NOVEL SLC6A8 MUTATION IN A PATIENT WITH CREATINE TRASPORTER DEFECT RESPONSIVE TO ARGININE SUPPLEMENTATION

Three inborn errors of creatine (Cr) metabolism are known, two a¡ecting Cr biosynthesis (arginine-glycine amidinotransferase and guanidinoacetate methyltransferase de¢ciency) and one its transport (CT1). Clinical picture is heterogeneous including mental retardation, epilepsy, movement disorders, language delay and autistic-like behavior. While Cr supplementation is able to correct biosynthetic defects, it is completely ine¡ective in the transporter defect. We report a new patient affected by CT1 defect who responded positively to the supplementation with Arginine, a precursor of Cr synthesis. A 9 year-old boy was born at term after an uneventful pregnancy and presented mild respiratory distress at birth. The psychomotor development was delayed and from the age of 13 months he presented partial seizures not completely drug responsive. The clinical examination showed clumsiness, behavioural and attentional disorder, delay of language comprehension and severe impairment of verbal communication (`empty speech') due to a severe oral dyspraxia. Brain 1H-MRS showed a decrease of Cr peak and GC/ MS plasmatic and urinary Cr values demonstrated increased urinary Cr (12543.66 mmol/L; n.v. 200-5500) and an high ratio Cr/Crn (2.35; n.v. 51.8). The mutational analysis of SLC6A8 identi¢ed a novel de novo mutation (c.1006delAAC) confirming the diagnosis of X-linked CT1 defect suggested by biochemical and spectroscopy findings. Cr uptake in cultured fibroblast was absent. Lacking any alternative treatment, we decided to evaluate the effect of Arginine supplementation (300 mg/kg/ day) on clinical status and brain Cr depletion. After five months of treatment a clinical improvement associated with a slight increase of 1H-MRS Cr peak was observed.