Figure 1110

Metabolic events in the primary hyperoxalurias. Primary hyperoxaluria type 1 (PH1) results from functional deficiency of the peroxisomal enzyme alanine:glyoxalate aminotransferase (AGT). PH2 results from a deficiency of the cytosolic enzyme d-glycerate dehydrogenase (DGDH), which also functions as glyoxalate reduc-tase. This figure presents a simplified illustration of the metabolic consequences of these defects. Both diseases are inherited as autosomal recessive traits.

In PH1, much clinical, biochemical, and molecular heterogeneity exists. Liver AGT catalytic activity is absent in approximately two thirds of patients with PH1. It is detectable in the remaining third, however, in whom the enzyme is targeted to the mitochondria rather than peroxisomes. Absence of peroxisomal AGT activity leads to impaired transamination of glyoxalate to glycine, with excessive production of oxalate and, usually, glycolate. In PH2, deficiency of cytosolic DGDH results in overproduction of oxalate and glycine. Mild cases of PH1, without nephrocalcinosis or systemic oxalosis, resemble PH2 clinically, but the two usually can be distinguished by measurement of urinary glycolate and glycine. Assay of AGT activity in liver biopsy specimens can be diagnostic in PH1 even when renal failure prevents analysis of urinary excretion.

The gene encoding AGT has been localized to chromosome 2q37.3 and has been cloned and sequenced. Mutations in this gene have been identified in patients with absent enzymatic activity, abnormal enzyme targeting to mitochondria, aggregation of AGT within peroxisomes, and absence of both enzymatic activity and immunoreactivity. However, mutations have not been identified in all patients with PH1 who have been studied, and molecular diagnosis is not yet routinely available [12]. (Adapted from Danpure and Purdue [12].)

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