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.
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
Diagnosis
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.
Presentations
Diagnostic Criteria and Classifications
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.
Imaging
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.
Genetics
Incidence & Prevalence
Differential Diagnosis
Comorbid Conditions
Prognosis
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.
Nutrition/Growth
Development
Transition
Services and Referrals
Biochemical Genetics (Metabolics)
(see OH providers
[0])
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 OH providers
[1])
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 OH providers
[1])
Particularly helpful to optimize development and to evaluate older
children with behavioral or learning concerns.
Early Intervention for Children with Disabilities/Delays
(see OH providers
[0])
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
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.
Resources
Information & Support
Related Portal Content
Argininemia
Guidance for primary care clinicians receiving a positive
newborn screen result.
Formulas for Metabolic Conditions ( 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.
Tools
ACT Sheet for Argininemia (ACMG) ( 348 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
Confirmatory Algorithms for Arginine Elevated (ACMG) ( 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 Ohio (OH)
Service Categories | # of providers* in: | OH | NW | Other states (4) (show) | | NM | NV | RI | UT |
---|---|---|---|---|---|---|---|---|---|
Biochemical Genetics (Metabolics) | 1 | 1 | 2 | 3 | 2 | ||||
Developmental - Behavioral Pediatrics | 1 | 2 | 3 | 12 | 9 | ||||
Early Intervention for Children with Disabilities/Delays | 3 | 34 | 30 | 13 | 51 | ||||
Nutrition, Metabolic | 11 | 11 | 13 | 13 | 11 |
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.
Studies
Arginase Deficiency (ClinicalTrials.gov)
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
Author: | Brian J. Shayota, MD, MPH |
2018: update: Nicola Longo, MD, Ph.D.A |
2011: first version: Lynne M. Kerr, MD, PhDA; Nicola Longo, MD, Ph.D.R |
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