Congenital erythropoietic porphyria (variant 2)

Symptoms

The disease is characterized mainly by the presence of erythrodontia (discolored brown teeth) and dark reddish-brown urine. Under ultraviolet light, the affected teeth fluoresce pink. The dark red pigmented urine is not due to hematuria or hemoglobinuria. In contrast to acute intermittent porphyria, CEP has normal blood counts and urine aminolevulinic acid (ALA) and porphobilinogen (PBG) levels are normal, while urine and plasma uroporphyrinogen I levels are markedly elevated.

Disease Management

Disease management focuses on supportive care to control clinical signs. As a preventive measure, avoidance of exposure to sunlight and other sources of ultraviolet light is recommended, although sensitivity to light in affected cats is questionable.

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, even if they do not show symptoms, is not recommended.

Technical report

Congenital erythropoietic porphyria (CEP) is an inherited disorder of heme group biosynthesis that affects both humans and animals, including cats. In this disease, deficiency of the enzyme uroporphyrinogen III cosynthetase (UROS) leads to an accumulation of porphyrins in tissues and body fluids. Porphyrins are organic compounds which, when combined with iron, form the heme group, an essential component of hemoglobin, cytochromes, catalases and peroxidases. The genetic mutations c.140C>T (p.S47F) and c.331G>A (p.G111S) in the UROS gene, present homozygously, result in a significantly less active and stable enzyme. The c.140C>T substitution does not cause significant effects on the activity of the mutant enzyme but reduces its thermal stability by approximately 50%. On the other hand, the c.331G>A variant has a large impact on the activity and thermal stability of the enzyme. However, the combination of both mutations results in a unique structure that markedly reduces the activity of the enzyme compared to either enzyme with a single mutation. Thus, the two substitutions in the enzyme act synergistically to inactivate and destabilize the double-mutant monomeric enzyme. In this case, we analyzed the c.331G>A variant.

Most affected breeds

Dom&eacute

Bibliography

Clavero S, Bishop DF, Giger U, et al. Feline congenital erythropoietic porphyria: two homozygous UROS missense mutations cause the enzyme deficiency and porphyrin accumulation. Mol Med. 2010 Sep-Oct