NAGS deficiency

NAGS Deficiency NAGS deficiency is a rare genetic disorder that affects the urea cycle, a series of biochemical reactions in the liver that convert ammonia into urea for excretion from the body. This condition is caused by mutations in the NAGS gene, which encodes the enzyme N-acetylglutamate synthase (NAGS). NAGS is essential for the activation of carbamoyl phosphate synthetase 1 (CPS1), the first enzyme in the urea cycle.

Pathophysiology

NAGS deficiency leads to a disruption in the urea cycle, resulting in the accumulation of ammonia in the blood, a condition known as hyperammonemia. Ammonia is a neurotoxin, and elevated levels can lead to neurological damage and other serious health issues.

Urea Cycle

The urea cycle is a critical metabolic pathway that converts toxic ammonia into urea, which is then excreted in the urine. The cycle involves several enzymes, including NAGS, CPS1, ornithine transcarbamylase (OTC), and others. NAGS deficiency impairs the activation of CPS1, leading to a bottleneck in the cycle.

Genetics

NAGS deficiency is inherited in an autosomal recessive manner. This means that an individual must inherit two copies of the mutated gene, one from each parent, to manifest the disease. Carriers, with only one copy of the mutation, typically do not show symptoms.

Symptoms

Symptoms of NAGS deficiency can vary but often include:

• Lethargy
• Vomiting
• Poor feeding
• Developmental delay
• Seizures
• Coma in severe cases

Diagnosis

Diagnosis of NAGS deficiency involves:

• Measurement of blood ammonia levels
• Genetic testing to identify mutations in the NAGS gene
• Enzyme assays to assess NAGS activity

Treatment

Treatment strategies for NAGS deficiency focus on reducing ammonia levels and may include:

• Dietary management with protein restriction
• Medications such as carglumic acid, which acts as a synthetic activator of CPS1
• In severe cases, liver transplantation may be considered

Prognosis

With early diagnosis and appropriate management, individuals with NAGS deficiency can lead relatively normal lives. However, untreated hyperammonemia can lead to irreversible neurological damage and can be life-threatening.

Research

Ongoing research aims to better understand the genetic and biochemical basis of NAGS deficiency and to develop more effective treatments. Gene therapy and enzyme replacement therapy are areas of active investigation.

See Also

• Urea cycle disorders
• Hyperammonemia
• Genetic testing

NIH genetic and rare disease info

• NIH info on NAGS deficiency

NAGS deficiency is a rare disease.