Molecular Genetics of Argininosuccinic Aciduria

Abstract

Argininosuccinic aciduria is an autosomal recessive disorder of the urea cycle caused by mutations in argininosuccinate lyase ( ASL ). Two main clinical phenotypes are reported: an acute neonatal form characterised by severe hyperammonaemia and coma, and a subacute, late‐onset form which may present with relatively milder neurological symptoms. More than 120 ASL mutations have been reported so far: the majority are missense, but virtually all types of point mutations are found. Large rearrangements are rare and standard genomic deoxyribonucleic acid (DNA) analysis has a high diagnostic yield. Genotype–phenotype correlations have been difficult to establish as standard biochemical techniques are not sufficiently sensitive to measure residual activity, and other factors such as intragenic complementation, overexpression of nonfunctional ASL transcripts and environmental factors may modulate the phenotype. Clinical manifestations result from the block in the urea cycle and also from impairment of nitric oxide biosynthesis, and the therapy is aimed at restoring these two functions. Key Concepts: Argininosuccinic aciduria is caused by deficiency of argininosuccinate lyase (ASL). ASL is a component of the urea cycle and is essential for detoxification of ammonia, and for the synthesis of arginine and nitric oxide (NO). Two clinical forms of argininosuccinic aciduria exist: an acute, potentially lethal, neonatal onset disease and a milder, late‐onset form. More than 120 ASL mutations have been described but the exact genotype/phenotype correlations are still not completely clear. Other factors (genetic and environmental) may influence the clinical phenotype. Treatment is based on protein restriction, arginine, nitrogen scavengers and NO donors.