DCXR – Pentosuria

Pentosuria is a benign autosomal recessive inborn error of metabolism characterized by massive urinary excretion of the pentose sugar L-xylulose due to deficiency of L-xylulose reductase. DCXR (HGNC:18985) encodes L-xylulose reductase, and biallelic loss-of-function variants in DCXR underlie pentosuria (PMID:22042873).

Genetic Evidence

Nine unrelated pentosuric individuals were studied: six homozygous for DCXR c.583del (p.His195fs), one homozygous for DCXR c.52+1G>A, and two compound heterozygotes for these alleles, consistent with autosomal recessive inheritance and complete penetrance. No additional segregating affected relatives were reported. Both variants truncate the enzyme and are absent or extremely rare in population databases; combined allele frequency in 1,067 Ashkenazi Jewish controls was 0.0173, predicting a disease frequency of ~1/3,300 in this population (PMID:22042873).

Functional Evidence

L-xylulose reductase activity was undetectable in patient‐derived cell lysates, and circulating L-xylulose levels were markedly elevated, directly linking DCXR LoF genotypes to the pentosuric phenotype. Enzyme deficiency assays confirm a loss-of-function mechanism for both c.583del (p.His195fs) and c.52+1G>A alleles (PMID:22042873).

Clinical Validity and Mechanism

The association between DCXR and pentosuria meets ClinGen criteria for a Strong gene–disease relationship based on nine probands with AR biallelic LoF variants, absence of enzyme activity, and concordant biochemical phenotype. The pathogenic mechanism is haploinsufficiency of L-xylulose reductase leading to benign L-xyluloseuria and avoidance of misdiagnosis as diabetes mellitus.

Clinical Utility

DCXR genetic testing confirms benign pentosuria in individuals with unexplained L-xyluloseuria, preventing inappropriate diabetic management. Urine sugar analysis combined with targeted DCXR sequencing enables rapid diagnosis.

References

• Proceedings of the National Academy of Sciences of the United States of America • 2011 • Garrod's fourth inborn error of metabolism solved by the identification of mutations causing pentosuria. PMID:22042873

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