What is ARG1-D?

ARG1-D is an ultra-rare urea cycle disorder with potentially devastating consequences

Under normal conditions, arginine is hydrolysed in the liver by the arginase 1 (ARG1) enzyme into ornithine and urea in the last step of the urea cycle
ARG1-D is a rare, progressive inherited metabolic disease caused by mutations in the ARG1 gene which result in impaired or absent arginase 1 enzyme activity^1,2
In the absence of a functional enzyme, arginine and arginine‑related metabolites, including ammonia and guanidino compounds, accumulate and are associated with neuromotor pathology^3,4
If left untreated, ARG1-D leads to cognitive and functional decline and may result in early mortality^2,5-7

Elevated arginine is the main driver of ARG1-D

Persistently elevated levels of arginine in patients with ARG1‑D are key drivers of disease manifestations, including progressive spasticity, developmental delay, and seizures⁸

Current treatment guidelines for ARG1-D recommend lowering plasma arginine levels to reduce the disease burden and improve clinical outcomes, including mobility and motor function^9-11

Carvalho DR, et al. Analysis of novel ARG1 Mutations causing hyperarginemia and correlation with arginase I activity in erythrocytes. Gene. 2012;509:124–130.
Carvalho DR, et al. Clinical Features and Neurologic Progression of Hyperarginemia. Pediatr Neurol. 2012;46:369–374.
Prasad A, et al. Argininemia: A Treatable Genetic Cause of Progressive Spastic Diplegia Simulating Cerebral Palsy: Case Reports and Literature Review. J Child Neurol. 1997;12:301-309.
Amayreh W, et al. Treatment of arginase deficiency revisited: guanidinoacetate as a therapeutic target and biomarker for therapeutic monitoring. Dev Med Child Neurol. 2014;56:1021-1024.
Diez-Fernandez C, et al. Mutations and common variants in the human arginase 1 (ARG1) gene: Impact on patients, diagnostics, and protein structure considerations Hum Mutat. 2018;39(8):1029-1050.
Schlune A, et al. Hyperarginemia due to arginase I deficiency: the original patients and their natural history, and a review of the literature. Amino Acids. 2015;47:1751–1762.
Scaglia F, Lee B. Clnical, Biochemical, and Molecular Spectrum of Hyperarginemia Due to Arginase I Deficiency. Am J Med Genet C Semin Med Genet. 2006;142:113–120
Diaz GA, et al. The role and control of arginine levels in arginase 1 deficiency. J Inherit Metab Dis. 2023 Jan;46(1):3-14.
Häberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders: First revision. J Inherit Metab Dis. 2019;1–39.
Uchino T, et al. Molecular basis of phenotypic variation in patients with argininemia. Hum Genet. 1995;96:255-260.
Cederbaum SD, et al. Treatment of Hyperargininaemia due to Arginase Deficiency with a Chemically Defined Diet J Inherit Metab Dis. 1982;5:95-99.