Arginase 1 Deficiency (ARG1-D) Testing Program

Program Overview

In partnership with Aeglea BioTherapeutics, this program provides physicians access to no-cost genetic testing for patients who are suspected of having Arginase 1 Deficiency (ARG1-D), also known as hyperargininemia, a debilitating, progressive, inherited metabolic disease associated with elevated levels of plasma arginine.

Qualified US healthcare providers can order no-cost genetic testing for US residents, who meet eligibility criteria, to help determine if they have ARG1-D.

Clinical Features

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).1,2

Manifestations of ARG1-D typically become evident in the first years of life, rather than in the first days or weeks, as is typical of other UCDs.1,3

  • Spasticity and toe walking, 2 of the first signs of disease, typically manifest after the first few years of life and progressively worsen into adulthood.2,3,4,5,6
  • 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 affected.2,3,5
  • Patients show a progressive and variable decline in neurologic, developmental, and functional skills.3,7
  • Patients with ARG1-D are less prone to hyperammonemic crises than patients with other UCDs, but they can still occur.1,5,8,9,10
  • Although they show overlapping features, ARG1-D manifestations differ from those of other UCDs.1,2,3,11


  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. Carvalho DR et al. Pediatr Neurol. 2012;46:369-374.
  3. Crombez EA, Cederbaum SD. Mol Genet Metab. 2005;84:243-251
  4. Huemer M et al. J Inherit Metab Dis. 2016;39:331-340.
  5. Burrage LC et al. Hum Mol Genet. 2015;24:1-11
  6. Prasad AN et al. J Child Neurol. 1997;12:301-309.
  7. Cai X et al. Medicine (Baltimore). 2018;97:e9880.
  8. NORD. The Physician’s Guide to Urea Cycle Disorders. 2012. Accessed April 27, 2022.
  9. Scaglia F, Lee B. Am J Med Genet C Semin Med Genet. 2006;142C:113-120.
  10. Amayreh W et al. Dev Med Child Neurol. 2014;56:1021-1024.
  11. Asrani KH et al. RNA Biol. 2018;15:914-922.


ARG1-D is an autosomal recessive disorder caused by pathogenic sequence variants in the ARG1 gene, which is located at chromosome 6q23. ARG1 pathogenic variants are the only known cause of hyperargininemia, and thus far approximately 75 pathogenic ARG1 sequence variants have been reported in the literature. Missense, nonsense and small deletion variants are the predominant types of disease causing variants in the ARG1 gene, though splice variants, small insertions, duplication and indels, as well as gross deletions, have all been reported (Human Gene Mutation Database).

ARG1 encodes arginase, a liver-specific enzyme that generates urea and ornithine from arginine in the last step of the urea cycle. The ARG1 gene product is also active in red blood cells.

Testing Strategy

This test provides full coverage of all coding exons of the ARG1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Note that this test includes coverage for the pathogenic deep intronic variant designated c.306-611T>C.

Criteria For Test

Diagnostic testing can be ordered for any patient 40 years or younger, living in the US who is suspected of having Arginase 1 Deficiency (ARG1-D) based on:

One of the following:

  • Elevated arginine value (documentation required).
  • Presumptive positive newborn screening for ARG1-D (documentation required).
  • Family history of ARG1-D

Or at least two of the following:

  • Protein aversion
  • Seizures
  • Spasticity
  • Progressive loss of ambulation
  • Global developmental delay


  1. Determine if the individual meets eligibility criteria and discuss the test.
  2. Order the test using the test requisition form.
  3. Collect a blood, saliva, or buccal specimen in the collection tube. For information on ordering specimen kits, see Specimen Collection and Shipping section.
  4. The genetic test will be processed at PreventionGenetics and the results will be sent to the ordering healthcare provider about 18 days after the lab receives the specimens and all appropriately completed paperwork. The ordering healthcare provider will discuss the results with the patient and/or caregiver.

Specimen Collection and Shipping

Specimen Collection


Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube).


OrageneTM or GeneFiXTM Saliva Collection kit used according to manufacturer instructions.


OCD-100 Buccal Swab used according to manufacturer instructions.

Shipping and Handling Instructions

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.


DO NOT FREEZE. During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube. In cold weather include an unfrozen ice pack in the shipping container as insulation. At room temperature, blood specimens are stable for up to 48 hours. If refrigerated, blood specimens are stable for up to one week.


Specimens may be shipped at room temperature.

Specimen collection kits: Blood, saliva, or buccal specimen collection kits, which contain the TRF and the shipping label, may be requested through the kit order form or via the online order form.