Argininosuccinic Aciduria

Definition

Definition of Argininosuccinic Aciduria
Argininosuccinic aciduria, also called argininosuccinic acidemia, is an inherited disorder that causes the accumulation of argininosuccinic acid (also known as "ASA") in the blood and urine. Some patients may also have an elevation of ammonia, a toxic chemical, which can affect the nervous system. Argininosuccinic aciduria may become evident in the first few days of life because of high blood ammonia, or later in life presenting with "sparse" or "brittle" hair, developmental delay, and tremors.

An infant with argininosuccinic aciduria may seem lethargic or be unwilling to eat, have poorly-controlled breathing rate or body temperature, experience seizures or unusual body movements, or go into a coma. Complications from argininosuccinic aciduria may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Immediate treatment and lifelong management (following a strict diet and using appropriate supplements) may prevent many of these complications.

Symptoms

Symptoms of Argininosuccinic Aciduria
The list of signs and symptoms for Argininosuccinic listed below:

1. Elevated blood ammonia level
2. Vomiting
3. Seizures
4. Abnormal hair shaft
5. Refusal to eat
6. Progressive lethargy
7. Enlarged liver
8. Liver fibrosis
9. Fragile hair
10. Lumps in hair structure
11. Feeding problems
12. Hypothermia
13. Respiratory alkalosis

Causes

Causes of Argininosuccinic Aciduria
Mutations in the ASL gene cause argininosuccinic aciduria. Argininosuccinic aciduria belongs to a class of genetic diseases called urea cycle disorders. The urea cycle is a sequence of reactions in the cells of the liver. It processes excess nitrogen, generated when protein is used by the body, to make a compound called urea that is excreted by the kidneys.

In argininosuccinic aciduria, the enzyme arginino succinase, that is involved in the conversion of arginino succinate to arginine within the urea cycle is damaged or missing. The urea cycle cannot proceed normally, and nitrogen accumulates in the bloodstream in the form of ammonia.
Ammonia is especially damaging to the nervous system, so argininosuccinic aciduria causes neurological problems as well as eventual damage to the liver.

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, the parents of an individual with an autosomal recessive disorder are carriers of one copy of the altered gene but do not show signs and symptoms of the disorder.

Diagnosis

Diagnosis of Argininosuccinic Aciduria
Newborn screening by tandem mass spectrometry using a dried blood spot can detect elevated levels of Citrulline with either disorder. The levels of Citrulline in Argininosuccinic Acid Synthetase Deficiency range up to 100 times the normal limit. Argininosuccinate Lyase Deficiency patients have measurable levels of Argininosuccinic acid in plasma, which is not normally detected. The activity of either enzyme can be measured from a liver biopsy. Both genes have been isolated and mutations identified. DNA studies can be performed for prenatal diagnosis when the mutation is known from both parents. Biochemical studies of cultured amniocytes and chorionic villus tissue are also informative. The presence of Argininosuccinic acid in the amniotic fluid of Argininosuccinate Lyase Deficiency patients has been used for prenatal diagnosis.

Treatment

Treatment of Argininosuccinic Aciduria
The symptoms of Citrullinemia seem to originate from the hyperammonemia rather than Citrulline accumulation. Acute hyperammonemia may necessitate hemodialysis, which is more effective for lowering ammonia than peritoneal dialysis or arteriovenous hemofiltration. Sodium benzoate is given to conjugate Glycine, a major amino acid that contributes ammonia to the urea cycle, forming hippurate, which is subsequently excreted in the urine. Intravenous Arginine results in ammonia clearance by enhancing formation of Citrulline in Argininosuccinic Acid Synthetase Deficiency or Argininosuccinate in Argininosuccinate Lyase Deficiency. Both of these metabolites are excreted in the urine and draw off excess nitrogen from ammonia. Patients who survive the initial presentation are placed on protein restriction. Patients with either defect having onset in the newborn period face a poor outcome and significant risk of neurological damage or demise.

Because the diagnosis and therapy of these metabolic disorders is complex, the pediatrician is strongly advised to manage the patient in close collaboration with a consulting pediatric metabolic disease specialist. It is recommended that parents travel with a letter of treatment guidelines from the patient’s physician.

Prognosis

Prognosis of Argininosuccinic Aciduria
There is a direct correlation between the duration of hyper-ammonemic coma and morbidity (mental retardation, developmental delays, cortical atrophy). Good prognosis if disorder is treated prospectively from birth.

Prevention

Prevention of Argininosuccinic Aciduria
Complications from argininosuccinic aciduria may include developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen. Immediate treatment and lifelong management (following a strict diet and using appropriate supplements) may prevent many of these complications.