PROGRESSION AND UNMET
NEED OF ARGINASE 1 DEFICIENCY

The manifestations of Arginase 1 Deficiency (ARG1‑D) are progressively debilitating due to high levels of plasma arginine,1-5 and current standards
of care fail to address this root cause5-7

ARG1‑D gradually progresses throughout life and may result in functional disability and impairment of activities of daily living2,4,8

ARG1‑D can be diagnosed in patients of all ages, from infancy and toddlerhood to adolescence and adulthood.2,5 Because the manifestations of ARG1‑D can be neurological, developmental, or functional,2,4,8 these challenges are difficult for those who have ARG1‑D, as well as those who care for them.

After the first years of life, some manifestations of ARG1‑D may appear that include, but are not limited to:

  • Lower and upper limb spasticity2,4
  • Seizures2,4
  • Global developmental delay2,4,9,10
  • Intellectual disability2,4

The manifestations of ARG1‑D place a significant burden on patients2,4,8 and caregivers

ARG1‑D patients show a progressive and/or variable decline in:

  • Neuromotor skills2,4
  • Normal mobility/gait2,4,11
  • Developmental milestones2,4,9
  • Intellectual ability2,4

Loved ones may have to provide lifelong care as some ARG1‑D patients:

  • Are unable to speak or read2
  • May be unable to walk independently2
  • Often experience poor appetite and periodic vomiting4

ARG1‑D disease progression is debilitating2,4

Patients with ARG1‑D have heterogeneous presentations of progression and morbidity2,4,11-13

ARG1‑D progession in infancy (6 - 12 months) - may present with seizures or hyperammonemia

Infancy

Initial 6–12 months may be uneventful3,4,14

May present with:

  • Seizures2,13
  • Episodes of hyperammonemia:
    • Irritability3,4,13
    • Feeding difficulties, poor appetite3,4,13
    • Nausea/vomiting3,4,13
    • Decreased alertness3,4,13

Toddlerhood (2‑4 years)

  • Spasticity in lower limbs (mainly tiptoe walking)2,4,13
  • Intellectual disability: delay or interruption of developmental milestones2,4,11,13
  • Spontaneous avoidance of protein is common2,4,11
  • Seizures: usually generalized tonic clonic2,4,11,13,14
ARG1‑D progression in toddlerhood (2- 4 years) - spasticity in lower limbs - tiptoe walking
ARG1‑D progression in childhood (5 - 10 years) - progressive spasticity and variable decline in growth

Childhood (5‑10 years)

  • Progressive spasticity2,4,11
  • Variable decline in growth2,4,9
  • Variable decline in neuromotor and intellectual abilities:
    • Loss of normal gait2,4,10
    • Decreased vocabulary or loss of spoken language2,4

Adolescence
(11‑17 years)

  • Potential loss of:
    • Ambulation4
    • Bowel and bladder control2,15
  • Severe intellectual disability with loss of language4,9
ARG1‑D progression adolescence (11 - 17 years) - loss of ambulation and bowel and bladder control
ARG1‑D progression adulthood - left untreated may result in variable decline

Adulthood (18+ years)

Left untreated, ARG1‑D results in variable decline that may result in early mortality2,4,9,16,17


Optimal care of patients with ARG1‑D involves an integrated, multidisciplinary team of specialists.

Management of ARG1‑D

Optimal care of patients with ARG1‑D involves an integrated, multidisciplinary team comprising specialists such as18:

  • Metabolic specialist
  • Geneticist
  • Pediatric neurologist
  • Neurologist
  • Movement disorder specialist
  • Pediatrician
  • Dietitian
  • Genetic counselor
  • Physical therapist

Current standard of care (severe dietary restriction, essential amino acid supplementation [EAA], and nitrogen scavengers) fails to fully prevent ongoing manifestations, and may be ineffective at reducing arginine to goal levels1,5-7

Present guidelines recommend rapidly and sustainably lowering plasma arginine levels, thereby reducing disease burden and improving clinical outcomes, including mobility and motor function.6,8,19

  • Arginine levels are increased not just by dietary intake, but also from protein turnover and endogenous synthesis20

  • Nitrogen scavengers may be administered to prevent hyperammonemia deriving from endogenous protein catabolism3,21

10-53g/day protein intake.
4-40 g/day ARG1‑D recommended daily protein intake.

*Protein intake amount varies by age and weight.

The challenges of adhering to a protein-restricted diet rigorous enough to lower plasma arginine below goal levels place a significant burden on patients2,23 and their families

  • Adherence to this diet may be difficult due to previously established eating habits2
  • Could exacerbate eating disorders24
  • Regular follow-ups are required to assess disease status25

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

A plasma amino acid panel and genetic test
can help diagnose ARG1‑D16,26

Elevated plasma arginine is the hallmark of ARG1‑D.3 Order a NO-CHARGE sponsored plasma amino acid panel and genetic test to confirm a diagnosis.

For plasma amino acid panel and genetic test patient eligibility criteria, please visit Order Testing.

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. 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. 4. Crombez EA, Cederbaum SD. Mol Genet Metab. 2005;84:243-251. 5. Huemer M, et al. J Inherit Metab Dis. 2016;39:331-340. 6. Häberle J, et al. Orphanet J Rare Dis. 2012;7:32. 7. Burrage LC, et al. Hum Mol Genet. 2015;24:6417-6427. 8. Uchino T, et al. Hum Genet. 1995;96:255-260. 9. Prasad A, et al. J Child Neurol. 1997;12:301-309. 10. Bélanger SA, et al. Paediatr Child Health. 2018;23:403-419. 11. Cai X, et al. Medicine (Baltimore). 2018;97:e9880. 12. Bakhiet M, et al. Medicine (Baltimore). 2018;97:e10780. 13. Sin YY, et al. J Mol Med (Berl). 2015;93:1287-1296. 14. Scaglia F, Lee B. Am J Med Genet C Semin Med Genet. 2006;142C:113-120. 15. Schlune A, et al. Amino Acids. 2015;47:1751-1762. 16. Sun A, et al. Arginase deficiency. In: Adam MP, et al, eds. GeneReviews®. Seattle, WA: University of Washington, Seattle; 2020. 17. Diaz GA, et al. Poster presented at: 13th European Paediatric Neurology Society (EPNS) Congress; September 17-21, 2019; Athens, Greece. Poster P06-34. 18. 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 September 14, 2021. 19. Cederbaum SD, et al. J Inherit Metab Dis. 1982;5:95-99. 20. Morris SM. Am J Clin Nutr. 2006;83:508S-512S. 21. Qureshi I, et al. J Pediatr. 1984;104:473-476. 22. WHO TRS 935. Protein and Amino Acid Requirements in Human Nutrition. 2007. Available at: WHO TRS 935. Protein and Amino Acid Requirements in Human Nutrition. Accessed September 14, 2021. 23. Jain-Ghai S, et al. Mol Genet Metab. 2011;104:107-111. 24. Adam S, et al. Mol Genet Metab. 2013;110:439-445. 25. Morales JA, Sticco KL. Arginase Deficiency. Treasure Island, FL: StatPearls Publishing; 2018. 26. Ah Mew N, et al. Urea Cycle Disorders Overview. 2003. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1217/. Accessed September 14, 2021.