Guanidinoacetate Methyltransferase Deficiency: A Review of Guanidinoacetate Neurotoxicity

Abstract Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of the metabolism of creatine that leads to depleted levels of creatine and excessive concentrations of guanidinoacetate (GAA). Patients affected develop neurological symptoms during childhood, such as muscular hypotonia, involuntary extrapyramidal movements, convulsions, slurred speech, and even autism. Although the pathophysiology of GAMT deficiency is unclear, neurological dysfunction is commonly found in this disease, and it has been mainly attributed to a reduction in creatine or/and an increase in GAA levels. Reports from literature suggest that GAA may interfere with neuronal γ-aminobutyric acid (GABA) receptors type A and cause epilepsy in human. Preclinical studies show that GAA increases free radical formation and decreases brain antioxidant defenses, inducing alteration in oxidative status. Guanidinoacetate also impairs energy metabolism in brain. The discussion of this review focuses on various and latest studies addressing GAMT deficiency and creatine metabolism, as well as addresses the question of neurotoxicity GAA.

Integrated Multianalyte Second-Tier Testing for Newborn Screening for MSUD, IVA, and GAMT Deficiencies

Abstract Advances in mass spectrometry have allowed for expansion of newborn screening test panels over the last decade but with increased numbers of disorders have come increased concerns with false-positive rates. The introduction of second-tier testing has improved the specificity of screening for a number of disorders without any corresponding sacrifice in sensitivity. Such testing does, however, put pressure on scarce laboratory resources including instrument and personnel time and even the bloodspot sample itself. The British Columbia Newborn Screening Program has developed an integrated second-tier screening approach to improve test performance without the requirement to resample and reprocess the original bloodspot specimen. By utilizing the residual extract from the first-tier assay and introducing a chromatography step as the second tier, we have been able to reduce false-positive rates due to interfering isobaric compounds for 3 different disorders (maple syrup urine disease, isovaleric aciduria, and guanidinoacetate methyltransferase) in a single multianalyte assay.

Guanidinoacetate alters antioxidant defenses and butyrylcholinesterase activity in the blood of rats

Deficiency of guanidinoacetate methyltransferase, the first described creatine biosynthesis defect, leads to depletion of creatine and phosphocreatine, and accumulation of guanidinoacetate (GAA) in brain and body fluids. The present study aimed to investigate the influence of GAA on the activities of antioxidant enzymes, as well as on thiobarbituric acid-reactive substances (TBARS) and butyrylcholinesterase (BuChE) activity in the blood of rats. We also evaluated the effect of trolox (6-hydr oxy-2,5,7,8-tetramethylchroman-2-carboxylic acid), GSH (glutathione) and L-NAME (NG-nitro-L-arginine methyl ester) on the alterations elicited by GAA. Methods: The rats were randomly divided into 8 groups: (1) control; (2) GAA (10, 30, 50, 100 mM/kg); (3) trolox (1 mM/kg) + control; (4) trolox (1 mM/kg) + GAA (100 mM/kg); (5) GSH (1 mM/kg) + control; (6) GSH (1 mM/kg) + GAA (100 mM/kg); (7) L-NAME (1 mM/kg) + control; (8) L-NAME + GAA (100 mM/kg). After the addition of compounds, erythrocytes and plasma were pre-incubated at 37°C for 1h and tested immediately. Results: GAA enhanced the activities of catalase (CAT) and glutathione peroxidase (GSH-Px) in the erythrocytes and BuChE activity. In addition, GAA enhanced TBARS levels in the plasma. Trolox, GSH and L-NAME addition prevented the majority of alterations in oxidative stress parameters and the increase of BuChE activity that were caused by GAA. Data suggest that GAA alters antioxidant defenses and induces lipid peroxidation in the blood, as well altering BuChE activity. However, in the presence of trolox, GSH and L-NAME some of these alterations in oxidative stress and BuChE activity were prevented. Conclusions: Our findings lend support to a potential therapeutic strategy for this condition, which may include the use of appropriate antioxidants for ameliorating the damage caused by GAA...