Molecular Genetics of Argininosuccinic Aciduria

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.