PROGRESSION AND UNMET
NEED OF ARG1-D

The manifestations of 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

Arginase 1 Deficiency (ARG1-D) is an inherited disease present at birth, but as early diagnosis may be missed, patients can present with symptoms and be diagnosed in 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 months of life, progressive 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 hyperammonaemia:
    • 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
  • Paediatric neurologist
  • Neurologist
  • Movement disorder specialist
  • Paediatrician
  • Dietitian
  • 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 hyperammonaemia deriving from endogenous protein catabolism3,21

The challenges of adhering to a protein-restricted diet rigorous enough to lower plasma arginine below goal levels place a significant burden on patients2,22 and their families

  • Adherence to this diet may be difficult due to previously established eating habits2
  • Could exacerbate eating disorders23
  • Regular follow-ups are required to assess disease status24

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. J Inherit Metab Dis. 2019;1–39. 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;23:403-410. 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 November 26, 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. Jain-Ghai S, et al. Mol Genet Metab. 2011;104:107-111. 23. Adam S, et al. Mol Genet Metab. 2013;110:439-445. 24. Morales JA, Sticco KL. Arginase Deficiency. Treasure Island, FL: StatPearls Publishing; 2018.