Methemoglobinemia, hereditary

Gene: CYB5R3

Transmission: Autosomal, probably recessive

For an autosomal recessive genetic disease an animal must have two copies of the mutation in question to be at risk of developing the disease.  Both parents of an affected animal must be carriers of at least one copy of the mutation.  Animals that have only one copy of the mutation are not at risk of developing the disease but are carrier animals that can pass the mutation on to future generations.

Mutations:

Mutation 1: Substitution, CYB5R3 gene; c.625 G>A; p.(G209S), chr.B4.

Mutation 2: Substitution, splicing error, CYB5R3 gene; c.226+5G>A, chr.B4.

Mutation 3: Substitution, splicing error, CYB5R3 gene; c.232-1 G>C, chr.B4.

Medical system: Blood

Breeds: Domestic Cat

Age of onset of symptoms: between 5 months and 2 years on average.

Methemoglobinemia is a condition in which the concentration of methemoglobin in the blood is higher than normal. Methemoglobin, which can have a genetic or an environmental cause, results when the iron ion Fe2+ in hemoglobin is oxidized to Fe3+.  The CYB5R3 gene codes for a cytochrome B5 reductase enzyme which normally reduces methemoglobin (Fe3+) to hemoglobin (Fe2+) within the red blood cells.  A mutation in the sequence of the CYB5R3 gene can be responsible for decreased enzyme activity and a high concentration of methemoglobin in the blood.  For genetic methemoglobinemia in cats the main clinical sign observed is cyanosis, a bluish or purple discoloration of the mucous membranes, possibly accompanied by a compensatory high hematocrit (red blood cell count). The main treatment described to date is intravenous injection of methylene blue.  The frequencies of mutations of the CYB5R3 gene within cat breeds and populations are not known.  To prevent the genetic disease, affected cats or cats suspected to be carriers should not be bred.

Note that clinical methemoglobinemia in the cat often has a toxic environmental cause rather than genetic cause.  Toxicity is due to ingestion of oxidizing agents (acetaminophen, lidocaine, onions, or garlic, to name a few).  Cats with toxic methemoglobinemia can be acutely ill and anemic in addition to being cyanotic.

References:

OMIA link: [2131-9685]

Jenni S, Ludwig-Peisker O, Jagannathan V, et al. (2023) Methemoglobinemia, increased deformability and reduced membrane stability of red blood cells in a cat with a CYB5R3 splice defect. Cells 12:991.  [pm/27048064]

Jaffey J, Reading NS, Giger U, et al. (2019) Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in cats. J Vet Intern Med 33(6):2725-2731. [pm/31650629]

Vasiliadou E, Karakitsou V, Kazakos G, et al. (2019) Hereditary methemoglobinemia in a cyanotic cat presented for ovariohysterectomy.  Can Vet J 60(5):502-506.  [pm/31080263]

Contributed by: Arianne Bélanger-Bouchard and Liza Shahin, Class of 2028, Faculty of Veterinary Medicine, University of Montreal. (Translation DWS).