What are the consequences of deficient N-Acetylglutamate (NAG) synthase?

From the Guidelines

N-acetylglutamate synthase (NAGS) deficiency leads to hyperammonemia because this enzyme produces N-acetylglutamate, an essential activator of carbamoyl phosphate synthetase 1 (CPS1) in the urea cycle, and its deficiency results in the accumulation of ammonia in the blood, causing symptoms ranging from nausea and vomiting to lethargy, seizures, coma, and potentially death if untreated, as reported in studies such as 1 and 1.

Pathophysiology of NAGS Deficiency

The urea cycle is a critical process by which the body removes excess ammonia, a toxic byproduct of protein metabolism. NAGS plays a crucial role in this cycle by producing N-acetylglutamate, which activates CPS1, the first enzyme in the urea cycle. Without proper NAGS function, CPS1 cannot effectively convert ammonia to carbamoyl phosphate, leading to ammonia accumulation in the blood. This can result in severe neurological symptoms, including lethargy, seizures, and coma, as described in 1 and 1.

Clinical Manifestations

The clinical features of NAGS deficiency can vary depending on the age of the patient and the severity of the deficiency. Neonates with NAGS deficiency may present with lethargy, loss of appetite, and vomiting, which can progress to hypotonia, hyperventilation, and respiratory alkalosis if left untreated, as noted in 1. Late-onset NAGS deficiency can result in failure to thrive, irritability, seizures, and intellectual disabilities, as reported in 1.

Treatment and Management

Treatment of NAGS deficiency typically involves the use of carglumic acid (Carbaglu), a synthetic analog of N-acetylglutamate that bypasses the deficient enzyme and activates CPS1 directly, as described in 1. The recommended dosage is 100-250 mg/kg/day, divided into 2-4 doses, adjusted based on ammonia levels. Acute management also includes protein restriction, intravenous fluids, and ammonia scavengers like sodium benzoate. Long-term management requires lifelong carglumic acid supplementation, dietary protein management, and regular monitoring of ammonia levels to prevent neurological damage and ensure normal development, as outlined in 1 and 1.

Some key points to consider in the management of NAGS deficiency include:

• The importance of prompt diagnosis and treatment to prevent neurological damage and improve outcomes, as emphasized in 1 and 1
• The need for lifelong carglumic acid supplementation and dietary protein management to control ammonia levels, as reported in 1 and 1
• The importance of regular monitoring of ammonia levels and adjustment of treatment as needed, as described in 1 and 1

From the Research

Deficient N-Acetylglutamate Synthase: Consequences and Treatment

• N-Acetylglutamate synthase (NAGS) deficiency is a rare autosomal recessive metabolic disorder that affects the urea cycle, leading to episodes of hyperammonemia, which can cause significant morbidity and mortality 2.
• The deficiency can be treated with carbamylglutamate, a structural analog of N-acetylglutamate, which is effective in treating acute hyperammonemia and maintaining normal plasma ammonia levels during long-term treatment 3.
• Carglumic acid, another name for carbamylglutamate, has been shown to be effective in treating acute hyperammonemia due to primary NAGS deficiency and has the potential to be used in treating acute hyperammonemias in general 4, 5.
• The treatment of NAGS deficiency usually consists of carbamylglutamate, with or without other measures such as protein restriction, ammonia scavengers, and dialytic therapy 2.
• DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful 2.
• The presentation of NAGS deficiency varies by age and symptoms, and both diagnosis and management have evolved over time and vary across clinics 2.

Triggers and Management of Hyperammonemic Episodes

• Hyperammonemic episodes in NAGS deficiency can be triggered by various factors, including protein intake, illness, and other stressors 2, 3.
• Management of hyperammonemic episodes typically involves treatment with carbamylglutamate, as well as other measures such as protein restriction, ammonia scavengers, and dialytic therapy 2, 3.
• Carglumic acid has been shown to be effective in reducing plasma ammonia levels and improving outcomes in patients with NAGS deficiency 4, 5.

Role of Carglumic Acid in Treatment

• Carglumic acid is a structural analog of N-acetylglutamate and has been shown to be effective in treating acute hyperammonemia due to primary NAGS deficiency 3, 5.
• It works by reactivating the urea cycle and reducing plasma ammonia levels, thereby improving outcomes in patients with NAGS deficiency 4, 5.
• Carglumic acid has been approved for the treatment of primary NAGS deficiency and acute hyperammonemia in patients with specific organic acidurias that can lead to NAG deficiency secondary to inhibition of NAGS 5.