Knowledge on rare diseases and orphan drugs

The incidence of this condition is estimated at 1/800,000-1,000,000. As newborn screening for argininemia (or arginase-1 deficiency; ArgD) is not common, its incidence is probably underestimated. Males and females are equally affected.

The clinical course of the disease is highly variable and some symptoms differ from those observed in other classical urea cycle defects. The risk of metabolic decompensation with hyperammonemia — which may occur in the neonatal period and manifest as coma, central dysregulation, hyperventilation and epileptic seizures — is lower. Most patients are asymptomatic from birth to toddlerhood. Typically, the first symptoms are observed at age 1-3 years. Clinical manifestations include spasticity, predominantly affecting lower extremities, which may later progress to paraplegia, reduced mobility and gait disturbances, intellectual disability, developmental delay and even loss of developmental milestones. Attention deficit hyperactivity disorder (ADHD) and aggressive behavior are frequently observed. Complete loss of bowel and bladder control may occur. The disease is highly progressive in most patients. As extracerebral manifestation, liver dysfunction may be observed. Life expectancy is limited in most patients.

ArgD is due to deficiency of arginase 1, encoded by the ARG1 gene. Arginase 1 is one of six enzymes of the urea cycle that detoxify ammonia. Its dysfunction results in hyperammonemia, especially during catabolic episodes, and leads to hyperargininemia. Elevated arginine levels and its derivatives, such as the epileptogenic guanidinoacetate, cause direct neurotoxicity.

The presentation of hyperammonemia or spasticity in a patient may prompt a blood amino acid analysis, revealing highly elevated arginine levels, which is pathognomonic for ArgD. Molecular genetic testing typically identifies two pathogenic variants (PVs) in the ARG1 gene. Enzyme analysis of arginase in erythrocytes is rarely performed but may be helpful when genetic testing detects variants of uncertain significance (VUS). Newborn mass screening for early detection of the disease is not widely available yet.

If hyperammonemia is the primary finding, primary hyperammonemia (six enzymes and two transporter deficiencies of urea cycle) and secondary hyperammonemic conditions such as organic acidurias, carbonic anhydrase 5A deficiency, mitochondriopathies and liver failure should be considered. If spasticity is the clinical hallmark, static spastic diplegia without progression (cerebral palsy) due to brain injury or other forms of spastic paraplegia must be excluded.

Prenatal diagnosis is possible if there is an index case in the family. Genetic testing is recommended if PVs are known; alternatively, postnatal arginine determination can be performed. Successful enzyme replacement therapy with pegzylarginase reduces the justification for prenatal diagnostic procedures.

Genetic counseling is recommended for family planning. As there is some genotype-phenotype correlation, parents may be counselled regarding the severity of the disease. If both parents are carriers of a pathogenic variant, the risk to future offsprings is 25%.

Classical treatment involves reducing arginine concentration and ammonia levels in blood by a low-protein diet supplemented with essential amino acids and administration of scavenger drugs like phenylbutyrate and/or benzoate, through a preparation of sodium phenylbutyrate or glycerophenylbutyrate (which has better pharmacokinetic properties), to enable excretion of nitrogen via urine independently of the deficient urea cycle. Supportive measures like physio-/occupational-therapy are offered. In patients suffering from frequent hyperammonemic crises, liver transplantation is considered. Recently, pegzylarginase, administered intravenously or subcutaneously once a week, has been approved as an enzyme replacement therapy.

Classical treatments often fail to prevent neurological symptoms, leading to a guarded prognosis. Life expectancy is reduced. Enzyme therapy may improve outcomes if started early. Newborn screening is crucial for timely therapy initiation, as early clinical diagnosis is difficult due to unspecific symptoms.

Last update: March 2025 - Expert reviewer(s): Pr Anibh DAS | MetabERN*

* European Reference Network