Hyperoxaluria, Primary, Type Ii

A number sign (#) is used with this entry because of evidence that type II primary hyperoxaluria (HP2) is caused by homozygous or compound heterozygous mutation in the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; 604296) on chromosome 9p13.

For a discussion of genetic heterogeneity of primary hyperoxaluria, see 259900.

Clinical Features

Seargeant et al. (1991) reported 8 HP2 patients who belonged to 3 Saulteaux-Ojibway Canadian Indian families living in 2 isolated communities in northwestern Ontario. All had increased urinary oxalic acid and L-glyceric acid. Four patients presented with symptoms resulting from calcium oxalate nephrolithiasis, including dysuria, hematuria, and urinary tract infections in infancy or early childhood; 3 did not have recurrences. The other 4 affected patients were free of symptoms, suggesting that HP2 may be a much milder disease with a better long-term prognosis for renal function than HP1 (259900). Seargeant et al. (1991) noted that 7 of 8 previously reported patients (Williams and Smith, 1968 and Chalmers et al., 1984) had renal calculi between 18 months and 24 years of age. One patient seemed to have had no symptoms and was identified only because his younger brother had the disorder (Chalmers et al., 1984).

Kemper et al. (1997) stated that only 24 patients with primary hyperoxaluria type II had been reported, and noted that the disorder 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 I 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.

Takayama et al. (2014) reported 4 Japanese patients with HP2. The patients developed symptoms of hematuria or urinary tract infection between 10 months and 3 years of age. All developed stones in the kidney or bladder, but only 1 patient showed renal parenchymal calcifications. Laboratory studies showed increased urinary oxalate and L-glycerate. All patients had normal renal function at follow-up between 7 and 25 years of age.

Biochemical Features

Williams and Smith (1971) presented evidence that in HP2, 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.

Van Schaftingen et al. (1989) presented evidence that D-glycerate dehydrogenase should be considered an NADPH-linked reductase. This property accounts 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.

In patients with HP2, Seargeant et al. (1991) demonstrated combined deficiencies of D-glycerate dehydrogenase and glyoxylate reductase, which 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.

Inheritance

The transmission pattern of HP2 in the families reported by Takayama et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

Cramer et al. (1999) found homozygosity for an identical mutation in the GRHPR gene (604296.0001) in 2 pairs of sibs from unrelated families with type II primary hyperoxaluria.

Webster et al. (2000) identified 5 other mutations in patients with type II hyperoxaluria. Ten of 11 patients that they had genotyped were homozygous for 1 of the 6 known mutations. In the case of two-thirds of the patients, the parents were related. Genotyping also showed the possible presence of a founder effect for the 2 most common mutations: 103delG and R99X (604296.0002).

In 4 Japanese patients with HP2, Takayama et al. (2014) identified homozygous or compound heterozygous mutations in the GRHPR gene (604296.0003-604296.0005). Three of the patients were homozygous for the same mutation (c.864delTG; 604296.0003).

Population Genetics

Takayama et al. (2014) found the GRHPR c.103delG mutation (604296.0001) only in Caucasian patients of northern European or American origin, and the c.864delTG mutation (604296.0003) only in patients of Japanese or Chinese origin.