Pentosuria

A number sign (#) is used with this entry because pentosuria (PNTSU) is caused by homozygous or compound heterozygous mutation in the DCXR gene (608347) on chromosome 17q25.

Description

Essential pentosuria is an inborn error of metabolism in which 1 to 4 gm of the pentose L-xylulose is excreted in the urine each day. It is a benign condition that occurs principally in individuals of Ashkenazi Jewish descent (summary by Hiatt, 2001).

Biochemical Features

Levene and La Forge (1914) showed that the excreted pentose in pentosuria is L-xylulose.

By direct biochemical means applied to erythrocytes, Wang and Van Eys (1970) demonstrated that the basic fault in pentosuria concerns NADP-linked xylitol dehydrogenase, the enzyme that catalyzes the conversion of L-xylulose to xylitol. Although the glucuronic acid pathway, in which metabolic block is situated, was elucidated in the 1950s (Touster, 1959) and the site of the metabolic block became evident, actual demonstration of the responsible enzyme deficiency required the finding of L-xylulose reductase activity in normal red cells. Biopsy of liver and kidney, which had the highest enzyme activity, could not be justified in this benign condition.

Lane (1985) found that 2 distinct L-xylulose reductases are produced in human tissues. The major isozyme is missing in pentosuria, whereas the minor isozyme, which presumably is coded by a separate gene, is retained. The major isozyme occurs in both the cytosol and the mitochondria, whereas the minor isozyme is limited to the cytosol (Lane and Jenkins, 1985).

Heterozygotes can be recognized by demonstrating either an intermediate level of erythrocyte activity of xylitol dehydrogenase or increased urinary or serum L-xylulose, or both, in a glucuronolactone loading test (Hiatt, 2001).

Inheritance

The inheritance pattern of pentosuria is autosomal recessive (Pierce et al., 2011).

Politzer and Fleischmann (1962) suggested dominant inheritance for pentosuria in 1 Lebanese family. Lane and Jenkins (1985) restudied the family, using an improved assay for red cell enzyme in the identification of heterozygotes, and concluded that pseudodominance of the usual recessive trait was actually the case. They discussed the possibility that the Lebanese and Ashkenazim gene may have the same mutation, i.e., descended from a single mutation in the past. The minimum estimate of the frequency of the pentosuria allele in Ashkenazim was calculated to be 0.0127.

Molecular Genetics

In 9 probands of Ashkenazi Jewish descent with pentosuria, Pierce et al. (2011) identified homozygous or compound heterozygous loss-of-function mutations in the DCXR gene (608347.0001 and 608347.0002). Patient cells showed a complete lack of the DCXR protein. The allele frequency of the 2 alleles combined among 1,067 individuals of Ashkenazi Jewish descent was 0.0173, leading to an expected frequency of pentosuria of 1 in 3,300 individuals in this population. These families had originally been studied by Margaret Lasker in the mid-20th century.

Population Genetics

Pentosuria occurs almost exclusively in individuals of Ashkenazi Jewish descent. The frequency in American Jews is estimated at 1 in 2,000 to 2,500 (Hiatt, 2001).

Khachadurian (1962) and Politzer and Fleischmann (1962) described pentosuria in Lebanese families.

Soyama and Furukawa (1985) described a Japanese case of pentosuria.

History

Pentosuria was one of the original 4 inborn errors of metabolism discussed by Garrod (1908) in his famous lectures. In the early- and mid-20th century, pentosuria was often confused with diabetes mellitus. Some individuals were inappropriately treated with insulin, leading to hypoglycemic reactions (summary by Pierce et al., 2011).