Knowledge on rare diseases and orphan drugs

The prevalence at birth of argininosuccinic aciduria (ASA) ranges between 1/70,000-218,000 worldwide.

ASA can have a variable clinical picture with either a neonatal-onset or a late-onset (at any age outside the newborn period). Neonates with severe neonatal-onset ASA usually appear normal during the first 24-48 hours after birth but within a few days present with severe hyperammonemia manifesting with lethargy, somnolence, refusal to feed, vomiting, tachypnea and respiratory alkalosis. If untreated, worsening lethargy, seizures, coma and death may occur. Late-onset ASA is usually triggered by an acute infection, stress or after high protein intake. A presentation of late-onset cognitive impairment or learning disabilities in the absence of hyperammonemic episodes has also been reported. Some patients can be clinically asymptomatic despite showing clear biochemical signs of the disease. Long-term complications associated with both forms of ASA include chronic hepatomegaly, liver dysfunction (fibrosis or cirrhosis), neurocognitive deficits (i.e. cognitive impairment, seizures, and developmental delay), brittle hair (i.e. trichorrhexis nodosa), hypokalemia and arterial hypertension.

ASA is caused by mutations in the ASL gene (7q11.21) that encodes the enzyme argininosuccinate lyase. This enzyme catalyzes the conversion of argininosuccinic acid into arginine and fumarate during the fourth step of the urea cycle. Defects in this step of the urea cycle lead to an accumulation of plasma ammonia, argininosuccinic acid, citrulline, and urinary orotic acid, and to a plasma arginine deficiency.

Diagnosis is based mainly on clinical findings and laboratory test results. Plasma concentrations of ammonia (>150 µmol/L) and citrulline (200-300 µmol/L) are elevated. Elevated levels of argininosuccinic acid (5-110 µmol/L) in the plasma or urine are diagnostic. Molecular genetic testing confirms diagnosis. Newborn screening for ASA is available in the U.S. and parts of Australia, and is considered in several European countries.

Differential diagnoses include other urea cycle disorders such as carbamoyl-phosphate synthetase 1 deficiency, ornithine transcarbamylase deficiency, citrullinemia type I and arginase deficiency, although neither of these exhibits the classical marker argininosuccinic acid.

Prenatal diagnosis is possible in families with a known disease causing mutation on both alleles.

ASA is inherited in an autosomal recessive manner; where both parents are unaffected carriers, the risk of disease transmission is 25%.

During an acute hyperammonemic episode, oral proteins must be avoided (for 24-48 hours' maximum) and intravenous (I.V.) lipids, glucose and insulin (if needed) should be given to promote anabolism. I.V. nitrogen scavenging therapy (with sodium benzoate and/or sodium phenylacetate/phenylbutyrate) should normalize ammonia levels, but if unsuccessful or in case of severe hyperammonemic encephalopathy, hemodialysis is recommended. Long-term management involves dietary protein restriction as well as arginine supplementation; in those with frequent episodes of metabolic decompensation or with hyperammonemia even when following a protein-restricted diet, daily oral nitrogen scavenging therapy (sodium benzoate and/or sodium or glycerol phenylbutyrate) may be successful. Orthotopic liver transplantation offers long-term relief of hyperammonemia but does not seem to sufficiently correct neurological complications. Arterial hypertension can be treated by restoring nitric oxide deficiency.

With early diagnosis and treatment, hyperammonemic episodes can be avoided but long-term complications (neurocognitive impairment, hepatic disease and arterial hypertension) are frequent and have a negative effect on life-expectancy and quality of life.

Last update: November 2019 - Expert reviewer(s): Pr Johannes HÄBERLE