Inherited error of metabolism of glyoxylate causing
urolithiasis and progressive renal insufficiency. Two types are described,
depending on the missing enzyme.
Type I: Oxalosis I; Glycolic aciduria; Alanine-Glyoxylate Aminotransferase
Deficiency; Peroxisomal Alanine: Glyoxylate Aminotransferase Deficiency;
Hepatic AGT Deficiency.
Type II: Oxalosis II; Glyceric aciduria; d-Glycerate Dehydrogenase Deficiency.
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.
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
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.
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).
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 ...