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Inherited error of metabolism of glyoxylate causing urolithiasis and progressive renal insufficiency. Two types are described, depending on the missing enzyme.

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Type I: Oxalosis I; Glycolic aciduria; Alanine-Glyoxylate Aminotransferase Deficiency; Peroxisomal Alanine: Glyoxylate Aminotransferase Deficiency; Hepatic AGT Deficiency.

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Type II: Oxalosis II; Glyceric aciduria; d-Glycerate Dehydrogenase Deficiency.

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Incidence is estimated between 1:60,000 and 1:120,000 children (United Kingdom, France, Switzerland). It may be responsible for 10 to 13% of end-stage renal failure in children in developing countries. Type II is less frequent than type I.

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Autosomal recessive inheritance. In type I, the missing enzyme is alanine-glyoxylate aminotransferase (i.e., the AGT gene), which is normally found only in the hepatic peroxisomes. This enzyme is necessary to detoxify glyoxylate (gene map locus 2q36-q37). In type II, the missing enzyme is d-glyceric dehydrogenase, which can be detected in leukocyte preparations.

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Loss of specific enzymatic activity in glyoxylate metabolism. With the normal metabolic pathway blocked, the alternative pathway that leads to oxalate production from glycolate metabolism becomes very active and considerable amounts of oxalate are produced, leading to extremely high oxalate concentrations within the proximal tubular cells. These high oxalate levels have direct toxic effects on renal tubular cells.

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Family history, elevated urine oxalate excretion, high plasma levels of oxalate, progressive bilateral oxalate urolithiasis, and nephrocalcinosis. A liver biopsy can help determine which enzyme defect is present. Urinary oxalate excretion usually is more than 100 mg/day in both types of primary hyperoxaluria. Prenatal diagnosis is possible (glyoxylate metabolite analysis in amniotic fluid; linkage and mutation analysis of DNA isolated from chorionic villus samples in the first trimester; AGT enzyme assay, immunoassay, and immuno-electron microscopy of fetal liver biopsies is possible in the second trimester).

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The clinical course is very similar in both types of primary hyperoxaluria (end-stage renal disease occurs slightly later and pyridoxine is usually not effective in type II). Recurrent urolithiasis and nephrocalcinosis are the main symptoms leading to progressive loss of renal function. Fifty percent of patients are affected by 5 years of age. Clinical severity is not correlated with the mutation or the degree of residual functional AGT activity. Wide variations in clinical, biochemical, and genetic heterogeneity; some patients present in infancy with renal failure, others experience only occasional passage of stones in adult life, with maintained renal function. Systemic oxalosis occurs when the critical saturation point for plasma oxalate is reached in early renal insufficiency. Clinical manifestations of oxalate osteopathy are pain, spontaneous fractures, and erythropoietin-resistant anemia. Important sites of calcium oxalate deposits are the media of the arteries (with subsequent ischemia and gangrene), the peripheral nervous system (neuropathy), the myocardium (atrioventricular block), the thyroid gland, the skin (livedo reticularis), and the retina. Soft tissue calcifications in joints may limit mobility. Death from renal failure occurs in childhood or early adult life. Kidney transplantation is associated with a high rate of recurrence of ...

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