Arginase Deficiency

Etiology

Biallelic pathogenic or likely pathogenic variants in the ARG1 gene lead to deficiency or instability of the arginase 1 enzyme. The ARG1 gene is located on chromosome 6q23.2. The product of this gene, the arginase 1 enzyme, is found primarily in the hepatic cytosol and is responsible for the final step of the urea cycle: the hydrolysis of L-arginine into urea and ornithine.[3] In arginase deficiency, this defect prevents the proper breakdown of arginine, leading to its systemic accumulation. A second gene, ARG2, encodes a different arginase enzyme (arginase 2) that is found mainly in the mitochondria of extrahepatic tissues, such as the kidney, brain, and gastrointestinal tract. However, arginase 2 expression is insufficient, and the enzyme is located in a different cellular compartment, preventing compensation for the primary defect in the hepatic urea cycle.[4]

Epidemiology

Arginase deficiency is the rarest of the urea cycle disorders, with an estimated incidence ranging from approximately 1 in 300,000 to 1 in 1,000,000 births.[5] More than 250 cases have been reported in the literature to date. While a precise genotype-phenotype correlation has not been fully established, disease severity often appears to correlate with the nature of the biallelic ARG1 variants. For instance, homozygous or compound heterozygous loss-of-function variants are typically associated with a more severe, classic phenotype than are some missense variants. The disorder occurs in all racial and ethnic groups and does not appear to have a higher prevalence in any specific population.[1][6][7]

Pathophysiology

Arginase 1, encoded by the ARG1 gene and found primarily in the liver and erythrocytes, catalyzes the fifth and final reaction of the urea cycle: the hydrolysis of L-arginine into ornithine and urea (see Image. Urea Cycle Disorder: Arginase Deficiency). A deficiency or absence of arginase 1 activity blocks this final step, causing the systemic accumulation of arginine (hyperargininemia) in the blood and central nervous system. Arginine accumulation begins at birth. Unlike proximal urea cycle disorders, significant hyperammonemia is often absent. The primary pathophysiology is driven by the neurotoxicity of arginine itself, which is shunted into alternative metabolic pathways. Alternative arginine metabolism generates toxic metabolites, such as guanidino compounds, which are believed to be responsible for the characteristic progressive neurologic symptoms (eg, spasticity and cognitive delay) that typically become clinically apparent around 1 to 3 years of age.[8]

A characteristic biochemical finding is the accumulation of orotic acid (orotic aciduria). Orotic aciduria occurs because the block in arginine hydrolysis leads to a relative deficiency of ornithine. Ornithine is required for ornithine transcarbamylase to function. Reduced ornithine availability causes an accumulation of carbamoyl phosphate, which is subsequently shunted from the urea cycle into the pyrimidine synthesis pathway, resulting in orotic acid overproduction.[6][9]

Toxicokinetics

The toxicokinetics of argininemia are distinct from those of other urea cycle disorders and are not primarily driven by ammonia accumulation. The central mechanism is the neurotoxicity of chronic hyperargininemia and its metabolic byproducts. Extremely high cellular arginine levels saturate alternative enzyme pathways, most notably arginine-glycine amidinotransferase. Shunting through this pathway leads to the overproduction of guanidino compounds.[2] Guanidino compounds are believed to be the primary neurotoxins responsible for the characteristic progressive spasticity and cognitive decline.[10] Furthermore, excess arginine dysregulates the nitric oxide pathway by overwhelming nitric oxide synthase. Dysregulation of the nitric oxide pathway can contribute to endothelial dysfunction and has been proposed as another mechanism of neurotoxicity.[8] Although chronic, progressive cerebral injury (including cortical atrophy in the parietal, occipital, and frontal lobes) is linked to these toxic metabolites, acute hyperammonemia can still occur, particularly during catabolic states (eg, illness).[11] A sudden increase in the ammonia level can cause cerebral edema, but acute hyperammonemia is an intermittent event and does not account for the characteristic progressive course of the disease.

History and Physical

Arginase deficiency (argininemia) rarely presents during the neonatal period or infancy with the life-threatening hyperammonemia characteristic of proximal urea cycle disorders. The classic presentation is a progressive neurologic syndrome that typically becomes clinically apparent between 1 and 3 years of age. The earliest signs are often slowed linear growth, followed by the hallmark finding of the condition: progressive spastic diplegia (abnormal muscle tightening and stiffness, primarily in the lower extremities). Progressive spastic diplegia is accompanied by a plateau or regression of cognitive development and the loss of previously acquired motor milestones.[3] Because the primary clinical picture is progressive spasticity, often with only mild or intermittent hyperammonemia, the condition is frequently misdiagnosed as cerebral palsy or hereditary spastic paraplegia. Progressive spasticity occurs in nearly 80% to 90% of affected individuals and is the most consistent neurologic finding on physical examination.

As the disease progresses, especially if undiagnosed or inadequately treated, patients develop severe complications.[12] Complications include worsening spasticity leading to loss of ambulation, intellectual disability, seizures, and behavioral issues such as attention-deficit/hyperactivity disorder and aggression.[13] Nearly half to two-thirds of the affected individuals manifest with seizures, and generalized tonic-clonic seizures are the most common type. Intermittent episodic hyperammonemia can still occur, especially when induced by catabolic stressors (eg, infections), high protein intake, or certain medications (eg, valproate), but hyperammonemia does not cause the chronic, progressive neurologic decline.[13] Extraneurological manifestations are less common but can include liver dysfunction (usually mild, although fibrosis or cirrhosis have occasionally been reported) and bone involvement.[3]

Evaluation

The evaluation for arginase deficiency is typically initiated after positive newborn screening results or, increasingly, in a symptomatic child not identified through screening.

Newborn Screening

Newborn screening programs screen for hyperargininemia by quantifying arginine levels in dried blood spots. However, not all screening panels include arginase deficiency. Furthermore, false-negative results are known to occur because arginine levels may be only mildly elevated during the neonatal period before significant protein catabolism begins.[2][5]

Symptomatic Presentation

A high index of suspicion is warranted for any child presenting with progressive spastic diplegia, developmental regression, or seizures, especially when cognitive decline has been noted.[13][14]

Biochemical Diagnosis

 The essential diagnostic evaluation for a suspected case includes:

• Plasma amino acid analysis: This is the most critical test. Results reveal an isolated elevation in the plasma arginine level, often 4 to 10 times the upper limit of the reference range.
• Urine organic acid analysis: Results typically show an elevated orotic acid level (orotic aciduria). Orotic aciduria is a key finding that differentiates arginase deficiency from other diagnoses and confirms a block in the urea cycle.
• Plasma ammonia level: The plasma ammonia level provides supportive diagnostic information. Results may be within the reference range, mildly elevated, or significantly elevated (eg, greater than 200 µg/dL), depending on the patient's current metabolic (catabolic) state. An ammonia level within the reference range does not rule out argininemia.

Neuroimaging 

Neuroimaging findings in the central nervous system result directly from chronic neurotoxicity caused by elevated plasma arginine levels and guanidino compound metabolites. Common findings include cortical atrophy, particularly in the frontal and parietal lobes, ischemic changes, and edema. Neuroimaging findings may resemble the cerebral injury seen in patients affected by hypoxic-ischemic events. The similarity between these findings is a primary reason the clinical presentation is frequently misdiagnosed as cerebral palsy.[11]

Confirmatory Testing

The diagnosis is confirmed by molecular genetic testing of ARG1 to identify biallelic pathogenic variants. Molecular genetic testing is now the standard confirmatory step.[5] Less commonly, an enzyme assay on red blood cells can be performed, with results showing arginase 1 activity of less than 1%. More than 98% of cases with confirmed molecular genetic analysis have sequence variants, and less than 2% may have copy number variants, so the molecular genetic test should be planned accordingly. The genotype-phenotype correlation in arginase deficiency is related to the residual enzyme activity associated with the variant.

Critical Diagnostic Warning

The initial evaluation is critical. Argininemia is a distal urea cycle disorder in which arginine is the primary toxin. In contrast, proximal urea cycle disorders, such as ornithine transcarbamylase deficiency, are treated with supplemental arginine to promote nitrogen excretion. Misdiagnosing argininemia as a proximal urea cycle disorder and administering arginine can cause severe, rapid neurologic harm.

Treatment / Management

Treatment of arginase deficiency is lifelong and focuses on 2 distinct clinical scenarios: acute hyperammonemic crises and the more common progressive chronic disease.

Management of Acute Hyperammonemia

Acute hyperammonemic crises are less frequent than those associated with other urea cycle disorders but are medical emergencies. Treatment includes:

• Protein cessation: All protein intake should be stopped for 24 to 48 hours.
• Intravenous fluids and calories: Provide high-calorie, protein-free sources (eg, 10% intravenous dextrose) to promote anabolism and reverse catabolism.
• Nitrogen scavengers: Intravenous nitrogen-scavenging medications, such as sodium phenylacetate or sodium benzoate, are used to treat moderate or severe hyperammonemia.
• Dialysis: In cases of severe hyperammonemia refractory to medical interventions, hemodialysis or continuous renal replacement therapy is highly effective.[13]
(B3)

Long-Term Management

The primary goal of chronic therapy is to control plasma arginine levels to prevent progressive, irreversible neurotoxicity.[8]

Foundational therapy: The traditional approach aims to limit arginine intake and provide alternative pathways for the excretion of nitrogen waste.

• Diet:  Lifelong dietary protein restriction is required. A specialized arginine-free essential amino acid formula supplements the diet to prevent malnutrition.
• Nitrogen scavengers: Daily maintenance dosing of nitrogen scavengers (eg, sodium phenylbutyrate or glycerol phenylbutyrate) is used.
• Limitations of the standard of care: Results from recent natural history studies indicate that foundational therapy is often insufficient.[12] Many patients do not maintain target arginine levels, and the highly restrictive diet creates a significant treatment burden. Most importantly, foundational therapy has not been shown to reliably halt the progression of neurologic symptoms, such as spasticity, in many patients.
(A1)

Enzyme replacement therapy: The most significant advancement in treatment is the development of enzyme replacement therapy, which directly targets elevated arginine levels, the underlying metabolic abnormality.

• Drug: Pegzilarginase-nbln is a recombinant human arginase 1 enzyme administered via subcutaneous injection.
• Mechanism: Pegzilarginase-nbln provides an exogenous source of arginase 1 enzyme activity and lowers plasma arginine levels by converting arginine to urea and ornithine.
• Efficacy: Results from the phase 3 Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints (PEACE) trial demonstrated rapid, significant, and sustained reductions in plasma arginine levels.[15] This metabolic control was directly associated with statistically significant improvements in mobility and functional outcomes compared to placebo. Motor function outcomes improved with pegzilarginase-nbln, although the difference compared with placebo was not statistically significant. Pegzilarginase-nbln received accelerated approval from the US Food and Drug Administration on February 23, 2026, for the treatment of hyperargininemia in adults and children aged 2 years or older with arginase 1 deficiency, in conjunction with dietary protein restriction. The accelerated approval was based on reduced plasma arginine levels, and continued approval may depend on confirmation of clinical benefit. [FDA. Loargys Prescribing Information] Pegzilarginase was previously authorized in the European Union in December 2023 under exceptional circumstances and additional monitoring.[EMA. Loargys]
(A1)

Supportive Care and Other Treatment

Supportive care: Physical and occupational therapy are critical for managing spasticity and maintaining mobility.

Developmental support: Care from a developmental pediatrician and an interdisciplinary team is paramount for nearly all affected individuals from an early age. An individualized education plan is needed for most affected individuals to maximize independence and productivity later in life.

Seizure treatment: Seizures are common and treated with standard antiseizure medications, such as phenobarbital or carbamazepine. Valproate (valproic acid) is strongly contraindicated because it interferes with the urea cycle and can induce hyperammonemia.[13](B3)

Liver transplant: Individuals with chronic end-stage liver disease may require a liver transplant. Liver transplant most closely approximates curative therapy because it provides a fully functional liver. However, the significant associated risks must be carefully weighed against the benefits of newer medical therapies. Moreover, direct evidence demonstrating its effects on elevated arginine levels and neurologic status is lacking.

Monitoring: Lifelong, regular monitoring by a metabolic specialist and a dietitian is essential. Monitoring includes frequent measurement of plasma amino acid levels (especially arginine), plasma ammonia levels, and liver function.

Investigational Therapies

Research into one-time, curative treatments continues. Results from preclinical studies of messenger RNA-based therapy, gene therapy using adeno-associated virus vectors, and clustered regularly interspaced short palindromic repeats-based genome editing to correct the gene in hepatocytes showed promise, but these therapies remain investigational.[5][9][16][17]

Differential Diagnosis

A differential diagnosis must address 2 domains: the clinical presentation and the biochemical profile.

Clinical and Neurological Differential

This is the most common pitfall, leading to significant diagnostic delays.

• Cerebral palsy: Argininemia is most frequently misdiagnosed as cerebral palsy.[14] The key differentiator between cerebral palsy and arginase deficiency is progression: cerebral palsy is a nonprogressive motor disorder, whereas the symptoms of argininemia will progressively worsen over time.
• Hereditary spastic paraplegia: This group of genetic disorders also causes progressive lower-extremity spasticity. Argininemia is now considered a treatable form of spastic paraplegia and should be excluded through plasma amino acid analysis during the evaluation of hereditary spastic paraplegia.

Biochemical Differential

Proximal urea cycle disorders (eg, ornithine transcarbamylase deficiency and carbamoyl phosphate synthetase 1 deficiency): These disorders are biochemically distinct. They present with severe, life-threatening hyperammonemia during the neonatal period and low to reference-range plasma arginine levels. In contrast, argininemia presents with significantly elevated plasma arginine levels and often reference-range or only mildly elevated ammonia levels.

Lysinuric protein intolerance: This rare autosomal recessive disorder is caused by variants in the SLC7A7 gene. Lysinuric protein intolerance can also present with hyperammonemia and elevated plasma arginine levels, mimicking argininemia on newborn screening.[9] The key differentiator is that lysinuric protein intolerance is an amino acid transport disorder characterized by elevated urinary levels of lysine, ornithine, and arginine (lysinuria), as well as low plasma levels of these amino acids.

Prognosis

The prognosis for argininemia is variable but predictable, depending directly on 2 factors: the age at diagnosis and the success of long-term metabolic control. Historically, the prognosis was poor because foundational therapy alone was often inadequate. Results from natural history studies showed that treatment with a protein-restricted diet and nitrogen-scavenging medications was frequently insufficient to control plasma arginine levels.[12] As a result, most patients experienced progressive, irreversible neurologic damage, including severe spasticity, loss of ambulation, and moderate to severe intellectual disability, leading to reduced quality of life.

The prognosis may improve with arginine-lowering enzyme replacement therapy. Results from the PEACE trial demonstrated that pegzilarginase significantly reduced plasma arginine levels, with mobility outcomes favoring treatment.[15] Results from a recent extension study showed that pegzilarginase improved biochemical and clinical outcomes. Temporary treatment discontinuation was associated with worsening outcomes, whereas treatment resumption was associated with subsequent improvement in clinical and biochemical markers.[18]

The key prognostic factor remains the irreversibility of existing neurologic damage.[2] Patients diagnosed late (eg, after a misdiagnosis of cerebral palsy) and treated with enzyme replacement therapy may experience stabilization of disease progression and recovery of some lost motor or cognitive milestones. The potential for irreversible injury underscores the critical importance of early diagnosis and timely, effective treatment.

Complications

The primary complications of argininemia result from chronic, irreversible neurologic damage caused by hyperargininemia and related metabolites. If the diagnosis is delayed or treatment does not adequately control plasma arginine levels, patients may develop:

• Progressive spastic diplegia, leading to joint contractures and loss of ambulation
• Seizures
• Moderate-to-severe intellectual disability
• Cognitive and behavioral deficits
• Short stature
• Hepatic complications: While neurological symptoms predominate, the liver is the primary site of the enzyme defect. Late manifestations, reflecting long-term metabolic stress, can include the development of hepatic fibrosis, cirrhosis, and, in rare cases, hepatocellular carcinoma.[19]

Results from natural history studies showed that these complications can develop even in patients adhering to standard-of-care dietary and nitrogen-scavenging therapy.[12] Although many infants are now identified through newborn screening, screening is not universal, and false-negative results can occur. Delayed diagnosis, often due to a misdiagnosis of cerebral palsy, is a major complication that contributes to poor prognosis.