Methemoglobinemia

Methemoglobinemia is a condition in which part of the hemoglobin in the blood is converted to methemoglobin, which is unable to bind oxygen. Symptoms include cyanosis—a bluish discoloration of the mucous membranes and tongue, rapid breathing, and exercise intolerance. In more severe cases, weakness, lethargy, or even organ hypoxia may be observed.

In Chihuahuas, Pomeranians, and Rat Terriers, the disease is caused by a missense mutation c.580A>C in the CYB5R3 gene, which encodes cytochrome b5 reductase, a key enzyme for maintaining hemoglobin in its functional form.

The mutation is inherited in an autosomal recessive manner. This means that the disease only develops in individuals who inherit the mutated gene from both parents. Carriers of the mutated gene are clinically healthy, but they pass the mutation on to their offspring. In the case of mating between two heterozygous individuals, theoretically 25% of offspring will be completely healthy, 50% will be carriers, and 25% will inherit the mutated gene from both parents and will therefore be affected by the disease.

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References:

Shino, H., Otsuka-Yamasaki, Y., Sato, T., Ooi, K., Inanami, O., Sato, R., Yamasaki, M.: Familial congenital methemoglobinemia in Pomeranian dogs caused by a missense variant in the NADH-cytochrome B5 reductase gene. J Vet Intern Med 32:165-171, 2018. Pubmed reference: 29356095