Arginase-1 deficiency

Abstract

Arginase-1 (ARG1) deficiency is a rare autosomal recessive disorder that affects the liver-based urea cycle, leading to impaired ureagenesis. This genetic disorder is caused by 40+ mutations found fairly uniformly spread throughout the ARG1 gene, resulting in partial or complete loss of enzyme function, which catalyzes the hydrolysis of arginine to ornithine and urea. ARG1-deficient patients exhibit hyperargininemia with spastic paraparesis, progressive neurological and intellectual impairment, persistent growth retardation, and infrequent episodes of hyperammonemia, a clinical pattern that differs strikingly from other urea cycle disorders. This review briefly highlights the current understanding of the etiology and pathophysiology of ARG1 deficiency derived from clinical case reports and therapeutic strategies stretching over several decades and reports on several exciting new developments regarding the pathophysiology of the disorder using ARG1 global and inducible knockout mouse models. Gene transfer studies in these mice are revealing potential therapeutic options that can be exploited in the future. However, caution is advised in extrapolating results since the lethal disease phenotype in mice is much more severe than in humans indicating that the mouse models may not precisely recapitulate human disease etiology. Finally, some of the functions and implications of ARG1 in non-urea cycle activities are considered. Lingering questions and future areas to be addressed relating to the clinical manifestations of ARG1 deficiency in liver and brain are also presented. Hopefully, this review will spark invigorated research efforts that lead to treatments with better clinical outcomes.

Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations

“…Including all published (Amayreh et al., ; Brockstedt, Smit, de Grauw, van der Klei‐van Moorsel, & Jakobs, ; Cardoso et al., ; Carvalho et al., ; Cohen et al., ; Edwards et al., ; Haraguchi et al., ; Hertecant et al., ; Huemer et al., ; Häberle & Koch, ; Jain‐Ghai et al., ; Korman et al., ; Kuster et al., ; Lambert et al., ; Lee et al., ; Mullane et al., ; Mustafa et al., ; Rodrigues, Martins, Ferreira, Vilarinho, & Leao Teles, ; Schiff et al., ; Scholl‐Bürgi et al., ; Segawa et al., ; Sin et al., ; Snyderman, Sansaricq, Chen, Norton, & Phansalkar, ; Snyderman, Sansaricq, Norton, & Goldstein, ; Tsang et al., ; Uchino et al., ; Uchino et al., ; Villegas‐Ruiz et al., ; Vockley et al., ,b; Vockley et al., ; Wu et al., ; Wu et al., ; Zhang et al., ) and novel cases, 66 mutations in ARG1 from 112 patients are compiled here (Tables and , Figures C and A). All of these mutations have been included in the LOVD database (https://databases.lovd.nl/shared/variants/ARG1/unique).…”

“…Clinically, it is associated with hyperargininemia, spastic paraparesis, progressive neurological and intellectual impairment, and persistent growth retardation. In contrast to other urea cycle disorders (UCDs), episodes of hyperammonemia are scarce (Sin, Baron, Schulze, & Funk, ). In spite of this, ARGD has been associated with greatest risk for low IQ and poor performance in neuropsychological functioning, when compared with patients with the other distal UCDs (argininosuccinate synthetase deficiency and argininosuccinate lyase deficiency) (Waisbren et al., ).…”

An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease

“…These include deficiencies of carbamoyl phosphate synthetase 1 (CPS1) (MIM #237300) [22], ornithine transcarbamylase (OTC) (MIM #311250) [23], argininosuccinate synthetase (ASS1) (NIM #215700) [24], argininosuccinate lyase (ASL) (NIM #207900) [25] and arginase (ARG) (NIM #207800) [26] (Fig. 1).…”

Hepatic arginase deficiency fosters dysmyelination during postnatal CNS development

“…palsy in some patients (5). Later findings include microcephaly, seizures, loss of ambulation, growth retardation, intellectual disabilities, and progressive neurological decline (4,6,7).…”