Dihydropyrimidinase Deficiency

Dihydropyrimidinase (DHP) is the second enzyme in the pyrimidine degradation pathway, and its deficiency causes a rare metabolic syndrome known as dihydropyrimidinase deficiency. The DPYS gene is responsible for encoding this enzyme, and specific mutations in this gene can lead to a deficiency in enzyme activity, which manifests with symptoms such as hyperammonemia, vomiting and depression.

Symptoms

Clinical signs of dihydropyrimidinase deficiency in cats include hyperammonemia, which manifests as lethargy, depression and frequent vomiting. These symptoms may be worsened by a high-protein diet. In addition to increased blood ammonia concentration, significant elevations of dihydrouracil and dihydrothymine, as well as moderate increases in uracil and thymine, are observed.

Disease Management

Management of the disease is mainly based on a low-protein diet to reduce ammonia accumulation in the blood and minimize clinical symptoms. Avoidance of foods rich in pyrimidines is also recommended. In some cases, medications may be used to manage acute episodes of hyperammonemia.

Genetic basis

This disease follows an autosomal recessive mode of inheritance. Autosomal recessive inheritance means that the cat, regardless of sex, must receive two copies of the mutation or pathogenic variant to be at risk of developing the disease. Both parents of an affected cat must carry at least one copy of the mutation. Animals with only one copy of the mutation are not at increased risk of developing the disease, but may pass the mutation on to future generations. Breeding between cats carrying genetic variants that may cause disease is not recommended, even if they do not show symptoms.

Technical report

Dihydropyrimidinase (DHP) deficiency is a metabolic disorder that affects the degradation of pyrimidine, uracil and thymine bases. This disorder is associated with a mutation in the DPYS gene, which encodes the enzyme dihydropyrimidinase. This enzyme is involved in the degradation of dihydrouracil and dihydrothymine into β-ureidopropionic and β-ureidoisobutyric acids. In one case report, a cat was found to have a homozygous missense and very low prevalence mutation (c.1303G>A) in exon 8 of the DPYS gene, resulting in the accumulation of dihydrouracil and dihydrothymine in the animal`s blood and urine. This mutation in the DPYS gene has been associated with a mutation observed in humans with DHPuria, suggesting that this genetic alteration is the underlying cause of the deficiency in the affected feline.

Most affected breeds

Not specified

Bibliography

Chang HS, Shibata T, Arai S, et al. Dihydropyrimidinase deficiency: the first feline case of dihydropyrimidinuria with clinical and molecular findings. JIMD Rep. 2012