Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring

Abstract

Hyperargininaemia is a disorder of the last step of the urea cycle. It is an autosomal recessive disease caused by deficiency of liver arginase‐1 and usually presents later in childhood with progressive neurological symptoms including marked spasticity. In contrast with other urea cycle disorders, hyperammonaemia is not usually present but can be a feature. A number of guanidine compounds may accumulate in the blood and cerebrospinal fluid of these patients, which could play an important pathophysiological role. Guanidinoacetate is of particular interest as a well‐known potent epileptogenic compound in guanidinoacetate methyltransferase deficiency. We found markedly elevated guanidinoacetate levels in a patient with arginase deficiency, which dropped significantly in response to dietary and medical treatment. Measurement of guanidinoacetate and other guanidino compounds may, therefore, be important for therapeutic monitoring in arginase deficiency.

Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency

“…GAA levels exceed reference ranges in patients with ARG1 deficiency. Whether GAA plays a part in the pathophysiology of ARG1 deficiency is an interesting question under the perspective that lowering GAA levels by arginine restriction and ornithine supplementation (Schulze and Battini 2008)aspracticed in GAMT deficiency could be a new therapeutic option in ARG1 deficiency (Amayreh et al 2014). The significantly elevated GAA levels in GAMT deficiency are considered neuropathogenic.…”

“…Arginine is a substrate for the enzyme arginine-glycine amidinotransferase (AGAT), which forms guanidinoacetate (GAA) and ornithine from glycine and arginine (Schulze and Battini 2008). GAA enhances oxidative stress in the rat brain (Zugno et al 2008) and these changes have been hypothesized to contribute to the central nervous system (CNS) pathophysiology in guanidinoacetate:methyltransferase (GAMT) deficiency (Amayreh et al 2014;Grioni et al 2014;Kolling and Wyse 2010). It has been suggested that elevated plasma GAA contributes to neuropathology in ARG1 deficiency (Amayreh et al 2014).…”

“…GAA enhances oxidative stress in the rat brain (Zugno et al 2008) and these changes have been hypothesized to contribute to the central nervous system (CNS) pathophysiology in guanidinoacetate:methyltransferase (GAMT) deficiency (Amayreh et al 2014;Grioni et al 2014;Kolling and Wyse 2010). It has been suggested that elevated plasma GAA contributes to neuropathology in ARG1 deficiency (Amayreh et al 2014). Other findings however suggest that neurotoxic guanidino compounds other than GAA may be of greater pathophysiological importance and that despite high plasma levels GAA may not be significantly elevated in brain tissue (Deignan et al 2008;Deignan et al 2010).…”

Laboratory diagnosis of creatine deficiency syndromes: a technical standard and guideline of the American College of Medical Genetics and Genomics

“…33 Guanidinoacetate can be elevated in patients with urea cycle defects such as arginase deficiency, although creatine concentrations tend to be normal or mildly elevated in this situation. 69,70 While not a CDS indicator, it is worth noting that elevated creatine in plasma has been suggested as a potential biomarker for mitochondrial disorders. 71,72 In general, the use of creatinine as a biomarker for the diagnosis of CDSs (aside from the creatine-to-creatinine ratio for CRTR deficiency) is of limited value.…”

Cellular bioenergetics of guanidinoacetic acid: the role of mitochondria

“…This is probably related to the chemical stability of unsubstituted internal nitrogen atom and the absence of the methyl group in GAA (Ellington 2001). Elevated GAA levels were also found by Amayreh et al (2014) in the blood and cerebrospinal fluid of patients with arginase deficiency, an autosomal recessive disease caused by deficiency of arginase-1, yet the degree of GAA utilization as an energy donor in this disorder is currently unknown.…”