P6030 Three diverse mutations underlying canine xanthine urolithiasis

Tate, Nicole M.; Minor, Katie M.; Mickelson, James R.; Peterson, Karl; Lulich, Jody P; Furrow, Eva

doi:10.2527/jas2016.94supplement4163a

Cited by 5 publications

(8 citation statements)

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“…Hereditary xanthinuria has been reported in cats (OMIA 001283‐9685), dogs (OMIA 001283‐9615), and cattle (OMIA 001819‐9913) . In some reports, the genetic basis was established by sequencing; in other cases, a primary cause was presumed after eliminating a history of XDH inhibitor use . Similar to the goat in our study, many of the other domestic species with hereditary xanthinuria had severe disease characterized by a juvenile or young adult onset, nephrolithiasis, and renal pathology …”

Section: Discussionsupporting

confidence: 65%

“…Specifically, a study on sheep with xanthine calculi concluded that low dietary molybdenum could be causative because of molybdenum's role in purine metabolism . Hereditary xanthinuria has been reported in cats (OMIA 001283‐9685), dogs (OMIA 001283‐9615), and cattle (OMIA 001819‐9913) . In some reports, the genetic basis was established by sequencing; in other cases, a primary cause was presumed after eliminating a history of XDH inhibitor use .…”

Section: Discussionmentioning

confidence: 99%

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Hereditary xanthinuria in a goat

Vail

Tate

Likavec

et al. 2019

Veterinary Internal Medicne

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A 2‐year‐old mixed breed goat was presented for a 1‐day history of anorexia and 1 week of weight loss. Serum biochemistry disclosed severe azotemia. Abdominal ultrasound examination showed decreased renal corticomedullary distinction, poor visualization of the renal pelves, and dilated ureters. On necropsy, the kidneys were small, the pelves were dilated, and the medulla was partially effaced by variably sized yellow nephroliths. Histologically, cortical and medullary tubules were distended by yellow‐brown, multilayered crystals. Stone composition was 100% xanthine. Exonic sequencing of xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) identified 2 putative pathogenic variants: a heterozygous XDH p.Leu128Pro variant and a homozygous MOCOS p.Asp303Gly variant. Variant frequencies were determined in 7 herd mates, 12 goats undergoing necropsy, and 443 goats from genome databases. The XDH variant was not present in any of these 462 goats. The MOCOS variant allele frequency was 0.03 overall, with 3 homozygotes detected. Hereditary xanthinuria is a recessive disorder in other species, but the XDH variant could be causal if the case goat is a compound heterozygote harboring a second variant in a regulatory region not analyzed or if the combination of the XDH and MOCOS variants together abolish XDH activity. Alternatively, the MOCOS variant alone could be causal despite the presence of other homozygotes, because hereditary xanthinuria in humans often is asymptomatic. Ours is the first report describing the clinical presentation and pathology associated with xanthine urolithiasis in a goat. The data support hereditary xanthinuria, but functional studies are needed to conclusively determine the causal variant(s).

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Hereditary xanthinuria in a goat

Vail

Tate

Likavec

et al. 2019

Veterinary Internal Medicne

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“…This form is caused by variants in the molybdenum cofactor sulfurase gene ( MOCOS ), resulting in a lack of enzyme activation (Ichida et al, 2001; Lee et al, 2021; Zhou et al, 2015). While xanthinuria has not been subdivided into type I and type II in animals, variants in XDH and MOCOS have been identified in animals affected by xanthinuria (Murgiano et al, 2016; Sedda et al, 2021; Tate et al, 2016). To date, genetic studies of individual cases have not revealed a genetic variant associated with feline purine urolithiasis.…”

Section: Gene Polymorphism (Genomic Dna)a Polymorphism (Genomic Dna)b...mentioning

confidence: 99%

“…While no longer a functional enzyme in humans, hepatic uricase converts uric acid to allantoin in most mammals, which is subsequently excreted by the kidney (Kratzer et al, 2014). Heritable defects associated with xanthinuria and urate crystalluria have been described in humans, dogs, goats, and cattle, and there is evidence that this condition is also heritable in cats (Furman et al, 2015;Gok et al, 2003;Ichida et al, 2012;Miranda et al, 2010;Murgiano et al, 2016;Tate et al, 2016;Vail et al, 2019;Westropp et al, 2017). While relatively rare and predominantly benign in humans, xanthinuria in humans has been subdivided (Ichida et al, 1997(Ichida et al, , 2001.…”

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confidence: 99%

Candidate causative variant for xanthinuria in a Domestic Shorthair cat

Pritchard

Samaha

Mizzi³

et al. 2023

Animal Genetics

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Xanthinuria is a clinically significant form of urolithiasis in cats with poor clinical outcomes and limited treatment options. In humans, xanthinuria has an autosomal recessive mode of inheritance, with variants in xanthine dehydrogenase (XDH) and molybdenum cofactor sulfurase (MOCOS) responsible for cases. While causative genetic variants have not been identified in the domestic cat, a recessive mode of inheritance has been suggested. DNA was extracted from EDTA-stabilised blood obtained from a Domestic Shorthair cat with clinically confirmed xanthinuria.Whole-genome sequencing and variant assessment in XDH and MOCOS identified XDH:c.2042C>T (XDH:p.(A681V)) as a candidate causative variant for xanthinuria in this cat. The variant is located in a highly conserved part of the molybdenum-pterin co-factor domain, responsible for catalysing the hydroxylation of hypoxanthine to xanthine and uric acid. Variants in this domain of XDH have been shown to disrupt enzyme function and to cause xanthinuria in other species. When assessed in the wider cat population, the variant had an allele frequency of 15.8%, with 0.9% of the animals assessed homozygous for the alternative allele. Cats diagnosed with xanthinuria should be tested for this variant to validate its clinical relevance in the wider population.

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“…4,8,9 Xanthinuria can also be subclinical, further complicating diagnosis. 5,[10][11][12][13] In the absence of xanthine dehydrogenase (XDH) inhibitory therapy, xanthinuria is typically hereditary, with an autosomal recessive mode of inheritance, and results from variants affecting the function of XDH (type I xanthinuria) or its cofactor molybdenum cofactor sulfurase (MOCOS) (type II xanthinuria). Causative genetic variants associated with xanthinuria have been identified in humans, dogs, goats and cattle.…”

Section: Introductionmentioning

confidence: 99%

Xanthinuria in a familial group of Munchkin cats and an unrelated domestic shorthair cat

Pritchard,

Haase,

Wall

et al. 2024

Journal of Feline Medicine and Surgery

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Case series summary Four confirmed cases of xanthinuria in cats, and one suspected case based on pedigree analysis, were identified. Clinical presentations varied and included haematuria, pollakiuria, dysuria, and urethral and ureteral obstruction. All cats had upper urinary tract uroliths. Diagnosis was obtained through infrared mass spectrometry of uroliths or urine. Clinical signs commenced at 3–8 months of age and reduced in all cats in the medium to long term after the introduction of a protein-restricted diet. Four cats were castrated males and one was a spayed female. Cases consisted of four Munchkin pedigree cats and one unrelated domestic shorthair cat. All four affected Munchkin pedigree cats were related, with three cases full siblings and the fourth case a half-sibling. No connection to the Munchkin pedigree could be established for the domestic shorthair cat. A candidate causative genetic variant ( XDH p.A681V) proposed for this cat was excluded in the Munchkin family. Relevance and novel information All affected cats presented diagnostic challenges and routine urinalysis was insufficient to obtain a diagnosis. Cases of feline xanthinuria may be underdiagnosed due to situations where uroliths cannot be retrieved for analysis and there is an inability to make a diagnosis using crystal morphology alone on routine urinalysis. Metabolic screening of urine may provide an effective mechanism to confirm xanthinuria in suspected cases where uroliths are inaccessible or absent. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs and urethral obstruction developing secondary to xanthine urolithiasis. A protein-restricted diet appears to reduce clinical signs as part of long-term management. Plain language summary Four closely related Munchkin cats and one domestic shorthair cat were found with a suspected genetic disease causing high levels of xanthine in their urine. The case series looks at similarities and differences in their clinical signs, as well as difficulties experienced in obtaining a correct diagnosis. All cats had upper urinary tract stones and required metabolic testing of the stones or urine to diagnose. All cats were young when their clinical signs started and were on a high-protein diet. Four cats were desexed males and one was a desexed female. A genetic variant that may have caused the disease in the domestic shorthair cat was ruled out in the Munchkin family. Cases of high xanthine levels in feline urine may be underdiagnosed as the stones may not be accessed for testing. In this case series, male cats were more common. Their anatomy may increase the risk of lower urinary tract signs. A protein-restricted diet appears to reduce clinical signs as part of long-term management.

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P6030 Three diverse mutations underlying canine xanthine urolithiasis

Cited by 5 publications

References 0 publications

Hereditary xanthinuria in a goat

Hereditary xanthinuria in a goat

Candidate causative variant for xanthinuria in a Domestic Shorthair cat

Xanthinuria in a familial group of Munchkin cats and an unrelated domestic shorthair cat

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