Pentosuria is one of four conditions hypothesized by Archibald Garrod in 1908 to be
inborn errors of metabolism. Mutations responsible for the other three conditions (
albinism,
alkaptonuria, and
cystinuria) have been identified, but the mutations responsible for
pentosuria remained unknown.
Pentosuria, which affects almost exclusively individuals of Ashkenazi Jewish ancestry, is characterized by high levels of the
pentose sugar L-
xylulose in blood and urine and deficiency of the
enzyme L-xylulose reductase. The condition is autosomal-recessive and completely clinically benign, but in the early and mid-20th century attracted attention because it was often confused with
diabetes mellitus and inappropriately treated with
insulin. Persons with
pentosuria were identified from records of Margaret Lasker, who studied the condition in the 1930s to 1960s. In the DCXR gene encoding
L-xylulose reductase, we identified two mutations, DCXR c.583ΔC and DCXR c.52(+1)G > A, each predicted to lead to loss of
enzyme activity. Of nine unrelated living pentosuric subjects, six were homozygous for DCXR c.583ΔC, one was homozygous for DCXR c.52(+1)G > A, and two were compound heterozygous for the two mutant alleles.
L-xylulose reductase was not detectable in
protein lysates from subjects' cells and high levels of
xylulose were detected in their sera, confirming the relationship between the DCXR genotypes and the pentosuric phenotype. The combined frequency of the two mutant DCXR alleles in 1,067 Ashkenazi Jewish controls was 0.0173, suggesting a
pentosuria frequency of approximately one in 3,300 in this population. Haplotype analysis indicated that the DCXR c.52(+1)G > A mutation arose more recently than the DCXR c.583ΔC mutation.