arginase deficiency

Arginase deficiency is an inherited disorder of the urea cycle, the body’s pathway for removing excess nitrogen, that primarily affects the liver, brain, and muscles. It is caused by pathogenic variants in the ARG1 gene, which reduce or eliminate activity of the arginase 1 enzyme and lead to accumulation of arginine and, at times, ammonia in the bloodstream. Symptoms usually begin in early childhood, often after the age of three, and can involve both physical and cognitive challenges. The condition affects fewer than one in a million people worldwide, making it very rare, and it is seen in both boys and girls. Severity and symptoms vary widely between individuals, even within the same family.

Children with arginase deficiency often appear healthy at birth and during infancy. Early features that draw medical attention include episodic vomiting, frequent falls due to a spastic or stiff-legged gait, and enlargement of the liver (hepatomegaly). As the disorder progresses, many children experience cognitive and developmental challenges, such as global developmental delay, atypical behavior, speech difficulties, and in some cases severe intellectual disability. Neurological findings can evolve to include cerebellar atrophy on brain imaging, progressive spasticity that may lead to quadriplegia, and seizures in a subset of affected individuals. Liver involvement may advance from persistent cholestasis to portal fibrosis and micronodular cirrhosis. Periodic rises in blood ammonia (hyperammonemia) can occur, especially during illness or high-protein intake, and may worsen neurological symptoms. Not all individuals experience all features, and the degree of movement problems, liver disease, and cognitive impact can differ considerably from person to person.

Arginase deficiency results from pathogenic variants in the ARG1 gene. This gene provides instructions for making arginase 1, an enzyme that converts arginine into ornithine and urea as the final step of the urea cycle. When arginase 1 activity is greatly reduced, arginine and nitrogen-rich compounds build up in the body, leading to the neurological and liver-related symptoms described above. The disorder is inherited in an autosomal recessive pattern, meaning a child must receive an altered ARG1 gene from both parents to be affected. Parents who each carry one altered copy are usually healthy themselves but have a 25 percent chance with every pregnancy of having a child with the condition. Because the disorder is very rare, it is more likely to occur in families where parents share a common ancestor, as this increases the chance that both carry the same rare genetic change. Genetic counseling can help relatives understand carrier testing, reproductive options, and implications for extended family members.

Currently, management focuses on supportive care and symptom management tailored to each individual. A low-protein diet coordinated by a metabolic dietitian aims to reduce nitrogen load, and episodes of high ammonia are treated promptly, often in hospital, using standard ammonia-lowering strategies. Physical and occupational therapies help maintain mobility and address spasticity, while speech therapy supports communication skills. Because the condition affects the liver, regular surveillance is essential, including periodic liver function tests and imaging to detect fibrosis or cirrhosis early. Neurological monitoring, such as developmental assessments and seizure evaluation when indicated, guides therapy adjustments. Care is best provided by a multidisciplinary team that may include metabolic specialists, neurologists, hepatologists, physiatrists, and genetic counselors. Families should discuss emerging clinical trials or investigational therapies with their care team to determine whether participation is appropriate.

Outcomes for individuals with arginase deficiency depend on how early the condition is recognized, the effectiveness of dietary management, and the frequency of hyperammonemic episodes. With careful metabolic control, many children achieve improved growth, better cognitive outcomes, and reduced hospitalization for ammonia crises, though challenges with spasticity and learning may persist. Long-term liver complications remain a concern and require ongoing monitoring. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with metabolic disease centers, genetic counselors, and patient support networks to stay informed about advances and to share practical strategies for daily living.

Several clinical trials are currently investigating new treatments, including enzyme replacement and gene-directed approaches aimed at correcting the underlying metabolic defect. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their healthcare team about eligibility and potential benefits or risks of participation.