Xanthinuria, Type Ii

A number sign (#) is used with this entry because of evidence that xanthinuria type II (XAN2) is caused by homozygous or compound heterozygous mutation in the MOCOS gene (613274) on chromosome 18q12. One patient with a heterozygous mutation has been reported.

Description

Xanthinuria type II is an autosomal recessive inborn error of metabolism resulting from a defect in the synthesis of the molybdenum cofactor, which is necessary for the 2 enzymes that degrade xanthine: XDH (607633) and AOX1 (602841). Most individuals with type II xanthinuria are asymptomatic, but some develop urinary tract calculi, acute renal failure, or myositis due to tissue deposition of xanthine. Laboratory studies show increased serum and urinary hypoxanthine and xanthine and decreased serum and urinary uric acid (summary by Ichida et al., 2001).

Two clinically similar but distinct forms of xanthinuria are recognized. In type I xanthinuria (XAN1; 278300), there is an isolated deficiency of xanthine dehydrogenase resulting from mutation in the XDH gene; in type II, there is a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Type I patients can metabolize allopurinol, whereas type II patients cannot (Simmonds et al., 1995).

Clinical Features

Ichida et al. (2001) reported 2 unrelated Japanese men with xanthinuria type II. One was a 66-year-old man who presented with hypouricemia and chronic renal failure due to polycystic kidneys, whereas the other was a 45-year-old man with low serum uric acid and undetectable urinary uric acid. Both also had high serum hypoxanthine and xanthine. The diagnosis was confirmed by the allopurinol loading test; neither patient could properly metabolize allopurinol.

Peretz et al. (2007) reported 4 sibs, born of consanguineous Bedouin Arab parents, with xanthinuria type II. The proband was a 2-year-old girl who presented with a urinary tract infection and was found to have a renal stone. Laboratory studies showed severe hypouricemia and zero urinary uric acid. Serum and urinary hypoxanthine and xanthine were markedly elevated. An unrelated woman of Jewish descent with the disorder was also reported: she had urinary complaints in the absence of sonographic evidence of stones or infection. All patients were diagnosed with the disorder by the allopurinol loading test.

Inheritance

The transmission pattern of xanthinuria type II in the family reported by Ichida et al. (2001) was consistent with autosomal recessive inheritance.

Pathogenesis

Beaudet (1999) indicated that the mutation in type II xanthinuria may not be in the structural gene for either xanthine dehydrogenase or aldehyde oxidase, but possibly in the mechanism responsible for inserting the essential sulfur atom into the active center of both enzymes.

Molecular Genetics

In 2 unrelated Japanese men with xanthinuria type II, Ichida et al. (2001) identified a homozygous nonsense mutation in the MOCOS gene (R419X; 613274.0001). No XDH or AOX1 activity was detected in the liver of 1 of the patients.

In 2 sisters with xanthinuria type II, Yamamoto et al. (2003) identified a homozygous missense mutation in the MOCOS gene (613274.0002). Functional studies of the variant were not performed.

In 4 sibs, born of consanguineous Bedouin-Arab parents, with xanthinuria type II, Peretz et al. (2007) identified a homozygous missense mutation in the MOCOS gene (R776C; 613274.0003). Functional studies of the variant were not performed. An unrelated woman of Jewish descent with the disorder was compound heterozygous for the R776C mutation and a truncating mutation (613274.0004). Haplotype analysis excluded a founder effect for the R776C mutation.

Zhou et al. (2015) identified a heterozygous R419X mutation in a 42-year-old man with xanthinuria type II. He had no history of urinary calculi or myositis, but was ascertained due to hypouricemia. He had decreased, but not absent, serum levels of MOCOS, as well as increased xanthine and hypoxanthine and significantly decreased activities of XDH and AOX1. Cellular knockdown of the MOCOS gene resulted in high levels of xanthine and hypoxanthine as well as absence of XDH and AOX1 activity, confirming the pathogenic effect of the mutation.