ARG1-D is a distinct urea cycle disorder (UCD)8
ARG1-D, also known as hyperargininaemia, is an autosomal recessive disease
caused by mutations in the ARG1 gene that encodes the arginase-1 enzyme (ARG1).2,9
The ARG1 enzyme breaks down arginine into
ornithine and urea in the last step of the urea
cycle. The urea cycle comprises five main
steps, takes place mostly in the liver, and
converts ammonia (NH3), derived from protein
breakdown, to urea.10
- Arginine is an amino acid that plays an important role in maintaining vascular homeostasis and other physiological functions11
- In the absence of a functional enzyme, arginine and arginine‑related metabolites, including ammonia and guanidino compounds, accumulate and are associated with neuromotor pathology12,13
- Persistently elevated levels of arginine in patients with ARG1‑D are key drivers of disease manifestations, including progressive spasticity, developmental delay, and seizures4,5,14,15
- Hyperammonaemia is not a hallmark of ARG1-D and acute episodes of hyperammonaemia occur infrequently14-16
The persistent elevation of plasma arginine and its metabolites puts patients at an
increased risk for significant morbidity and early mortality1-7
Affecting children and continuing into adulthood, patients have heterogeneous presentations of ARG1-D.2,5,18-20
Key manifestations that may present include: progressive spasticity, developmental delay, intellectual disability, and seizures.2,5,19
- Manifestations typically start in childhood and persist over time due to accumulating levels of plasma arginine2
- Spasticity typically manifests after the first few months of life and progressively worsens into adulthood2,9,12,16
- Spastic diplegia and tiptoe gait are frequent manifestations of ARG1-D2,16
- Initial onset is typically confined to the lower limbs; however, as spasticity worsens, the upper limbs can also become affected2
- Patients show a progressive and variable decline in neurological, developmental, and functional skills2,5,19,21
High levels of plasma arginine ultimately distinguish ARG1-D from other UCDs, as well as from neurometabolic and neurologic disorders such as cerebral palsy or hereditary spastic paraplegia2,4,12
References:
1. Diez-Fernandez C, et al. Hum Mutat. 2018;39:1029-1050. 2. Carvalho DR, et al. Pediatr Neurol. 2012;46:369-374. 3. Häberle J, et al. J Inherit Metab Dis. 2019;1–39. 4. De Deyn PP, et al. Hyperargininemia: a treatable inborn error of metabolism. In: Guanidino Compounds in Biology and Medicine. London, UK: John Libbey Company Ltd; 1997:53-69. 5. Crombez EA, Cederbaum SD. Mol Genet Metab. 2005;84:243-251. 6. Sun A, et al. Arginase deficiency. In: Adams MP, et al, eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2020. 7. Diaz GA, et al. Poster presented at: 13th European Paediatric Neurology Society (EPNS) Congress; September 17-21, 2019; Athens, Greece. Poster P06-34. 8. Carvalho DR, et al. Gene. 2012;509:124-130. 9. Huemer M, et al. J Inherit Metab Dis. 2016;39:331-340. 10. Barmore W, et al. Physiology, Urea Cycle. [Updated 2021 May 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Available at: https://www.ncbi.nlm.nih.gov/books/NBK513323. Accessed December 3, 2021. 11. Tapiero H, et al. Biomed Pharmacother. 2002;56:439-445. 12. Prasad A, et al. J Child Neurol. 1997;12:301-309. 13. Amayreh W, et al. Dev Med Child Neurol. 2014;56:1021-1024. 14. Scaglia F, Lee B. Am J Med Genet C Semin Med Genet. 2006;142C:113-120. 15. NORD. The Physician’s Guide to Urea Cycle Disorders. 2012. Available at: http://www.nucdf.org/documents/NORD_Physician_Guide_to_Urea_Cycle_Disorders.pdf. Accessed November 26, 2021. 16. Burrage LC, et al. Hum Mol Genet. 2015;24:6417-6427. 17. Bélanger SA, et al. Paediatr Child Health. 2018;23:403-410. 18. Sin YY, et al. J Mol Med (Berl). 2015;93:1287-1296. 19. Cai X, et al. Medicine (Baltimore). 2018;97:e9880. 20. Bakhiet M, et al. Medicine (Baltimore). 2018;97:e10780. 21. Schlune A, et al. Amino Acids. 2015;47:1751-1762.
