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ABSTRACT

  • Guanidinoacetate methyltransferase (GAMT)-deficiency (MIM 601240) is a disease of creatine biosynthesis. Creatine is synthesized in a two-step mechanism from glycine, arginine, and methionine. In the first reaction, guanidinoacetate and ornithine are formed by arginine: glycine aminidinotransferase. In the second reaction, catalyzed by GAMT, S-adenosylmethionine donates the methyl group for formation of creatine from guanidinoacetate.

  • GAMT-deficiency manifests during the first months of life as developmental delay or arrest. Neurologic symptoms are heterogeneous, including muscular hypotonia and weakness, poor head control, involuntary extrapyramidal movements, epilepsy, and, in older patients, autistic behavior. Abnormal signals in the globus pallidus, as observed on MRI scans, may provide an important clue for diagnosis.

  • Diagnosis of the disease is based on the demonstration of excessive amounts of guanidinoacetate in body fluids, the deficiency of creatine/phosphocreatine in brain, and the absence of GAMT activity in fibroblasts, lymphocytes, or amniotic fluid cells.

  • GAMT deficiency is an autosomal recessive disorder. Two GAMT deficiency alleles have been characterized, which account for four of the six alleles in the three patients analyzed so far. The two alleles give rise to transcripts that encode truncated or elongated, presumably nonfunctional polypeptides.

  • The bulk of creatine is synthesized in liver, pancreas, and kidney; released into the blood; and taken up by cells via creatine transporters. In tissues with highly fluctuating demand for energy, such as muscle and brain, the creatine/phosphocreatine system serves as a temporal and spatial energy buffering system. Some of the abnormalities observed in GAMT deficiency can be explained by the deficiency of high-energy phosphate in such cells, while others appear to be related to the accumulation of guanidinoacetate.

  • Oral supplementation of creatine in GAMT deficiency patients partially restores the creatine/phosphocreatine in brain and has beneficial effects on the clinical manifestations. The elevation of guanidinoacetate in plasma is largely refractory to oral supplementation of creatine, which may explain the persistence of some of the clinical symptoms.

HISTORY

As early as 1928, Hunter1 wrote in his monograph on creatine and creatinine, “creatine, in fact, is probably not a waste product but an essential tissue constituent with a special function.” The chemical was first described and named “creatine” by Chevreul2 in 1835 and von Liebig3 in 1847, and its biosynthesis and metabolism were clarified over a period of more than 100 years.4 Around 1930 it became apparent that oral supplementation increases the creatine/phosphocreatine pool in animals and humans,1,5 and phosphocreatine, which diminishes during electrical stimulation of muscle,6 was recognized as a key intermediate of skeletal muscle metabolism.7

Although there are ample biochemical publications on the role of creatine in energy metabolism of different tissues and the creatine transport systems, little attention was paid to these topics in clinical medicine. The concentration of the end-product, creatinine, in plasma and its excretion in urine has been used as an indicator of kidney function: High concentrations of creatinine in plasma indicate impairment, while ...

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