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      Inborn Metabolic Diseases 

      Primary Hyperoxalurias

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      Springer Berlin Heidelberg

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          The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II.

          Primary hyperoxaluria type II (PH2) is a rare monogenic disorder that is characterized by a lack of the enzyme that catalyzes the reduction of hydroxypyruvate to D-glycerate, the reduction of glyoxylate to glycolate and the oxidation of D-glycerate to hydroxypyruvate. The disease is characterized by an elevated urinary excretion of oxalate and L-glycerate. The increased oxalate excretion can cause nephrolithiasis and nephrocalci-nosis and can, in some cases, result in renal failure and systemic oxalate deposition. We identified a glyoxylate reductase/hydroxypyruvate reductase (GRHPR) cDNA clone from a human liver expressed sequence tag (EST) library. Nucleotide sequence analysis identified a 1198 nucleotide clone that encoded a 984 nucleotide open reading frame. The open reading frame encodes a predicted 328 amino acid protein with a mass of 35 563 Da. Transient transfection of the cDNA clone into COS cells verified that it encoded an enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Database analysis of human ESTs reveals widespread tissue expression, indicating that the enzyme may have a previously unrecognized role in metabolism. The genomic structure of the human GRHPR gene was determined and contains nine exons and eight introns and spans approximately 9 kb pericentromeric on chromosome 9. Four PH2 patients representing two pairs of siblings from two unrelated families were analyzed for mutations in GRHPR by single strand conformation polymorphism analysis. All four patients were homozygous for a single nucleotide deletion at codon 35 in exon 2, resulting in a premature stop codon at codon 45. The cDNA that we have identified represents the first characterization of an animal GRHPR sequence. The data we present will facilitate future genetic testing to confirm the clinical diagnosis of PH2. These data will also facilitate heterozygote testing and prenatal testing in families affected with PH2 to aid in genetic counseling.
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            Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria.

            The prognosis for patients with primary hyperoxaluria has been ominous, with the expectation of renal failure, poor results with transplantation, and early death. We studied the long-term effects of orthophosphate and pyridoxine therapy in 25 patients with primary hyperoxaluria who were treated for an average of 10 years (range, 0.3 to 26). Their mean age at the start of treatment was 12 years (median, 6; range, 0.5 to 32). We also studied the effect of orthophosphate and pyridoxine on urinary supersaturation with calcium oxalate, crystal inhibition using a seeded growth system, and crystal formation using scanning electron microscopy in 12 patients during three-day stays in the clinical research center. The mean (+/- SD) glomerular filtration rate at the start of treatment was 91 +/- 26 ml per minute per 1.73 m2. The median decline in glomerular filtration rates was 1.4 ml per minute per 1.73 m2 of body-surface area per year. The actuarial survival free of end-stage renal disease was 96, 89, 74, and 74 percent of 5, 10, 15, and 20 years, respectively. Treatment with orthophosphate and pyridoxine reduced urinary supersaturation with calcium oxalate from 8.3 +/- 3.0 to 2.1 +/- 1.7 kJ per mole at 38 degrees C (P < 0.001), increased the inhibition of calcium oxalate formation from 63 +/- 11 to 108 +/- 10 inhibitor units per 24 hours (P < 0.001), and improved the crystalluria score from 2.6 +/- 0.3 to 0.6 +/- 0.1 (P < 0.001). Treatment of patients with primary hyperoxaluria with orthophosphate and pyridoxine decreases urinary calcium oxalate crystallization and appears to preserve renal function.
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              Management of primary hyperoxaluria: efficacy of oral citrate administration.

              The prognosis of primary hyperoxaluria (PH) is not only related to endogenous oxalate production and the response (if any) to pyridoxine (in type I), but is greatly influenced by extrarenal factors like dehydration. The earlier the diagnosis of PH, the better the chances of improving the prognosis in individual patients. Measures to enhance the solubility of calcium oxalate are important. Besides ensuring at all times a generous fluid intake (> 2 l/m2), administration of alkali citrate (0.15 g/kg), which has not been advocated so far in PH, appears very promising. We studied the effect of sodium citrate in six patients with PH. Mean urinary citrate excretion (mmol/day per 1.73 m2) without oral citrate was very low (0.57) and rose to 2.49 with citrate administration. This was accompanied by a significant decrease in the calcium oxalate saturation (calculated by equil 2) from 11.7 to 6.9 (P < 0.05). Treatment in five patients over 10-36 months resulted in improved (1) or stabilized (4) renal function and reduced passage of stones. Additional measures include restriction of salt and of oxalate-rich food. We conclude that long-term administration of alkali citrate is beneficial in patients with PH.
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                Book Chapter
                2000
                : 446-452
                10.1007/978-3-662-04285-4_40
                101f0a83-602a-4cca-91ba-7f5e78f7139b
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