PROGRESSION AND IMPACT OF ARGINASE 1 DEFICIENCY

Long-term exposure to elevated arginine levels has been associated with disease progression.1,2 Arginine levels are difficult to control with current standard of care.1,3,4

Current standard of care fails to consistently reduce arginine and maintain it at normal levels1,3,4

Present guidelines recommend rapidly and sustainably lowering plasma arginine levels, thereby reducing disease burden and improving clinical outcomes, including mobility and motor function.4,5

Current standard of care includes severe protein restriction, essential amino acid supplementation, and the administration of nitrogen scavengers, but these treatments fail to fully prevent ongoing symptoms and are insufficient for helping patients maintain normal arginine levels.1,3,4

  • Arginine levels are increased by dietary intake, protein turnover, and endogenous synthesis6
  • Nitrogen scavengers may be administered to prevent hyperammonemia deriving from endogenous protein catabolism4

The challenges of adhering to a protein-restricted diet rigorous enough to lower plasma arginine below goal levels place a significant burden on patients and their families.7,8

  • Adherence to this diet may be difficult due to previously established eating habits7
  • Could potentially exacerbate eating disorders9
  • Regular follow-ups are required to assess disease status10

To effectively manage disease progression, arginine levels must be addressed1,3,4,11

The challenge of meeting target arginine levels

In a Urea Cycle Disorders Consortium (UCDC) longitudinal study of 22 patients with ARG1‑D under current standard of care, 97% of subjects had elevated plasma arginine levels, ie, consistently higher than normal range (40-115 μmol/L).3

Arginine levels in all patients fluctuated over time, even in patients under current standard of care.3,*†

ULN=upper limit of normal.
*Longitudinal Study of Urea Cycle Disorders conducted by the Urea Cycle Disorders Consortium included 11 males and 11 females diagnosed with ARG1‑D ranging from 8 days to 12 years old.3
†All data points for each person are presented.

ARG1‑D gradually progresses throughout life and may result in functional disability and impairment of activities of daily living2,7,12

ARG1‑D can be diagnosed in patients of all ages, from infancy and toddlerhood to adolescence and adulthood. Because the manifestations of ARG1‑D can be neurological, developmental, or functional, these challenges are difficult for those who have ARG1‑D, as well as those who care for them.2,4,7

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

  • Lower and upper limb spasticity1,7
  • Seizures1,7
  • Global developmental delay1,7
  • Intellectual disability1,7
Image: child w/blocks

The manifestations of ARG1‑D place a significant burden on patients and caregivers4,13

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

  • Neuromotor skills7
  • Normal mobility/gait2,7,14
  • Developmental milestones2,7
  • Intellectual ability2,7

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

  • Are unable to speak or read7
  • May be unable to walk independently12
  • Often experience poor appetite and periodic vomiting2

Children with ARG1‑D have heterogeneous presentations that continue into adulthood7

THE PROGRESSIVE IMPACT OF PERSISTENTLY ELEVATED PLASMA ARGININE2,15

Long-term exposure to elevated arginine levels has been associated with disease progression1,2

Elevated levels of arginine in childhood may lead to debilitating complications that may include irreversible neuromotor pathology in adulthood.2,16,17

The key driver of pathophysiology and progression in ARG1‑D is arginine reaching levels persistently above the normal range of 40 to 115 µmol/L.7,15,18

ARG1‑D disease progression is debilitating2,7

Patients with ARG1‑D have heterogeneous presentations of progression and morbidity2,7,12,14,19

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

Infancy

Symptoms may not appear during the initial 6-12 months, but patients may present with2,7,11,20,21:

  • Seizures7,20
  • Episodes of hyperammonemia2,8:
    • Irritability2,11,20
    • Feeding difficulties, poor appetite2,11,20
    • Nausea/vomiting2,11,20
    • Decreased alertness2,11,20

Toddlerhood (2‑4 years)

  • First signs of disease progression: Spasticity in lower limbs (toe walking and ankle tightness)1,2

Other signs may include:

  • Intellectual disability:
    • Delay or interruption of developmental milestones2,20
  • Spontaneous avoidance of protein is common1,7
  • Seizures, usually generalized tonic-clonic7
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 spasticity7,14,19
  • Variable decline in growth2,7,22
  • Variable decline in neuromotor and intellectual abilities7:
    • Loss of normal gait2,7,14
    • Decreased vocabulary or loss of spoken language7,16

Adolescence
(11‑17 years)

  • Potential loss of:
    • Ambulation2,7
    • Bowel and bladder control7,23
  • Severe intellectual disability with loss of language2,7,20
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)

  • ARG1‑D results in variable decline that may result in early mortality2,20

In patients with ARG1‑D, management of arginine levels is important to address
the ongoing burden of this progressive disease15,24

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 as20:

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

Risks associated with high arginine levels

A natural history study published by the Urea Cycle Disorders Consortium found that the following manifestations were associated with persistently elevated arginine levels25

ARG1‑D patients were at greater risk for low IQ and poor performance in all domains assessed

Elevation in arginine tends to be associated with poorer global functioning and memory deficits

Higher arginine levels were significantly correlated with worse motor composite scores

Increasing cumulative exposure (ie, duration of disease) was an indicator of worse neuropsychiatric outcomes

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.15,24 Order a no-charge sponsored genetic test*

*Eligibility requirements apply.

References:
1. Huemer M et al. J Inherit Metab Dis. 2016;39:331-340. 2. Crombez EA, Cederbaum SD. Mol Genet Metab. 2005;84:243-251. 3. Burrage LC et al. Hum Mol Genet. 2015;24:1-11. 4. Häberle J et al. J Inherit Metab Dis. 2019;1-39. 5. Cederbaum SD et al. J Inherit Metab Dis. 1982;5:95-99. 6. Morris SM. Am J Clin Nutr. 2006;83:508S-512S. 7. Carvalho DR et al. Pediatr Neurol. 2012;46:369-374. 8. Jain-Ghai S et al. Mol Genet Metab. 2011;104:107-111. 9. Adam S et al. Mol Genet Metab. 2016. http://dx.doi.org/10.1016/j.ymgme.2017.06.003. Accessed July 15, 2022. 10. Morales JA, Sticco KL. Arginase Deficiency. Treasure Island, FL: StatPearls Publishing; 2021. 11. 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. 12. Bakhiet M et al. Medicine (Baltimore). 2018;97:e10780. 13. Fabre A et al. Health Qual Life Outcomes. 2013;11:158. 14. Cai X et al. Medicine (Baltimore). 2018;97:e9880. 15. Diez-Fernandez C et al. Hum Mutat. 2018;39:1029-1050. 16. 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. 17. Asrani KH et al. RNA Biol. 2018;15:914-922. 18. Lüneburg N et al. J Nutr. 2011;141:2186-2190. 19. Sin YY et al. J Mol Med (Berl). 2015;93:1287-1296. 20. 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. 21. Scaglia F, Lee B. Am J Med Genet C Semin Med Genet. 2006;142C:113-120. 22. Prasad AN et al. J Child Neurol. 1997;12:301-309. 23. Schlune A et al. Amino Acids. 2015;47:1751-1762. 24. Edwards RL et al. J Inherit Metab Dis. 2009;32:S197-S200. 25. Waisbren SE et al. J Inherit Metab Dis. 2018;41: 657-667.