Arginase Deficiency: Symptoms, Types, Causes and Treatment

Arginase deficiency is a rare, inherited metabolic disorder that sits at the crossroads of genetics, neurology, and liver health. Despite its rarity, understanding this condition is crucial for affected families, clinicians, and researchers, as it presents distinctive features compared to other urea cycle disorders. In this article, we’ll explore the key symptoms, the different types, underlying causes, and the full spectrum of current and emerging treatment options—giving you a clear and up-to-date picture of arginase deficiency.

Symptoms of Arginase Deficiency

Arginase deficiency has a unique clinical signature, setting it apart from other urea cycle disorders. Symptoms tend to emerge in early childhood but can vary in severity and progression.

Symptom	Description	Typical Onset	Source(s)
Neurological	Spasticity, intellectual decline, seizures	2–4 years	1 3 4 5 7 8 9
Growth	Persistent growth retardation	Childhood	1 2 3 5 7 9
Hyperammonemia	Mild to moderate, infrequent	Any age	1 2 3 4 5 7 9
Hepatic	Liver abnormalities, hepatomegaly	Variable	1 4 9

Table 1: Key Symptoms

Neurological Manifestations

The most defining symptoms are neurological. Children typically begin to show developmental delays, progressive loss of milestones, and spasticity (increased muscle tone, often affecting the legs). Over time, many develop spastic paraparesis or even lose the ability to walk. Seizures and intellectual disability are common, and if untreated, symptoms are progressive and can become severe 1 3 4 5 7 8 9.

Growth and Physical Development

Unlike other urea cycle disorders that often present with catastrophic neonatal illness, arginase deficiency usually manifests as persistent growth retardation. Children may not grow at the expected rate, and this can be an early sign to prompt investigation 1 2 3 5 7 9.

Hyperammonemia: Mild but Present

Whereas most urea cycle disorders cause life-threatening hyperammonemia soon after birth, arginase deficiency typically features either normal or mildly elevated ammonia levels. Episodes of hyperammonemia can occur, sometimes triggered by increased protein intake or physiological stress, but are generally less severe and less frequent than in other urea cycle defects 1 2 3 4 5 7 9.

Liver and Other Organ Involvement

Hepatic involvement is variable. Some patients show liver enlargement, abnormal liver function, or even chronic liver disease such as fibrosis or, rarely, hepatocellular carcinoma. Laboratory tests may reveal elevated liver enzymes 1 4 9.

Biochemical Clues

Laboratory findings consistently show high plasma arginine—often 4–7 times normal. Other amino acids may also be affected, and guanidino compounds (toxic metabolites) are increased in blood and cerebrospinal fluid, believed to contribute to neurological symptoms 4 5 8 9.

Types of Arginase Deficiency

Arginase exists in two forms in mammals, but only one is clinically relevant in humans. Understanding this distinction is critical for diagnosis and research.

Type	Gene/Enzyme	Tissue Localization	Clinical Relevance	Source(s)
Arginase I	ARG1	Liver, RBCs	Causes disease	3 6 7 9
Arginase II	ARG2	Kidney, other	No human disease	3 6 8

Table 2: Types of Arginase Deficiency

Arginase I (ARG1) Deficiency

• Enzyme: Arginase I
• Gene: ARG1 on chromosome 6
• Tissue Expression: Predominantly in the liver, also present in erythrocytes (red blood cells)
• Clinical Impact: Only deficiency of arginase I leads to the well-characterized disorder known as hyperargininemia or arginase deficiency 3 7 9.

This type is inherited in an autosomal recessive pattern. Over 40 mutations in ARG1 have been identified, leading to partial or complete loss of enzyme function 7.

Arginase II (ARG2) Deficiency

• Enzyme: Arginase II
• Gene: ARG2
• Tissue Expression: Primarily in the kidney and other extrahepatic tissues
• Clinical Impact: No cases of arginase II deficiency have been documented in humans. Animal studies show some metabolic changes, but affected mice are viable and healthy, indicating that arginase II does not play a critical role in urea formation or cause disease in humans 6 8.

Distinction from Other Urea Cycle Disorders

Arginase I deficiency is unique among urea cycle disorders. Others (such as ornithine transcarbamylase or carbamoyl phosphate synthetase deficiencies) typically present in the newborn period with severe hyperammonemia and multi-organ crisis, while arginase deficiency is later-onset and primarily neurological 3 7 9.

Causes of Arginase Deficiency

Understanding the underlying cause of arginase deficiency helps clarify why it presents differently from other urea cycle disorders and guides approaches for diagnosis and treatment.

Cause	Nature	Consequence	Source(s)
Genetic	Mutations in ARG1	Enzyme deficiency	3 7 9
Inheritance	Autosomal recessive	Both alleles mutated	3 7
Biochemical	Urea cycle defect	Hyperargininemia	1 3 4 5 7 9
Pathophysiology	Accumulation of arginine & guanidino compounds	Neurotoxicity	4 5 8 9

Table 3: Causes of Arginase Deficiency

Genetic Mutation

The root cause is biallelic (both copies) mutations in the ARG1 gene, leading to partial or complete loss of arginase I enzyme activity. This inheritance pattern is autosomal recessive—meaning both parents must carry a faulty gene for a child to be affected 3 7 9.

Enzyme Deficiency and Urea Cycle Disruption

Arginase I is the final enzyme in the urea cycle, responsible for converting arginine into ornithine and urea. Its deficiency disrupts this process, leading to a build-up of arginine and related metabolites in the blood and tissues 1 3 4 5 7 9.

Pathophysiology: Why the Symptoms?

• Hyperargininemia: Excess arginine is thought to be neurotoxic at high concentrations.
• Guanidino Compounds: These arginine-derived metabolites accumulate and are strongly believed to be responsible for the neurological features, including spasticity and intellectual decline 5 8 9.
• Ammonia: While ammonia is less elevated than in other urea cycle disorders, mild to moderate hyperammonemia can still occur, especially during illness or increased protein intake 1 3 4 5 7 9.

Family History and Carrier Status

Parents and siblings of affected individuals may have reduced arginase activity but do not develop symptoms, highlighting the necessity of both alleles being mutated for disease to manifest 4.

Treatment of Arginase Deficiency

While there is currently no cure, treatment strategies for arginase deficiency aim to reduce arginine levels, manage symptoms, and prevent further neurological decline. Recent advances offer hope for more effective therapies in the future.

Treatment	Mechanism/Approach	Goal/Outcome	Source(s)
Diet	Protein-restricted diet	Lower arginine, prevent symptoms	3 5 7 9 12
Medications	Nitrogen scavengers, e.g., sodium phenylbutyrate	Reduce ammonia, alternative waste removal	1 3 12
Enzyme Therapy	Recombinant arginase, enzyme-loaded RBCs	Lower plasma arginine	5 13
Gene Therapy	AAV vectors, mRNA therapy, LNPs	Restore arginase activity	10 11 12

Table 4: Treatment Approaches

Dietary Management

• Protein Restriction: The mainstay of treatment is a low-protein diet to reduce nitrogen load and arginine production 3 5 7 9.
• Essential Amino Acid Supplementation: To prevent malnutrition, essential amino acids are supplemented.
• Monitoring: Frequent monitoring of plasma arginine, ammonia, and nutritional status is critical 3 5 7.

Pharmacological Interventions

• Nitrogen Scavengers: Medications like sodium phenylbutyrate can help lower ammonia by providing alternative pathways for nitrogen excretion 1 3 12.
• Arginine-Lowering Agents: Human recombinant arginase enzymes (e.g., AEB1102) have been shown to reduce plasma arginine in animal models and may have therapeutic potential for patients, although more research is needed 5.

Experimental and Emerging Therapies

• Gene Therapy: Adeno-associated viral (AAV) vector-mediated gene transfer or delivery of codon-optimized mRNA using lipid nanoparticles (LNPs) have shown significant promise in animal models—restoring ureagenesis, normalizing ammonia and arginine levels, and prolonging survival 10 11 12.
• Enzyme Replacement in Erythrocytes: Experimental studies have shown that loading patient erythrocytes with human arginase can correct metabolic defects in vitro. This concept may pave the way for new forms of enzyme replacement therapy 13.
• Ongoing Research: mRNA therapies, liver-targeted nanoparticle delivery, and improved enzyme formulations are all in development, with the aim of providing more effective, less burdensome treatments 10 12.

Supportive Care and Prognosis

• Early Diagnosis: Early initiation of treatment can halt progression and, in some cases, improve neurological function 3 5 7 9.
• Long-term Care: Despite treatment, many patients experience some degree of intellectual or physical disability. Regular follow-up with a metabolic specialist is essential.

Conclusion

Arginase deficiency is a complex but fascinating disorder that teaches us much about genetic diseases, metabolism, and neurology. Here’s a summary of what we’ve covered:

• Unique symptoms: Primarily neurological, including spasticity and intellectual impairment, with less severe hyperammonemia than other urea cycle defects.
• One main type: Only arginase I (ARG1) deficiency causes human disease.
• Genetic cause: Autosomal recessive mutations in ARG1 disrupt the urea cycle and lead to toxic metabolite accumulation.
• Treatment focus: Diet, medications, and experimental approaches (gene/mRNA therapies) aim to reduce arginine levels and prevent neurological damage.
• Research outlook: New therapies, including gene and mRNA-based approaches, are on the horizon and could significantly improve outcomes.

By understanding the symptoms, types, causes, and treatments of arginase deficiency, families and healthcare teams can work together to optimize quality of life and hope for better options in the future.