Adenylosuccinate Lyase - Role in Disease

Role in Disease

Mutated adenylosuccinate lyase (ASL) causes clinical disease in patients that is referred to as adenylosuccinate lyase deficiency. This condition is rare, and it presents with varying degrees of psychomotor retardation, autism, muscle wasting, and epilepsy. The exact cause of disease is unknown, but possibilities include not enough purine nucleotide synthesis for cell replication, malfunctioning of the purine nucleotide cycle, and a buildup of substrates to toxic levels. Several disease-linked point mutations have been identified, and those who are heterozygous for a point mutation are healthy, but those who are homozygous develop clinical disease. The number of disease-causing genotypes keeps increasing as more mutations are discovered, and now thirty different point mutations have been identified so far, and one deletion, that cause adenylosuccinate lyase deficiency.

When the substrates of ASL (adenylosucinate and SAICAR) build up due to enzyme deficiency, they are dephosphorylated and turn into succinyladenosine (S-Ado) and succinylaminoimidazole carboximide riboside (SAICA riboside). Normally these compounds are not present in the cerebrospinal fluid or urine because ASL acts on the majority of the substrate molecules before they can build up and be phosphorylated. In the past there has not been a good test for adenylosuccinate lyase deficiency, making the rare disease difficult to diagnose, but recently a test was developed to detect SAICA and S-Ado in the urine. The test is inexpensive and had no false positives or false negatives in the researchers’ small sample.

It is thought that SAICA riboside may be the more toxic compound as it is found at higher levels in patients with severe clinical symptoms, and some researchers think S-Ado may even be protective. More research needs to be done on what determines disease severity, but the instability of human ASL in the lab setting has been an obstacle to this research.