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  • Updated 02.27.2024
  • Released 03.30.1995
  • Expires For CME 02.27.2027




Arginase 1 deficiency is an inherited urea cycle disorder that may cause hyperammonemia. Arginase 1 deficiency mainly affects the central nervous system and results in a distinct neurologic condition manifesting primarily between ages of 2 and 4 years (or above). Nearly all patients show a combination of spastic diplegia/paraplegia, cognitive impairment, developmental delay, and seizures. Growth is usually retarded unless treated. In addition, less commonly observed neurologic symptoms are tremor, ataxia, and choreatic movements. Unlike other urea cycle disorders, individuals with arginase 1 deficiency usually do not present with hyperammonemic episodes; however, recurrently elevated ammonia concentrations may occur at any time and are more frequently observed (70% of the cases) than initially expected. The diagnosis is made on markedly elevated concentrations of plasma arginine, deficient arginase 1 activity in red blood cells, or genetic testing. Treatment recommendations consist of a protein-restricted diet and ammonia scavenger drugs. Liver transplantation cures arginase 1 deficiency, but the prospect of reversing or ameliorating neurologic sequelae is poor. Pegzilarginase (AEB1102), an investigational enzyme therapy, is being investigated as a novel arginine lowering approach in a phase 1/2 and open-label extension study.

International networks for rare metabolic diseases (UCDC, E-IMD, JUCDC) aim to more precisely describe the initial and evolving clinical phenotype of urea cycle disorders (UCDs) such as arginase 1 deficiency. Furthermore, they want to determine if the natural disease course can be favorably modulated by diagnostic and therapeutic interventions. These networks collect systematic data to improve clinical knowledge, develop guidelines, and provide patients and professionals with reliable data on disease manifestations, complications, as well as long-term outcomes of urea cycle disorders. These networks include the Urea Cycle Disorders Consortium (UCDC), established in 2006; the European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD), established in 2011; and the Japanese Urea Cycle Disorders Consortium (JUCDC), established in 2012 (75).

Key points

• Patients suffering from arginase 1 deficiency usually have a clinical phenotype distinct from other urea cycle disorders; progressive spastic paraplegia and neurologic impairment are the clinical hallmarks. However, acute or recurrent hyperammonemia may occur.

• Treatment with a low-protein diet and essential amino acid supplementation is only partially effective in ameliorating or preventing the neurologic abnormalities.

• The impact of interventional measures, eg, diagnostic and therapeutic interventions, on clinical outcome remains to be elucidated.

Historical note and terminology

Hyperargininemia was first described in 1969 (77). Its name derives from the marked elevation of L-arginine in the blood of affected individuals. It is caused by a deficiency of the cytosolic liver and red blood cell enzyme arginase 1. Hyperargininemia may also be called "argininemia" or "arginase/arginase 1 deficiency (ARG1D)".

Due to the rarity of the disease, mainly case studies are presented in the literature. More recently, large international longitudinal studies aiming to collect data on the natural history of urea cycle disorders, to educate professionals and patients, and to develop new treatments have been launched.

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