Arginase 1 Deficiency (ARG1‑D), also know as hyperargininemia, is a debilitating, progressive, inherited metabolic disease associated with elevated levels of plasma arginine1-3

ARG1‑D is caused by mutations in the ARG1 gene, which encodes the arginase 1 enzyme, or ARG1.3

  • Persistently elevated levels of arginine in patients with ARG1‑D are a key driver of disease manifestations and disease progression1,4
  • The most common manifestations of ARG1‑D are severe spasticity-related mobility limitations, developmental delay, and seizures4-6

Symptoms of ARG1‑D may not present during the first months of life. However, plasma arginine levels could still be high and may lead to debilitating manifestations later in life.5,7,8

Approximately 1/3 of patients with ARG1‑D have family members who are also affected1

Elevated levels of arginine may put patients at an increased risk for early mortality5,10,11


The urea cycle comprises 5 main steps, takes place mostly in the liver, and converts ammonia (NH3), derived from protein breakdown, to urea. In the last step of the cycle, the ARG1 enzyme breaks down arginine into ornithine and urea.12

When a patient has insufficient amounts of the ARG1 enzyme, arginine accumulates in the blood, with levels greatly exceeding the normal range of 40 to 115 μmol/L.13,14

  • Arginine is an amino acid that plays an important role in maintaining vascular homeostasis and other physiological functions15
  • In the absence of a functional enzyme, arginine and arginine‑related metabolites, including ammonia and guanidino compounds, accumulate and are associated with neuromotor pathology16,17

Urea Cycle Dysfunction in Arginase 1 Deficiency18

ARG1‑D is a distinct urea cycle disorder1,5,10

Elevated plasma arginine levels are a distinguishing characteristic of ARG1‑D1

Onset of clinical manifestations of ARG1‑D typically becomes evident in the first years of life, rather than in the first days or weeks, as is typical of other UCDs.1,5

  • Spasticity and toe walking, 2 of the first signs of disease progression, typically manifest after the first few years of life and progressively worsen into adulthood2,3,5,14,16
  • Spastic diplegia is a frequent manifestation of ARG1‑D. Initial onset is typically confined to the lower limbs; however, as spasticity worsens, the upper limbs can also become affected3,5,14
  • Patients show a progressive and variable decline in neurologic, developmental, and functional skills5,19
  • Patients with ARG1‑D are less prone to hyperammonemic crises than patients with other UCDs1,6,8,14,17
  • Although they show overlapping features, ARG1‑D manifestations differ from those of other UCDs, as indicated in the chart at right1,3,5,10

Distinguishing ARG1‑D from other UCDs

These differences suggest a distinct biochemical mechanism
driving disease manifestations and progression in ARG1‑D

High levels of arginine ultimately distinguish ARG1‑D from other UCDs as well as from neurologic disorders such as cerebral palsy (CP) or hereditary spastic paraplegia (HSP)1,3

The burden of arginase 1 deficiency is progressively debilitating2,4

The manifestations of ARG1‑D place a significant burden on patients and caregivers23,26

  • Patients with ARG1‑D may be unable to walk independently7
  • Some patients are unable to speak or read3
  • Patients with ARG1‑D may experience poor appetite and periodic vomiting5
  • Patients with ARG1‑D may also experience seizures2

Affected children have heterogeneous presentations of ARG1‑D that continue into adulthood.3

Manifestations of uncontrolled arginine levels can be progressively debilitating and vary from patient to patient2-5,16

Symptoms of ARG1‑D may be limited in early childhood, or appear to be minor, as arginine levels may fluctuate14

Prolonged exposure to excess, accumulated arginine results in neurological, developmental, and functional manifestations that can lead to functional disability and the impairment of daily living activities3,5,7

Arginase 1 Deficiency (ARG1‑D) - order amino acid panel and genetic test

If you suspect your patient may have ARG1‑D

Early diagnosis of ARG1‑D could potentially reduce the burden of the disease.4,28 Order a no-charge sponsored genetic test*

*Eligibility requirements apply.

1. De Deyn PP et al. In: De Deyn PP et al, eds. Guanidino Compounds in Biology and Medicine. London, UK: John Libbey & Company Ltd; 1997:53-69. 2. Huemer M et al. J Inherit Metab Dis. 2016;39:331-340. 3. Carvalho DR et al. Pediatr Neurol. 2012;46:369-374. 4. Diez-Fernandez C et al. Hum Mutat. 2018;39:1029-1050. 5. Crombez EA, Cederbaum SD. Mol Genet Metab. 2005;84:243-251. 6. NORD. The Physician’s Guide to Urea Cycle Disorders. 2012. https://www.filiere-g2m.fr/images/NORD_Physician_Guide_to_Urea_Cycle_Disorders.pdf. Accessed August 26, 2022. 7. Bakhiet M et al. Medicine (Baltimore). 2018;97:e10780. 8. Scaglia F, Lee B. Am J Med Genet C Semin Med Genet. 2006;142C:113-120. 9. Data on file, Aeglea BioTherapeutics. 10. Asrani KH et al. RNA Biol. 2018;15:914-922. 11. Sun A et al. In: Adam MP et al, eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2020. https://www.ncbi.nlm.nih.gov/books/NBK1159/. Accessed July 15, 2022. 12. Barmore W et al. Physiology, Urea Cycle. Treasure Island, FL: StatPearls Publishing; 2021. 13. Lüneburg N et al. J Nutr. 2011;141:2186-2190. 14. Burrage LC et al. Hum Mol Genet. 2015;24:1-11. 15. Tapiero H et al. Biomed Pharmacother. 2002;56:439-445. 16. Prasad AN et al. J Child Neurol. 1997;12:301-309. 17. Amayreh W et al. Dev Med Child Neurol. 2014;56:1021-1024. 18. Diaz GA et al. Poster presented at: 13th European Paediatric Neurology Society (EPNS) Congress; September 17-21, 2019; Athens, Greece. Poster P06-34. 19. Cai X et al. Medicine (Baltimore). 2018;97:e9880. 20. Carvalho DR et al. Gene. 2012;509:124-130. 21. Uchino T et al. Hum Genet. 1995;96:255-260. 22. Diaz G et al. Ann Neurol. 2019;86:S137. 23. Häberle J et al. J Inherit Metab Dis. 2019;1-39. 24. Morales JA, Sticco KL. Arginase Deficiency. Treasure Island, FL: StatPearls Publishing; 2021. 25. Chandra SR et al. J Pediatr Neurosci. 2019;14:2-6. 26. Fabre A et al. Health Qual Life Outcomes. 2013;11:158. 27. Sin YY et al. J Mol Med (Berl). 2015;93:1287-1296. 28. Edwards RL et al. J Inherit Metab Dis. 2009;32:S197-S200.