#260000
ICD+
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| HYPEROXALURIA, PRIMARY, TYPE II | ||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||
| HP2 OXALOSIS II GLYCERIC ACIDURIA GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE DEFICIENCY D-GLYCERATE DEHYDROGENASE DEFICIENCY | ||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that type II primary hyperoxaluria is caused by mutation in the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; 604296). See entry 259900 for evidence of 2 separate types of hyperoxaluria which are biochemically distinct and presumably the result of mutation at separate loci. Williams and Smith (1971) presented evidence that in hyperoxaluria II, hydroxypyruvate, present in excess because of deficiency in the enzyme that converts it to D-glycerate, stimulates oxidation of glycolate to oxalate, and decreases reduction of glyoxylate to glycolate. This is a novel explanation for the phenotypic consequences of a garrodian inborn error of metabolism. D-glycerate dehydrogenase also has glyoxylate reductase activity; Seargeant et al. (1991) quoted the opinion that deficiency of glyoxylate reductase activity may be responsible for the hyperoxaluria in this disorder. To the 8 previously reported patients, they added 8 more who belong to 3 Saulteaux-Ojibway Canadian Indian families living in 2 isolated communities in northwestern Ontario. They demonstrated combined deficiencies of D-glycerate dehydrogenase and glyoxylate reductase. The 2 activities are attributable to a single enzyme. Deficiency of D-glycerate dehydrogenase activity presumably causes accumulation of its substrate, hydroxypyruvate, which is then converted to L-glycerate by the action of L-lactate dehydrogenase. Deficiency of glyoxylate reductase activity presumably causes impaired conversion of glyoxylate to glycolate. Conversion of glyoxylate to oxalate by L-lactate dehydrogenase would explain the observed hyperoxaluria. As in type I primary hyperoxaluria, the main clinical manifestation is calcium oxalate nephrolithiasis. Seven of the 8 previously reported patients had renal calculi between 18 months and 24 years of age. One patient seems to have had no symptoms and was identified only because his younger brother also had the disorder (Chalmers et al., 1984). Four of the 8 patients studied by Seargeant et al. (1991) were free of symptoms and 3 had not had recurrences. Thus, hyperoxaluria type II may be a much milder disease with a better long-term prognosis for renal function than is the case in type I. Van Schaftingen et al. (1989) presented evidence that D-glycerate dehydrogenase should be considered an NADPH-linked reductase. This property accounts well for the function of the enzyme, which is to maintain the cytosolic concentration of hydroxypyruvate and glyoxylate at a very low level, thus preventing the formation of oxalate. Kemper et al. (1997) stated that only 24 patients with primary hyperoxaluria type 2 had been reported. It should be considered in any patient presenting with urolithiasis or nephrocalcinosis due to hyperoxaluria. The metabolic defect is deficiency of D-glycerate dehydrogenase/glyoxylate reductase leading to characteristic hyperoxaluria and excretion of L-glycerate, the cornerstone of diagnosis of this form of primary hyperoxaluria. Although development of terminal renal failure may be less common than in type 1 primary hyperoxaluria, chronic as well as terminal renal insufficiency has been described. Therefore, specific therapeutic measures should aim at reduction of urinary calcium oxalate saturation by potassium citrate or pyrophosphate to reduce the incidence of nephrolithiasis and nephrocalcinosis and thus improve renal survival. Secondary complications (obstruction, urinary tract infections, and pyelonephritis) must be avoided. In patients with terminal renal failure, renal transplantation seems to carry a high risk of disease recurrence. Cramer et al. (1999) found homozygosity for an identical mutation in the GRHPR gene in 2 pairs of sibs from unrelated families with type II primary hyperoxaluria. | ||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||
| Williams and Smith (1978); Yendt and Cohanim (1985) | ||||||||||||||||||||||||
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