Hyperoxaluria is an excessive urinary excretion of oxalate. Individuals with hyperoxaluria often have calcium oxalate kidney stones. It is sometimes called Bird's disease, after Golding Bird, who first described the condition.
Type I (PH1) is associated with AGXT protein, a key enzyme involved in breakdown of oxalate. PH1 is also an example of a protein mistargeting disease, wherein AGXT shows a trafficking defect: instead of being trafficked to peroxisomes, it is targeted to mitochondria, where it is metabolically deficient despite being catalytically active. Type II is associated with GRHPR. It is also a complication of jejunoileal bypass, or in any patient who has lost much of the ileum with an intact colon. This is due to excessive absorption of oxalate from the colon.
The main therapeutic approach to primary hyperoxaluria is still restricted to symptomatic treatment, i.e. kidney transplantation once the disease has already reached mature or terminal stages. However, through genomics and proteomics approaches, efforts are currently being made to elucidate the kinetics of AGXT folding which has a direct bearing on its targeting to appropriate subcellular localization. Secondary hyperoxaluria is much more common than primary hyperoxaluria, and should be treated by limiting dietary oxalate and providing calcium supplementation. A child with primary hyperoxaluria was treated with a liver and kidney transplant. A favorable outcome is more likely if a kidney transplant is complemented by a liver transplant, given the disease originates in the liver.
Perhaps the key difficulty in understanding pathogenesis of primary hyperoxaluria, or more specifically, why AGXT ends up in mitochondria instead of peroxisomes, stems from AGXT's somewhat peculiar evolution. Namely, prior to its current peroxysomal 'destiny', AGXT indeed used to be bound to mitochondria. AGXT's peroxisomal targeting sequence is uniquely specific for mammalian species, suggesting the presence of additional peroxisomal targeting information elsewhere in the AGT molecule. As AGXT was redirected to peroxisomes over the course of evolution, it is plausible that its current aberrant localization to mitochondria owes to some hidden molecular signature in AGXT's spatial configuration unmasked by PH1 mutations affecting the AGXT gene.
- "Primary hyperoxaluria - Genetics Home Reference".
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