Two unrelated boys, aged 2 and 5 years, with psychomotor retardation, hyperactive behavior, and epilepsy, associated with a creatine synthesis defect, are reported from Free University Hospital, Amsterdam, The Netherlands. Independent walking was achieved at age 2 years or later, and examination revealed hypotonia, autistic behavior, and delayed language development. EEG showed multifocal epileptic activity. Seizures were controlled with valproate in one child, and with creatine monohydrate in the other. Urinalyses showed a generalized elevation of amino acids, organic acids, sialic and uric acid expressed as mmol/mol creatinine. Serum creatinine was normal or low. Treatment with creatine monohydrate (500 mg/kg/day) resulted in control of seizures, and improved tone and motor development. While autistic behavior improved, the hyperactivity and inattentiveness persisted. Concentrations of guanidino-acetate in urine and plasma decreased with treatment but were not normal. Diagnosis of creatine synthesis defect was confirmed by absence of guanidinoacetate methyltransferase in fibroblasts, [1]

COMMENT. A deficiency of guanidinoacetate methyltransferase, an inborn error of metabolism of creatine synthesis, results in a decrease in body creatine, accumulation of guanidinoacetate, and decreased urinary excretion of creatine. This rare syndrome of creatine synthesis defect is characterized by psychomotor developmental delay or regression, behavioral abnormalities, muscle hypotonia, extrapyramidal movements, and intractable epilepsy. Diagnosis is suspected when urine amino acids and organic acids are increased generally, relative to creatine. Treatment with creatine monohydrate is followed by improvement but not complete resolution of symptoms.