Cerebral creatine deficiency

Cerebral creatine deficiencies (CCDs) are a small group of inherited disorders that result from defects in creatine biosynthesis and transport. Commonly affected tissues include the brain and muscles. There are three distinct CCDs. The most common is creatine transporter deficiency (CTD), an X-linked disorder caused by pathogenic variants in creatine transporter SLC6A8. The main symptoms of CTD are intellectual disability and developmental delay, and these are caused by a lack of creatine in the brain, due to the defective transporter. There are also two enzymatic defects of creatine biosynthesis, arginine:glycine amidinotransferase deficiency (AGAT deficiency), caused by variants in GATM gene and guanidinoacetate methyltransferase deficiency (GAMT deficiency), caused by variants in GAMT gene. The two single enzyme defects are both inherited in an autosomal recessive manner.

Creatine is synthesized predominantly in the kidney and liver, by a two-step enzymatic process. In the first step, glycine and arginine are combined by arginine:glycine amidinotransferase (AGAT) to form guanidinoacetate. This step also results in the production of ornithine. Creatine is produced by the enzyme guanidinoacetate methyltransferase (GAMT). After production in the liver and kidneys, creatine is transported to organs and tissues with high energy demands, most commonly the brain and skeletal muscles. In addition to endogenous production, creatine can be obtained from dietary sources or supplementation. Ornithine aminotransferase deficiency can cause secondary creatine deficiency; however, it does not result in cerebral creatine deficiency.