What are the causes of N-acetylglutamate synthase deficiency?

The urea cycle is a series of chemical reactions that occur in liver cells and serves as the primary metabolic pathway for converting ammonia, produced through various metabolic processes in the body, into urea for excretion in urine. N-acetylglutamate synthase is responsible for producing N-acetylglutamate, which activates carbamoyl phosphate synthetase, the key rate-limiting enzyme in the first step of the urea cycle.

Patients with NAGSD have mutations in the gene encoding N-acetylglutamate synthase, leading to insufficient or absent enzyme activity. This disrupts the urea cycle, impairs ammonia metabolism, elevates blood ammonia levels, and causes the disease.

Which department should patients with N-acetylglutamate synthase deficiency visit?

English name: N-acetylglutamate synthase deficiency (NAGSD).

Aliases: Glutamate synthase deficiency, Acetylglutamate synthase deficiency.

Departments: Neonatology, Pediatric Neurology, Pediatrics, Neurology.

What kind of disease is N-acetylglutamate synthase deficiency?

N-acetylglutamate synthase deficiency (NAGSD) is a rare inherited metabolic disorder of the urea cycle, inherited in an autosomal recessive pattern.

Due to gene mutations, patients with NAGSD experience impaired ammonia clearance, leading to hyperammonemia and related clinical symptoms and complications.

Who is commonly affected by N-acetylglutamate synthase deficiency?

The age of onset varies, but symptoms often appear during the neonatal period.

What are the symptoms and manifestations of N-acetylglutamate synthase deficiency?

• Most affected infants show symptoms within days after birth, including refusal to feed, vomiting, lethargy, seizures, and coma. Some late-onset cases present with episodic vomiting, lethargy, and intellectual developmental abnormalities.
• Hyperammonemia is a clinical hallmark, which may cause increased intracranial pressure, rapid breathing, and, as the condition progresses, apnea, respiratory failure, or hepatomegaly.
• Neurological complications include intellectual disability, acute hyperammonemic coma, death, or long-term sequelae such as developmental delays.

How is N-acetylglutamate synthase deficiency diagnosed?

• Diagnosis is based on clinical symptoms, biochemical tests, blood amino acid analysis, urine organic acid analysis, and genetic testing. Blood ammonia measurement is crucial for early diagnosis.
• For patients with neurological symptoms and elevated blood ammonia levels, further blood amino acid and urine organic acid analyses should be performed. If metabolic abnormalities are detected, NAGSD is highly suspected, and confirmation requires genetic analysis of the NAGS gene.

How is N-acetylglutamate synthase deficiency treated?

There is no cure for this disease. Treatment focuses on correcting hyperammonemia by reducing protein intake and enhancing alternative nitrogen excretion pathways while ensuring the patient's growth and developmental needs.

1. Acute-phase treatment:
• Immediately restrict or eliminate protein intake and increase non-protein energy sources.
• Use sodium benzoate, arginine, citrulline, or carbamoyl glutamate to promote the urea cycle or employ dialysis to lower blood ammonia levels.
• Symptomatic and supportive treatments for seizures, cerebral edema, etc.
2. Long-term treatment:
• Provide sufficient calories and a low-protein diet, adjusted based on growth needs and blood ammonia levels.
3. Other treatments:
• Liver transplantation may be considered for some patients, while gene therapy is still under investigation.

What is the prognosis for N-acetylglutamate synthase deficiency?

The prognosis is poor. Severe cases may lead to neonatal death, while survivors may experience recurrent hyperammonemia and neurological complications. Early and aggressive treatment can improve outcomes.

How can N-acetylglutamate synthase deficiency be prevented?

• As a genetic disorder, prenatal genetic testing should be performed for families with a known history. High-risk fetuses should undergo prenatal diagnosis.
• Patients should avoid high-protein diets in daily life.