Argininosuccinate lyase deficiency-argininosuccinic aciduria and beyond

Abstract

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.

Figure 1

The urea cycle consists of six sequential enzymatic steps in which the nitrogen from ammonia and aspartate is transferred to urea. Deficiencies of all six urea cycle enzymes (depicted by green boxes) have been described. Deficiency of ASL leads to accumulation of argininosuccinate upstream of the block as well as deficiency of arginine downstream of the block. CPS1-CarbamylPhosphate Synthetase I, OTC- Ornithine Transcarbamylase, ASS Argininosuccinate Synthetase, ASL- Argininosuccinate Lyase, ARG- Arginase, ORNT1- Ornithine transporter.

Figure 2

Metabolic fates of arginine: Arginine is derived from dietary sources, protein catabolism, or endogenous synthesis. Arginine serves as the precursor for many biologically important molecules; a decrease in arginine may result in decreased production of compounds for which it serves as a precursor. GATM – Glycine Amidinotransferase, Arg1- Arginase 1, ADC - Arginine Decarboxylase, NOS - Nitric Oxide Synthetase, NO - Nitric Oxide, OTC - Ornithine Transcarbamoylase, ASS – Argininosuccinate Synthetase, ASA - Argininosuccinic acid, ASL - Argininosuccinate Lyase, GABA - γ-Amino Butyric Acid

Figure 3

Arginine-Citrulline Cycle. While ASS and ASS are involved in the urea cycle with no net synthesis of arginine in the liver, many tissues depend on these two enzymes for regeneration of arginine in various tissues. In ASL deficiency, arginine becomes an essential amino acid. Note that the production of nitric oxide is closely coupled with this arginine-citrulline cycle.