XDH and Xanthinuria Type I

Xanthinuria type I is a rare autosomal recessive metabolic disorder resulting from isolated deficiency of xanthine dehydrogenase (XDH), characterized by profound hypouricemia and excessive xanthine excretion in urine. The XDH gene (HGNC:12805) encodes the molybdenum-containing enzyme responsible for oxidizing hypoxanthine to xanthine and xanthine to uric acid. Biallelic loss-of-function variants in XDH underlie classical xanthinuria type I (MONDO:0010209), leading to variable clinical manifestations including nephrolithiasis, nephrocalcinosis, hematuria, and renal impairment.

Genetic Evidence

Inheritance is autosomal recessive, with homozygous and compound heterozygous XDH variants reported. The index Iranian‐Jewish patient was homozygous for the c.1664dup (p.Ala556fs) variant identified by PCR-SSCP and sequencing in exon 16 ([PMID:10844591]). A 78-year-old patient carried heterozygous c.641del (p.Pro214fs) and c.2729C>T (p.Thr910Met) variants ([PMID:20077140]). A multiexon deletion was observed in a German patient with classical xanthinuria ([PMID:23249873]). A recurrent c.2164A>T (p.Lys722Ter) founder allele was identified in Israeli Arab families, tracing back ~179 generations ([PMID:32071838]). Overall, >20 unrelated probands across >10 kindreds have been described.

Phenotypic Spectrum

Affected individuals present with undetectable serum and urinary uric acid, xanthine urolithiasis, nephrocalcinosis (HP:0000121), gross hematuria (HP:0012587), vomiting (HP:0002013), and variable renal insufficiency (HP:0000083). Clinical awareness is critical for diagnosis via urate measurement and allopurinol loading tests.

Functional Evidence

In vitro expression studies of missense and nonsense XDH variants demonstrate marked reduction or absence of xanthine oxidase activity. The p.Cys150Phe, p.Trp478Ter, and p.Arg825Ter variants impair molybdenum cofactor binding and enzyme biogenesis in heterologous systems ([PMID:34356852]). Additional pharmacogenetic analyses in COS-7 cells show decreased enzyme activity for p.Asn1109Thr and p.His1221Arg variants, confirming a loss-of-function mechanism ([PMID:18300946]).

Conflicting Evidence

No studies have refuted XDH as the causal gene for xanthinuria type I; type II xanthinuria is distinguished by dual XDH/MOCOS deficiency but does not overlap with type I phenotypes.

Integration and Clinical Utility

Biallelic XDH variants cause classical xanthinuria type I via enzyme deficiency, consistent across genetic and functional studies. Genetic testing including sequencing and copy-number analysis of XDH is recommended for patients with unexplained hypouricemia and xanthine stones. Early diagnosis enables dietary and hydration measures to prevent urolithiasis.

Key Take-home: Pathogenic variants in XDH are definitively associated with autosomal recessive xanthinuria type I, guiding genetic diagnosis and management.

References

• Kidney International | 2000 | XDH gene mutation is the underlying cause of classical xanthinuria: a second report. PMID:10844591
• Journal of Inherited Metabolic Disease | 2010 | Xanthine dehydrogenase deficiency with novel sequence variations presenting as rheumatoid arthritis in a 78-year-old patient. PMID:20077140
• Clinical Nephrology | 2013 | Multi-exon deletion in the XDH gene as a cause of classical xanthinuria. PMID:23249873
• Biomedicines | 2021 | Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects. PMID:34356852
• Pharmacogenetics and Genomics | 2008 | Functional characterization of human xanthine oxidase allelic variants. PMID:18300946

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