Guanidino Compound Analysis as a Complementary Diagnostic Parameter for Hyperargininemia: Follow-Up of Guanidino Compound Levels during Therapy

Abstract

ABSTRACT. The aim of this collaborative study was to normalized by therapy, the levels of the catabolites of investigate whether guanidino compound analyses in the arginine are still elevated. (Pediatr Res 27: 297-303,1990) biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange chromatographic system with a fluorescence detection method. The serum arginine, homoarginine, a-keto-6-guanidinoDeficiency of arginase, the last enzyme of the urea cycle, leads valeric acid, argininic acid, and N-a-acetylarginine levels to hyperargininemia. The first clinical and biochemical descripof all the hyperargininemic patients are higher than the tions of two sisters affected with hyperargininemia were pubnormal range. Similar increases were seen for the urinary lished in 1969 (1) and 1970 (2, 3). Five y later, another sister was excretion of a-keto-6-guanidinovaleric acid and argininic diagnosed shortly after birth (4). Since then, 19 other cases from acid. Untreated hyperargininemic patients have the highest 17 families have been reported (5-22). Patients with hyperargiguanidino compound levels in cerebrospinal fluid. How-ninemia present a neuropsychiatric syndrome consisting of varyever, even under therapy, the arginine, homoarginine, a-ing degrees of mental retardation, epilepsy, and progressive spasketo-6-guanidinovaleric acid, and argininic acid levels in ticity. This latter symptom is at variance with other defects of cerebrospinal fluid are still increased. Protein restriction the urea cycle. Some patients have, in addition, recurrent epialone is not sufficient to normalize the hyperargininemia, sodes of vomiting and irritability accompanied by moderate but protein restriction together with supplementation of hyperammonemia. As a consequence of the arginase deficiency, essential amino acids with or without sodium benzoate the patients accumulate excessive arginine. Some secondary cadecreases further the arginine levels. However, whereas tabolites of arginine, guanidino compounds, are massively exthe argininemia can be normalized, the catabolites of ar-creted in the urine of these patients (23). Figure 1 shows some ginine are still increased. We conclude that the urinary proposed catabolic pathways of arginine in patients with hyperamino acid levels may remain normal in hyperargininemia, argininemia. whereas consistent increases of the guanidino compounds In hyperargininemia it is unclear whether ammonia is the are observed. Thus, guanidino compound analyses can be principal toxin. Indeed, the presence of normal or only slightly used as a complementary biochemical diagnostic parameter elevated ammonia levels has been demonstrated in several pafor hyperargininemia. Although the argininemia can be tients (6,7,9,15), and the progressive spasticity typically en-

Clinical, biochemical, and molecular spectrum of hyperargininemia due to arginase I deficiency

“…There is an increase in guanidino compounds derived directly from arginine in many patients with hyperargininemia [Marescau et al, 1990;1992a;Marescau, 1992b], but their effect on the pathogenesis of disease remains unclear.…”

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

“…Elevation in petroselinic acid can suppress arachidonic acid which is a key lipid mediator that promotes airway inflammation (Weber et al 1995;Serrano-Mollar and Closa 2005). Reduction of 2-oxoarginine may help lessen certain lung toxicity (Marescau et al 1990). Artesunate also increased eicosadenoic acid, a n-6 polyunsaturated fatty acid, which can modulate inflammatory responses and be further converted to sciadonic acid, an anti-inflammatory fatty acid (Huang et al 2011).…”

Liver Transplantation Prevents Progressive Neurological Impairment in Argininemia

“…Argininemia treatments that successfully lower arginine and guanidino compounds levels should prevent neurological symptoms, but although arginine plasmatic levels may normalize under conventional treatment, the arginine's catabolites can remain elevated (Marescau et al 1990), and some of these guanidino compounds are neurotoxic (De Deyn et al 2009;Hiramatzu, 2003). In both of our patients, arginine concentration decreased significantly under conventional treatment (but never normalized), and guanidine compounds were markedly elevated in plasma and urine.…”

“…The neurological symptoms referred to here cannot be explained merely as a consequence of arginine levels and hyperammoniemia (which is observed intermittently), since neurological impairment sometimes progresses despite good compliance with treatment (presenting stable arginine and ammonia plasmatic levels). So it was suspected that other factors, such as the presence of guanidino compounds, might be implicated in the neurological impairment (Mizutani et al 1987), since the endogenous production of these substances may remain significant even when arginine is normalized (Marescau et al 1990). …”