N-acetylglutamate synthase deficiency

Other Names: Hyperammonemia due to N-Acetylglutamate Synthetase Deficiency; NAGS deficiency; NAG synthetase deficiency N-acetylglutamate synthase deficiency (NAGS) is type of metabolic disorder that affects the processing of proteins and removal of ammonia from the body. When proteins are processed by the body, ammonia is formed. Individuals with NAGS are not able to remove ammonia from the body and have symptoms due to toxic levels of ammonia that build up in the blood. NAGS and other similar disorders are a type of metabolic condition known as a urea cycle disorder.

In some affected individuals, signs and symptoms of N-acetylglutamate synthase deficiency do not appear until later in life. Some people with this form of the disorder notice that eating high-protein foods, such as meat, affects how they feel, although they may not know why. In many affected adults, illness or other stress can trigger episodes of vomiting, lack of coordination, headaches, confusion, behavioral changes, or coma.

Cause

Mutations in the NAGS gene cause N-acetylglutamate synthase deficiency. This condition belongs to a class of genetic diseases called urea cycle disorders because they are caused by problems with a process in the body called the urea cycle. The urea cycle is a sequence of reactions that occurs in liver cells. This cycle breaks down excess nitrogen, which is made when protein is used by the body, to make a compound called urea. Urea is removed from the body in urine.

The NAGS gene provides instructions for making the enzyme N-acetylglutamate synthase, which is integral to the first step of the urea cycle.

In people with N-acetylglutamate synthase deficiency, N-acetylglutamate synthase is not available in sufficient quantities, or is not present at all. As a result, the urea cycle is impaired, and nitrogen is not broken down efficiently. The excess nitrogen accumulates in the blood in the form of ammonia. This buildup of ammonia damages tissues in the brain and causes neurological problems and other signs and symptoms of N-acetylglutamate synthase deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Signs and symptoms

Signs and symptoms in newborns with NAGS may include a lack of energy, unwillingness to eat, seizures, unusual body movements, and poorly controlled breathing or body temperature. Complications may include coma, developmental delay, and learning disability. Some people have a less severe form of the deficiency with earliest symptoms manifesting later in life, particularly following high-protein meals, illness, or other stress. Signs and symptoms may include sudden vomiting, lack of coordination, confusion, and coma. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 30%-79% of people have these symptoms

• Infantile muscular hypotonia(Decreased muscle tone in infant)
• Nausea
• Vomiting(Throwing up)

5%-29% of people have these symptoms

• Acute hyperammonemia
• Agitation
• Anxiety(Excessive, persistent worry and fear)
• Cognitive impairment(Abnormality of cognition)
• Coma
• Drowsiness(Sleepy)
• Failure to thrive(Faltering weight)
• Fatigue(Tired)
• Feeding difficulties(Feeding problems)
• Global developmental delay
• Headache(Headaches)
• Hyperalaninemia(Increased blood alanine)
• Hyperglutaminemia(High plasma glutamine)
• Insomnia(Difficulty staying or falling asleep)
• Lethargy
• Loss of consciousness(Passing out)
• Mood changes(Moody)
• Poor appetite(Decreased appetite)
• Poor speech
• Seizure

Diagnosis

Diagnosis can be suspected by decreased liver NAGS activity and confirmed by DNA analysis.

Treatment

Although there is currently no cure, treatment includes injections of structurally similar compound, Carglumic acid, an analogue of N-Acetyl Glutamate. This analogue likewise activates CPS1. This treatment mitigates the intensity of the disorder.

If symptoms are detected early enough and the patient is injected with this compound, levels of severe mental retardation can be slightly lessened, but brain damage is irreversible.

Also: hemodialysis for emergent hyperammonemic crisis, Na benzoate, Na phenylacetate, Na phenylbutyrate, low-protein diet supplemented with essential amino acid mixture and arginine, citrulline, experimental attempts at gene therapy, liver transplantation (which is curative), and also N-carbamylglutamate supplementation. Early symptoms include lethargy, vomiting, and deep coma. The medication(s) listed below have been approved by the Food and Drug Administration (FDA) as orphan products for treatment of this condition.

• Carglumic acid (Brand name: Carbaglu) As an adjunctive therapy for the treatment of acute hyperammonemia due to the deficiency of the hepatic enzyme N-acetylglutamate synthase (NAGS) and as manitenance therapy for chronic hyperammonemia due to NAGS deficiency.