Advances in the enzymology and molecular genetics of primary hyperoxaluria type 1. Prospects for gene therapy.

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inborn error of glyoxylate metabolism caused by a deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). At the enzymic level, PH1 is usually heterogeneous. Several novel enzymic phenotypes have been identified, including the mistargeting of AGT from the peroxisomes to mitochondria, and the aggregation of AGT in the peroxisomal matrix. Seven PH1-specific point mutations, as well as a number of clinically useful normal polymorphisms, have been found so far in the AGT gene. The molecular elucidation of PH1 has led to changes in almost all aspects of its clinical management, most notably treatment. Liver transplantation as a form of enzyme replacement therapy has been used successfully in the treatment of PH1 over the last 10 years, but the long-term solution lies in gene therapy. Although PH1 is, in many respects, an ideal candidate for gene therapy, the strategies eventually adopted will need to take into account its unique metabolic and enzymic characteristics.