The
urea cycle consists of six consecutive enzymatic reactions that convert waste
nitrogen into
urea. Deficiencies of any of these
enzymes of the cycle result in
urea cycle disorders (UCD), a group of inborn errors of hepatic metabolism that often result in life threatening
hyperammonemia.
Argininosuccinate lyase (ASL) is a cytosolic
enzyme which catalyzes the fourth reaction in the cycle and the first degradative step, that is, the breakdown of
argininosuccinic acid to
arginine and
fumarate. Deficiency of ASL results in an accumulation of
argininosuccinic acid in tissues, and excretion of
argininosuccinic acid in urine leading to the condition
argininosuccinic aciduria (ASA). ASA is an autosomal recessive disorder and is the second most common UCD. In addition to the accumulation of
argininosuccinic acid,
ASL deficiency results in decreased synthesis of
arginine, a feature common to all UCDs except
argininemia.
Arginine is not only the precursor for the synthesis of
urea and
ornithine as part of the
urea cycle but it is also the substrate for the synthesis of
nitric oxide,
polyamines,
proline,
glutamate,
creatine, and
agmatine. Hence, while ASL is the only
enzyme in the body able to generate
arginine, at least four
enzymes use
arginine as substrate:
arginine decarboxylase,
arginase,
nitric oxide synthetase (NOS) and
arginine/
glycine aminotransferase. In the liver, the main function of ASL is ureagenesis, and hence, there is no net synthesis of
arginine. In contrast, in most other tissues, its role is to generate
arginine that is designated for the specific cell's needs. While patients with ASA share the acute clinical phenotype of
hyperammonemia,
encephalopathy, and
respiratory alkalosis common to other UCD, they also present with unique chronic complications most probably caused by a combination of tissue specific deficiency of
arginine and/or elevation of
argininosuccinic acid. This review article summarizes the clinical characterization, biochemical, enzymatic, and molecular features of this disorder. Current treatment, prenatal diagnosis, diagnosis through the newborn screening as well as hypothesis driven future treatment modalities are discussed.