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

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.

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

Genetics

Incidence & Prevalence

Differential Diagnosis

Comorbid Conditions

Prognosis

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

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

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.