Disease relevance of GAMT

• Pathological mutations in the coding region of GAMT were recently identified in two children with symptoms of muscular hypotonia, ataxia, seizures, and abnormal extrapyramidal movements [1].
• Since the mouse mutations jittery/hesitant are located on band C of mouse chromosome 10 in a region of conserved synteny with 19p13.3 and jittery mice exhibit ataxia and abnormal movement behaviour, the genomic sequence of GAMT was determined in wild-type and jittery mice [1].
• Guanidinoacetic acid seems to be responsible for intractable seizures and the movement disorder, both exclusively found in GAMT deficiency [2].
• Patients with GAMT deficiency exhibit a more complex clinical phenotype with dystonic hyperkinetic movement disorder and epilepsy that in some cases is unresponsive to pharmacological treatment [3].
• These mice revealed decreased weight gain and reduced life expectancy, disturbed fat metabolism, behavioral abnormalities and impaired learning capacity.Oral creatine supplementation improved the clinical symptoms in both AGAT and GAMT deficiency, but not in creatine transporter deficiency [4].

Psychiatry related information on GAMT

• Guanidinoacetate N-methyltransferase deficiency results in a severe neurologic disease (age of onset 3 months to 2 years) characterized by developmental arrest, neurologic deterioration, movement disorders, mental retardation, autistic-like behavior, and epilepsy [5].

High impact information on GAMT

• INTERPRETATION: Oral creatine replacement has proved to be effective in one child with an inborn error of GAMT [6].
• METHODS: We studied and treated an infant with extrapyramidal signs who was shown--by assay for urinary creatinine and by analysis of brain metabolites with use of nuclear magnetic resonance spectra--to have depletion of body and brain creatine, due to inborn deficiency of guanidinoacetate methyltransferase (GAMT) [6].
• In two children with an accumulation of guanidinoacetate in brain and a deficiency of creatine in blood, a severe deficiency of guanidinoacetate methyltransferase (GAMT) activity was detected in the liver [7].
• We provide evidence that GAMT deficiency in mice causes biochemical adaptations in brain and skeletal muscle [8].
• Disruption of the open reading frame of the murine GAMT gene in the first exon resulted in the elimination of 210 of the 237 amino acids present in mGAMT [8].

Chemical compound and disease context of GAMT

• In a child with severe muscular hypotonia and extrapyramidal movement disorder, elevation of guanidinoacetate and deficiency of creatine in brain suggested a defect in biosynthesis of creatine at the level of guanidinoacetate methyltransferase (GAMT) (Stöckler, S. et al. (1994) Pediatr. Res. 36, 409-413) [9].

Biological context of GAMT

• 3. The human GAMT gene has a size of about 5 kb and consists of six exons which agree with the published cDNA sequence [1].
• During contig construction in the telomeric region of human chromosome 19 we identified a cosmid clone carrying the entire GAMT gene [1].
• Some patients with GAMT deficiency exhibit a more complex clinical phenotype with extrapyramidal movement disorder [10].
• These catabolites were identified as 3'-amino-3'-deoxythymidine (AMT) by fast atom bombardment mass spectrometry and 3'-amino-3'-deoxythymidine glucuronide (GAMT) through specific enzymatic hydrolysis [11].
• The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies [12].

Anatomical context of GAMT

• Only the GAMT deficiency is in addition characterized by accumulation of guanidinoacetic acid in brain and body fluids [2].
• Overexpression of GAMT restores GAMT activity in primary GAMT-deficient fibroblasts [13].
• While GAZT and ddI-M, metabolites of AZT and ddI, respectively, as well as AZT 5'-monophosphate (MP) and ddI-MP were detected in the extracellular media of all species, AMT and GAMT were produced only by rat and monkey hepatocytes [14].
• Reverse transcription-polymerase chain reaction analysis revealed that L-arginine:glycine amidinotransferase and GAMT mRNAs were expressed in the retina and the Müller cell line, TR-MUL5 [15].

Associations of GAMT with chemical compounds

• Deficiency of GAMT is the first inborn error of creatine metabolism [7].
• Treatment of combined arginine restriction and ornithine substitution in GAMT deficiency is capable to decrease guanidinoacetic acid permanently and improves the clinical outcome [2].
• We developed a strategy for the detection of AGAT and GAMT defects by measurement of guanidinoacetate (GAA) and creatine plus creatinine (Cr+Crn) in biological fluids [16].
• In addition to unchanged drug and its 5'-O-glucuronide (zidovudine glucuronide), two novel catabolites of zidovudine were detected as 3'-amino-3'-deoxythymidine (AMT), and its 5'-O-glucuronide (GAMT) [17].
• However, AMT was not a substrate for uridine 5'-diphosphoglucuronyltransferase and GAMT was found to be a reductive product of GAZT [11].

Other interactions of GAMT

• Eight guanidinoacetate methyltransferase (GAMT) deficient patients and eight creatine transporter SLC6A8 deficient patients were investigated [18].
• Data suggest that in patients with guanidinoacetate N-methyltransferase deficiency, epilepsy and associated electroencephalographic abnormalities are more responsive to creatine supplementation than to conventional antiepilepsy drugs [5].
• Furthermore, confocal immunofluorescent microscopy of dual-labeled rat retinal sections demonstrated co-localization of GAMT with glutamine synthetase [15].

Analytical, diagnostic and therapeutic context of GAMT

• METHODS: Three patients with AGAT deficiency from the same pedigree and their eight relatives, as well as a patient affected by a GAMT defect and his parents were analyzed by a new HPLC procedure in comparison with 90 controls [16].
• Moreover, the expression of the GAMT-EGFP fusion protein was analyzed by Western blot, confirming the presence of GAMT fusion protein, both in the stable as well as in the transient transfectants [13].
• Cloning and sequence analysis of human guanidinoacetate N-methyltransferase cDNA [9].

References