3 - Creatine deficiency syndromes

Abstract

This chapter discusses the etiology, biochemical pathogenesis, and pathophysiology of creatine deficiency syndromes (CDS). CDSs are a novel group of inborn errors of creatine metabolism including the biosynthetic disorders arginine:glycine amidinotransferase deficiency (AGAT) and guanidinoacetate methyltransferase deficiency (GAMT), and a defect of the creatine transporter, SLC6A8 deficiency. Etiologically, CDSs are genetic disorders, with autosomal-recessive inheritance in GAMT and AGAT deficiency and X-chromosomal inheritance in SLC6A8 deficiency. Pathogenetically, CDSs are determined by biochemical changes, including both creatine deficiency and changes in the concentrations of substrates occurring elsewhere in the creatine biosynthetic pathway. The pathophysiology of CDS is determined (1) by the disjunction of creatine synthesis and usage, (2) by cellular creatine depletion and the consequential derangement of cellular functions normally supported by creatine, and (3) by changes in cellular concentrations of intermediates of creatine's biosynthetic pathway (mainly guanidinoacetate) and biochemical changes secondary to this. The prominent central nervous system (CNS) involvement in CDS has prompted speculation on additional roles of creatine in the brain, for example, as neuromodulator. The incongruent expression patterns of AGAT and GAMT during fetal development in rats, suggest a specific function of guanidinoacetate or ornithine (products of AGAT) during development of the adult brain.