Arginase Deficiency

Guidance for primary care clinicians diagnosing and treating children with arginase deficiency

Arginase deficiency is caused by insufficient activity of the enzyme arginase 1, which breaks down arginine to ornithine and urea in the final step of the urea cycle. As a result, hyperammonemia can occur, although it is typically a much milder feature of the condition than the other urea cycle defects. Rather, neurological manifestations like lower limb spasticity and developmental delays beginning around 1 to 4 years of age are much more common. Many children also develop microcephaly. If untreated, developmental regression and seizures often occur. Early diagnosis and nutritional management can control many of the deleterious neurological effects observed in this condition.

Other Names

  • Argininemia
  • ARG1 deficiency
  • Hyperargininemia

Key Points

Newborn screening does not catch all arginase deficiency diagnoses
Arginase deficiency can typically be identified on newborn screening as a secondary target by increased arginine levels. However, most states only recently have begun screening, so older children and adults may have been missed. Additionally, elevated arginine levels may not be present in all patients at all times, so even those with negative screens should be considered if clinically indicated.

Children who present with lethargy
IPhysicians should maintain a high index of suspicion in children who present with lethargy in the first few days of life. Obtain a plasma ammonia level if other causes for the clinical presentation are not identified.

In patients with a known diagnosis of arginase deficiency, lethargy almost certainly represents a hyperammonenic crisis and warrants immediate medical care to prevent irreversible cerebral swelling and damage. Metabolic genetics should be consulted immediately. Ammonia is decreased by the administration of oral nitrogen scavenger medications as well as intravenous fluids and calories in the form of glucose and intralipids. In some cases, dialysis or the administration of IV nitrogen-scavenging medications sodium phenylacetate and sodium benzoate are necessary.

Clinical characteristics
Although considered a urea cycle defect, hyperammonemia is typically much more mild and sporadic, if it occurs at all, and does not explain the lower limb spastic diplegia that is unique to arginase deficiency. Because of the spastic diplegia, arginase deficiency should be considered a differential for unexplained cerebral palsy. Children may also have developmental delays, seizures, and liver dysfunction.

What to do when receiving an abnormal newborn screen result
Every state has specific guidelines for the follow-up of abnormal results. An abnormal newborn screen does not equate to a diagnosis but significantly increases the probability of one. The state program will notify you of the next steps and should be accessible for questions. You do not need to notify the geneticist themselves unless the patient is experiencing any acute symptoms. Argininemia provides guidance for immediate steps after abnormal newborn screening results.

Developmental and neurological assessment
Children diagnosed with arginase deficiency after the newborn period should have developmental and neurologic assessments and may need therapy for spasticity and intellectual disability. See Cerebral Palsy and Intellectual Disability & Global Developmental Delay for assessment information and details of therapy.

Treatment goals
Treatment goals aim at reducing arginine levels as well as precursors to the urea cycle. Methods to achieve this goal include restricting natural protein intake (sometimes using special medical formulas), providing adequate overall caloric intake, avoiding fasting, and using oral nitrogen scavenger medications. During acute crises (a rare occurrence for this condition), hospitalization and more aggressive therapies may be necessary. Management for the other manifestations of the condition, such as developmental delays, spasticity, and seizures, are not specific to this diagnosis, and therefore standard therapies would be appropriate.

Important to avoid
Arginine is an amino acid present in all natural forms of protein. Therefore, excess protein intake should be avoided. Prolonged fasting, excessive physical activity, and infectious illnesses may also increase plasma arginine from endogenous sources and, as such, should be avoided as well (Arginase Deficiency (NECMP)). Finally, valproic acid can lead to hyperammonemia, so it should not be used to treat seizures in these patients.

Role of primary care clinician
The genetics team will typically manage complex treatment, such as specific diet recommendations, nitrogen scavenger prescriptions, and management in the acute setting, including hyperammonemic crises. The primary medical home can help by monitoring developmental progress and organizing any special services/therapies the patient may require. Additionally, infectious illnesses may trigger an acute crisis, so primary care providers serve as a first line in treating common illnesses, like bacterial infections, and alert the genetics provider when patients do not respond quickly or are beginning to display signs/symptoms of hyperammonemia.

When to alert the geneticist about an ill patient
Generally, if the patient has any signs/symptoms suggestive of hyperammonemia, they should be immediately sent to the ER where an ammonia level can be checked, and the geneticist should be notified. Most patients will have their own emergency letter available, which includes written instructions for what the ER physician should do in these acute cases. If the patient does not have any signs/symptoms of hyperammonemia but is experiencing an infectious illness, primary care clinicians should aggressively treat fevers and give antibiotics when indicated. It is most important that the patient maintain sufficient caloric intake, so high-calorie beverages like sports drinks or Pedialyte are preferred over water when not tolerating solid food intake.

Practice Guidelines

There are no published guidelines for care of children with arginase deficiency.


Most cases of arginase deficiency will be identified by newborn screening based on an elevated arginine level, but a negative newborn screen does not rule it out. Follow-up testing may include a plasma ammonia level and plasma amino acids. Confirmation of a diagnosis can be made by either arginase activity levels in red blood cells (typically <1% of normal) or molecular genetic testing of the ARG1 gene.


Without early diagnosis and treatment in the neonatal/early infancy period, delays in development can be noted early in life. Additional early signs of the untreated condition include increased deep tendon reflexes and lower limb spasticity, often with toe walking in the first few years of life. If allowed to progress, patients may then experience developmental regression, cognitive decline, seizures, and liver disease. Although most children with arginase deficiency will have an indolent course, there have been case reports of severe presentations in infancy with acute hyperammonemia as in other urea cycle disorders. [Jain-Ghai: 2011]

Diagnostic Criteria and Classifications

Diagnosis is based on elevated arginine on plasma amino acids, reduced arginase activity in red blood cells, and pathogenic variants in the ARG1 gene.

Diagnostic Testing & Screening

Arginase deficiency is often first suspected based on newborn screening results with an elevated arginine level. Some patients may be missed by newborn screening, so it is important to note that a negative test does not rule out the condition. Confirmation of the diagnosis is important, though, as there may be other causes for hyperargininemia. The diagnosis can be confirmed by either an arginase enzyme activity level of <1% of normal or molecular genetic testing that identifies biallelic pathogenic variants in the ARG1 gene. See Argininemia for protocol upon notification of a positive newborn screen.

Lab Testing

First-line testing consists of measuring plasma ammonia and plasma amino acids. The excretion of orotic acid in urine is usually markedly increased in these patients. These tests can be ordered in a patient presenting symptomatically or in patients identified by newborn screening with elevated arginine levels.

Levels of guanidinoacetate (part of laboratory testing for inborn errors of creatine metabolism) may also be increased in patients with arginase deficiency despite normal creatine levels.


Brain MRI can show brain atrophy in the absence of therapy. EEG as clinically necessary for suspicion of seizures.

Genetic Testing

Enzyme assay in red blood cells and sequencing of the ARG1 gene can confirm the diagnosis.

Other Testing

All children with arginase deficiency should have developmental and neurologic evaluations.

Testing for Family Members

Because individuals with arginase deficiency may be asymptomatic, full siblings of children with arginase deficiency should be tested. Testing usually involves plasma amino acid analysis, plasma ammonia, urine orotic acid, enzyme activity determination in red blood cells, and/or genetic testing if the specific variant in the family is known.


Arginase deficiency is an autosomal recessive disorder caused by variants in the ARG1 gene. It appears to be more common and/or more severe in northern Mexico and in the French Canadian population in northern Quebec. [Ibarra-González: 2010]] [[Qureshi: 1983] Enzyme activity can be tested in red blood cells.

Incidence & Prevalence

Arginase deficiency is one of the rarest types of urea cycle defects. Estimates of the incidence vary, but recent reports suggest a global incidence of 1:357,000 live births and a population prevalence of 1:726,000 people. [Catsburg: 2022]

Differential Diagnosis

Cerebral palsy: The most important differential diagnosis for arginase deficiency is cerebral palsy. [McNutt: 2023] [Freua: 2022] Spastic diplegia is the most common pattern of motor abnormalities in arginase deficiency. [Lee: 2011] For assessment information, see Cerebral Palsy.
Leukodystrophies: Arginase deficiency, leukodystrophy, and other uncommon conditions should be considered in children without a clear historical reason for or typical MRI findings of cerebral palsy. Assessment information can be found at Leukodystrophies.
Other urea cycle defects: If presenting with hyperammonemia, first consider some of the other more common urea cycle defects, as well as other inborn errors of metabolism and non-genetic conditions that can elevate ammonia levels. A metabolic geneticist should always be involved in the immediate work-up for a patient, especially a neonate, with hyperammonemia.

Comorbid Conditions

Developmental delay and intellectual disability occur frequently in children with arginase deficiency, although not typically as a result of persistent/recurrent hyperammonemia, as opposed to other urea cycle defects. Elevated arginine levels increase the synthesis and the accumulation of guanidinoacetate, which is neurotoxic and thought to be responsible for the neurological manifestations of the condition, including spasticity, developmental regression, and seizures. Therefore, developmental progress should be monitored closely, and referrals made to early intervention services as soon as any delay is identified. Referrals specifically to physical therapy may also be necessary if spastic diplegia occurs. See Developmental Screening.


The prognosis improves with treatment when a restricted-protein diet and nitrogen-scavenging medications are started before the onset of symptoms. Once children show symptoms, treatment may help stabilize the process, but it does not usually reverse the symptoms. Even with adequate treatment, some affected children will still show some degree of intellectual disability, which is likely related to the accumulation of arginine and related compounds in the brain.

Treatment & Management

Treatment goals aim to reduce arginine levels as well as precursors to the urea cycle. Methods to achieve this goal include restricting natural protein intake, sometimes by using special medical formulas, providing adequate overall caloric intake, avoiding fasting, and using oral nitrogen scavenger medications. During acute crises (a rare occurrence for this condition), hospitalization and more aggressive therapies may be necessary. Management for the other manifestations of the condition, such as developmental delays, spasticity, and seizures, are not specific to this diagnosis; therefore, standard therapies would be appropriate.


Treatment of arginase deficiency focuses on reducing plasma arginine levels and precursors of the urea cycle. As an amino acid, arginine is present in all natural proteins, so restriction of natural protein intake is necessary. Medical formulas that are low in nitrogen-based amino acids or free of protein altogether may be used to help achieve this goal of a low arginine diet. To prevent a deficiency of other amino acids, a mixture of essential amino acids may be prescribed as well. A metabolic dietitian will work closely with patients and their families to provide specific and tailored dietary guidelines for each patient.
Oral nitrogen-scavenging medications (sodium benzoate or sodium phenylbutyrate) may also be necessary for patients with arginase deficiency. Sodium phenylbutyrate and benzoate reduce the concentration of the urea cycle precursors glutamine and glycine and provide an alternative pathway for nitrogen to be excreted through the urine.
It is important to remember that the condition is aggravated by fasting. One common complication in older children is post-operative encephalopathy, in which the catabolic state is induced by the necessary fasting before anesthesia and surgery. This can be prevented by administering proper dextrose-containing IV fluids until the patient can tolerate adequate calories by mouth.


Most patients with arginase deficiency are only mildly delayed early in life, with the delays becoming more evident as the child becomes older. Delays in development are more likely to occur if the diet and other therapies are not strictly adhered to. Delays can be seen even in optimally treated children due to the accumulation of arginine and guanidino compounds that are neurotoxic. Children should be monitored carefully and receive developmental/educational therapies as needed. See Intellectual Disability & Global Developmental Delay.


Individuals will need to remain on the protein-restricted diet for life. The same metabolic geneticist will manage the patient throughout adulthood, but primary care should be transitioned to a provider of internal medicine or family practice for primary care needs with the process beginning around age 14. See Transition Issues for more information about the clinician's role in transitioning adolescents with special health care needs to adult care.

Services and Referrals

Biochemical Genetics (Metabolics) (see NM providers [1])
Evaluation is important for confirmation of the diagnosis and initiation of management. Ongoing management includes periodic visits. The frequency of visits should be determined by age and stability. Infants will need relatively frequent visits; older individuals who are not prone to episodes of hyperammonemia are generally seen annually.

Nutrition, Metabolic (see NM providers [11])
Refer for assessment and modification of the diet to changing needs. The metabolic nutritionist will also assess adequate intake of nutrients.

Developmental - Behavioral Pediatrics (see NM providers [2])
Particularly helpful to optimize development and to evaluate older children with behavioral or learning concerns.

Early Intervention for Children with Disabilities/Delays (see NM providers [34])
Infants with arginase deficiency, whether symptomatic or not, should be followed by an Early Intervention Program. Developmental milestone achievement and school progress should be monitored closely by the medical home.

ICD-10 Coding

E72.21, Argininemia
Further coding details can be found at ICD-10 for Argininemia (

Patient Education

Learn the Signs Act Early (CDC)
Offers many tools, videos, lists, learning materials, and a developmental Milestone Tracker app (ages 2 months to 5 years); Centers for Disease Control and Prevention.

Arginase Deficiency (FAQ)
Answers to questions families often have about caring for their child with arginase deficiency.


Information & Support

Related Portal Content
Guidance for primary care clinicians receiving a positive newborn screen result.

Formulas for Metabolic Conditions (PDF Document 138 KB)
Formulas by name, age, use, and manufacturer for those with metabolic conditions, including arginase deficiency.

Care Notebook
Medical information is in one place with fillable templates to help families and providers. Choose only the pages needed to keep track of the current health care summary, care team, care plan, and health coverage.

Developmental Screening
Guidelines, surveillance, and response to positive screens.

Working with Insurance Companies
Letters of Medical Necessity and appealing funding denials.


NM ACT Sheet for Argininemia (ACMG) (PDF Document 135 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Confirmatory Algorithms for Arginine Elevated (ACMG) (PDF Document 155 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Services for Patients & Families in New Mexico (NM)

For services not listed above, browse our Services categories or search our database.

* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.


Arginase Deficiency (
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Helpful Articles

PubMed search for arginase deficiency in children and adolescents

Carvalho DR, Brum JM, Speck-Martins CE, Ventura FD, Navarro MM, Coelho KE, Portugal D, Pratesi R.
Clinical features and neurologic progression of hyperargininemia.
Pediatr Neurol. 2012;46(6):369-74. PubMed abstract

Sin YY, Baron G, Schulze A, Funk CD.
Arginase-1 deficiency.
J Mol Med (Berl). 2015;93(12):1287-96. PubMed abstract

Authors & Reviewers

Initial publication: February 2015; last update/revision: October 2023
Current Authors and Reviewers:
Author: Brian J. Shayota, MD, MPH
Authoring history
2018: update: Nicola Longo, MD, Ph.D.A
2011: first version: Lynne M. Kerr, MD, PhDA; Nicola Longo, MD, Ph.D.R
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Carvalho DR, Brum JM, Speck-Martins CE, Ventura FD, Navarro MM, Coelho KE, Portugal D, Pratesi R.
Clinical features and neurologic progression of hyperargininemia.
Pediatr Neurol. 2012;46(6):369-74. PubMed abstract

Catsburg C, Anderson S, Upadhyaya N, Bechter M.
Arginase 1 Deficiency: using genetic databases as a tool to establish global prevalence.
Orphanet J Rare Dis. 2022;17(1):94. PubMed abstract / Full Text

Freua F, Almeida MEC, Nóbrega PR, Paiva ARB, Della-Ripa B, Cunha P, Macedo-Souza LI, Bueno C, Lynch DS, Houlden H, Lucato LT, Kok F.
Arginase 1 deficiency presenting as complicated hereditary spastic paraplegia.
Cold Spring Harb Mol Case Stud. 2022;8(6). PubMed abstract / Full Text

Ibarra-González I, Fernández-Lainez C, Vela-Amieva M.
Clinical and biochemical characteristics of patients with urea cycle disorders in a developing country.
Clin Biochem. 2010;43(4-5):461-6. PubMed abstract

Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A.
Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported?.
Mol Genet Metab. 2011;104(1-2):107-11. PubMed abstract / Full Text

Lee BH, Jin HY, Kim GH, Choi JH, Yoo HW.
Argininemia presenting with progressive spastic diplegia.
Pediatr Neurol. 2011;44(3):218-20. PubMed abstract

McNutt MC, Foreman N, Gotway G.
Arginase 1 Deficiency in Patients Initially Diagnosed with Hereditary Spastic Paraplegia.
Mov Disord Clin Pract. 2023;10(1):109-114. PubMed abstract / Full Text

Qureshi IA, Letarte J, Ouellet R, Larochelle J, Lemieux B.
A new French-Canadian family affected by hyperargininaemia.
J Inherit Metab Dis. 1983;6(4):179-82. PubMed abstract

Sin YY, Baron G, Schulze A, Funk CD.
Arginase-1 deficiency.
J Mol Med (Berl). 2015;93(12):1287-96. PubMed abstract