Chapter 133

## Abstract

Abstract

1. The term primary hyperoxaluria includes two rare, well-characterized autosomal recessive diseases, primary hyperoxaluria type 1 (PH1, MIM 259900) and primary hyperoxaluria type 2 (PH2, MIM 260000). The clinical phenotype of PH1, which is the more common of the two, is one of progressive renal deposition of calcium oxalate (CaOx) as urolithiasis and/or nephrocalcinosis leading to renal failure. Decreasing renal function is accompanied by increasing deposition of CaOx throughout the body as systemic oxalosis. In PH2, which is often considered to be a milder disease than PH1, renal failure is less common. At the biochemical level, PH1 is characterized by concomitant hyperoxaluria and hyperglycolic aciduria and PH2 by hyperoxaluria and hyper-L-glyceric aciduria.

2. PH1 is caused by a functional deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT) and PH2 by a deficiency of the cytosolic enzyme D-glycerate dehydrogenase/glyoxylate reductase (DGDH/GR). One-third of PH1 patients have significant levels of AGT catalytic activity, which in some cases is similar to the levels found in asymptomatic obligate heterozygotes. These patients have disease due to a unique intracellular protein trafficking defect in which AGT is erroneously localized to the mitochondria instead of the peroxisomes.

3. The AGT gene (AGXT) has been cloned and sequenced both at the cDNA and the genomic levels. The gene consists of 11 exons spanning about 10 kb and has been localized to chromosome 2q37.3. At least 18 mutations have been identified, many of which are associated with specific enzymic PH1 phenotypes, including the peroxisome-to-mitochondrion targeting defect, intraperoxisomal AGT aggregation, absence of AGT catalytic activity, and absence of both AGT catalytic activity and immunoreactivity.

4. AGT is targeted to peroxisomes via the peroxisomal targeting sequence type 1 (PTS1) import pathway, even though its C-terminal tripeptide (Lys-Lys-Leu) does not fit the conservative PTS1 consensus motif. AGT mistargeting to mitochondria is caused by a combination of a common polymorphism that generates a functionally weak mitochondrial targeting sequence (MTS) and a disease-specific mutation that, together with the polymorphism, enhances the efficiency of the MTS by inhibiting AGT dimerization.

5. A canine analogue of PH1 and a feline analogue of PH2 have been identified, but their clinical usefulness has yet to be determined.

6. Recent years have seen the development of new strategies for diagnosis, prenatal diagnosis, and treatment of PH1. The disease can be diagnosed definitively by AGT assay of percutaneous liver needle biopsies. Such a procedure can diagnose PH1 even in patients who present in renal failure and in whom urinalysis is not available. PH1 also can be diagnosed prenatally by AGT analysis of fetal liver biopsies obtained in the second trimester and DNA analysis of chorionic villus samples or amniocytes in the first trimester. The greatest change in the clinical management of PH1 over the past decade has been the introduction of liver transplantation as a form of enzyme-replacement therapy. Combined hepatorenal transplantation replaces not only the enzymically defective organ (i.e., the liver) but also the pathophysiologically defective organ (i.e., the kidney). Such treatment can correct the clinical and metabolic sequelae of PH1 and lead to resolution of some of the long-term ravages of systemic CaOx deposition.

7. The future for PH1 patients is brighter now than it has ever been. Our increasing understanding of the molecular genetics of the AGXT gene, the liver-specific localization of the gene product, and the lack of neurologic involvement all go to make PH1 a good candidate for gene therapy. Our increased understanding of the roles of AGT and GR as determinants of endogenous oxalate synthesis may contribute to a wider understanding of the processes involved in more common problems of inappropriate CaOx deposition, such as that which occurs in idiopathic CaOx stone disease.

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