X-linked creatine transporter defect: an overview

In 2001 we identified a new inborn error of metabolism caused by a defect in the X-linked creatine transporter SLC6A8 gene mapped at Xq28 (SLC6A8 deficiency, McKusick 300352). An X-linked creatine transporter defect was presumed because of (1) the absence of creatine in the brain as indicated by proton magnetic resonance spectroscopy (MRS); (2) the elevated creatine levels in urine and normal guanidinoacetate levels in plasma, ruling out a creatine biosynthesis defect; (3) the absence of an improvement on creatine supplementation; and (4) the fact that the pedigree suggested an X-linked disease. Our hypothesis was proved by the presence of a hemizygous nonsense mutation in the male index patient and by the impaired creatine uptake by cultured fibroblasts. Currently, at least 7 unrelated families (13 male patients and 13 carriers) with a SLC6A8 deficiency have been identified. Four families come from one metropolitan area. This suggests that SLC6A8 deficiency may have a relatively high incidence. The hallmarks of the disorder are X-linked mental retardation, expressive speech and language delay, epilepsy, developmental delay and autistic behaviour. In approximately 50% of the female carriers, learning disabilities of varying degrees have been noted.