as it crosses the blood-brain barrier and increases cerebral phosphocreatine (Moxon-Lester et al 2009).…”

The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

“…Contrary to other Cr deficiency syndromes [78][79][80], efforts to rescue Cr levels in the CTD brain by dietary supplementation had limited success [20]. Cr supplementation, alone or combined with arginine, glycine, and/or S-adenosylmethionine, failed to restore brain Cr content and to ameliorate clinical signs in the majority of patients with CTD [81][82][83][84][85]. Indeed, dietary strategies increased cerebral Cr and improved clinical parameters only in milder cases with residual brain Cr, and possible residual CRT protein function [86][87][88].…”

“…Indeed, dietary strategies increased cerebral Cr and improved clinical parameters only in milder cases with residual brain Cr, and possible residual CRT protein function [86][87][88]. Moreover, long-term administration of arginine and glycine might induce adverse effects [81][82][83][84].…”