Clinical, metabolic, and genetic characterization of hereditary methemoglobinemia caused by cytochrome b5 reductase deficiency in cats

• Published in: Journal of veterinary internal medicine Vol. 33; no. 6; pp. 2725 - 2731
• Main Authors: Jaffey, Jared A., Reading, N. Scott, Giger, Urs, Abdulmalik, Osheiza, Buckley, Ruben M., Johnstone, Sophie, Lyons, Leslie A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-11-2019; Wiley
• Subjects: Case Report; cyanosis; CYB5R3; cytochrome b5 reductase; methylene blue; SMALL ANIMAL; whole‐genome sequencing
• ISSN: 0891-6640; 1939-1676
• DOI: 10.1111/jvim.15637

Two non‐pedigreed male castrated cats had persistent cyanosis over a 3‐year observation period. Clinical cardiopulmonary evaluations did not reveal abnormalities, but the blood remained dark after exposure to air. Erythrocytic methemoglobin concentrations were high (~40% of hemoglobin) and cytochrome b5 reductase (CYB5R) activities in erythrocytes were low (≤15% of control). One cat remained intolerant of exertion, and the other cat developed anemia and died due to an unidentified comorbidity. Whole‐genome sequencing revealed a homozygous c.625G>A missense variant (B4:137967506) and a c.232‐1G>C splice acceptor variant (B4:137970815) in CYB5R3, respectively, which were absent in 193 unaffected additional cats. The p.Gly209Ser missense variant likely disrupts a nicotinamide adenine dinucleotide (NADH)‐binding domain, while the splicing error occurs at the acceptor site for exon 4, which likely affects downstream translation of the protein. The 2 novel CYB5R3 variants were associated with methemoglobinemia using clinical, biochemical, genomics, and in silico protein studies. The variant prevalence is unknown in the cat population.