Guanidinoacetate and Creatine plus Creatinine Assessment in Physiologic Fluids: An Effective Diagnostic Tool for the Biochemical Diagnosis of Arginine:Glycine Amidinotransferase and Guanidinoacetate Methyltransferase Deficiencies

Abstract

Background: Disorders of creatine metabolism arise from genetic alterations of arginine:glycine amidinotransferase (AGAT), guanidinoacetate methyltransferase (GAMT), and the creatine transporter. 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. 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. The method, which uses precolumn derivatization with benzoin, separation with a reversed-phase column, and fluorescence detection, has shown good precision and sensitivity and requires minimal sample handling. Results: In the three AGAT patients, plasma GAA was 0.01–0.04 μmol/L [mean (SD) for neurologically normal controls was 1.16 (0.59) μmol/L], Cr+Crn was 15–29 μmol/L [reference limit in our laboratory, 79 (38) μmol/L]. Urinary GAA was 2.4–5.8 μmol/L [reference, 311 (191) μmol/L], and Cr+Crn was 2.1–3.3 mmol/L [reference, 9.9 (4.1) mmol/L]. We found a smaller decrease in GAA and Cr+Crn in some carriers of an AGAT defect. In the patient with GAMT deficiency, plasma and urine GAA was increased (18.6 and 1783 μmol/L, respectively), and Cr+Crn was decreased in plasma (10.7 μmol/L) and urine (2.1 mmol/L). GAA was increased in the parents’ plasmas and in the mother’s urine. Conclusion: The assessment of GAA is a new tool for the detection of both GAMT and AGAT deficiencies.

Guanidinoacetic Acid and Creatine are Associated with Cardiometabolic Risk Factors in Healthy Men and Women: A Cross-Sectional Study

“…Baseline levels of GAA and creatine were in accordance with previous studies reporting reference values for these two compounds [ 23 , 24 , 25 ], and gender-related differences for serum creatine found in the present study could be attributed to the effects of testosterone and estrogen on creatine synthesis and transport. The CK activity, which regulates the use and consumption of creatine, is found to be sex-specific [ 26 ].…”

Inborn errors of creatine metabolism and epilepsy

“…1 H‐MRS demonstrated lack of the creatine peak in both patients. Serum GAA levels were low in one patient and within the low normal range in the other (Carducci et al., 2002). Both patients were homozygous for a point mutation, resulting in a stop codon on exon 3 of the AGAT gene (9093A>G) (Item et al., 2001).…”

“…High values of GAA can be detected also in dry blood spot since the first days of life (Carducci et al., 2006). A mild increase of GAA over the normal range has been detected in blood and/or urine of some carriers of GAMT gene mutations (Carducci et al., 2002; Caldeira Araujo et al., 2005). GAMT enzyme activity may be tested in liver tissue, skin fibroblasts, and lymphoblasts (Stöckler et al., 1996; Ilas et al., 2000; Alessandrì et al., 2004).…”

Folic Acid and Creatine as Therapeutic Approaches to Lower Blood Arsenic: A Randomized Controlled Trial

“…Plasma Cr+Crn and GAA. Plasma Cr+Crn and GAA were measured by HPLC with fluorescence detection according to the method described by Carducci et al (2002) . We used an Inertsil ODS-3 3-μm HPLC column 4.6 × 100 mm (GL Sciences Inc.) and an excitation and emission wavelengths of 335 and 435 nm, respectively.…”