Disorders of creatine synthesis

• The synthesis of creatine occurs in two steps:

1. Reaction catalyzed by L-argininglycinamide diffease (AGAT) – transfer of the amidine group from arginine to glycine to form guanidinoacetate
2. Raction catalyzed by guanidin acetate methyl transformerase (GAMT) – methylation of the amidine group of the guanidinoacetate molecule by the action of S-adenosylmethionine N-guanidinoacetate methyltransferase

• The synthesis of creatine takes place mainly in the kidneys and pancreas, which have high AGAT activity, and then in the liver, which have high GAMT activity.
• Creatine from these organs gets through the blood to the organs where it is used (mainly muscles and brain)
• When creatine enters tissue utilization, the human form of Cl-dependent creatine carrier (CRTR), SLC6A8
• Part of the intracellular creatine is reversibly converted to high-energy creatine phospahte by the action of creatine kinase (CK), which exists in three cytosol isoforms, the brain type BB-CK, the muscle type MM-CK and the heterodimer MB-CK creatine phosphate turn into creatinine non-enzymate in the muscle

Creatine synthesis disorders

• Common features are mental retardation, speech delay and epilepsy due to creatine deficiency in the brain
  • They are diagnosable magnetic resonance spectroscopy of the brain, then in the blood, urine and amniotic fluid

• L-argininglycinamide aminotransferase deficiency (AGAT)
• Guanidine acetate deficiency methyltransferase (GAMT) – guanidinoacetate accumulates, the most severe clinical manifestations, convulsions, extrapyramidal symptoms
• SLC6A8 deficiency - increased creatine/creatinine ratio

Inheritance:

• AGAT and GAMT deficit are autosomal recessive inherited
• SLC6A8 deficiency is X-linked hereditary

Treatment:

• Oral creatine supplementation in the form of creatine monohydrate in AGAT and GAMT deficiency
• Dietary restriction of arginine in GAMT deficiency
• In patients with SLC6A8 deficiency, no effective treatment has yet been found, the application of extremely high doses of creatine is being tried, glycine and arginine are also administered.

Links

Literature

• FERNANDES, John. Diagnosis and treatment of hereditary metabolic disorders. 1st edition. Praha : Triton, 2008. s. 576-580. ISBN 978-80-7387-096-6.