Congenital Methemoglobinemia in a Dog with a Promoter Deletion and a Nonsynonymous Coding Variant in the Gene Encoding Cytochrome b 5

The reduction of methemoglobin back to hemoglobin is catalyzed primarily by methemoglobin reductase, now recognized as the 2 enzyme system cytochrome b5 (b5) and cytochrome b5 reductase (b5R) (Fig 1). A negligible amount of methemoglobin is reduced by another enzyme, reduced nicotinamide adenine dinucleotide phosphate (NADPH) methemoglobin reductase. Treatment with methylene blue (MB) decreases methemoglobin concentrations dramatically by increasing the activity of the NADPH methemoglobin reductase pathway roughly 5to 10-fold. This report describes the diagnosis of a dog with congenital methemoglobinemia with normal b5R activity, 2 potentially deleterious variants in the cytochrome b5 gene (CYB5A), and the preoperative treatment of this dog with MB. A 4-year-old male castrated Pit Bull mix breed dog was referred for evaluation of markedly cyanotic mucous membranes and poor oxygen saturation, noted at the time of anesthetic induction for planned orthopedic correction for a right cranial cruciate ligament rupture. The surgery was aborted, but the dog reportedly experienced a prolonged anesthetic recovery. Results of a preanesthetic CBC and serum chemistry panel, as well as an electrocardiogram reportedly detected no abnormalities. Thoracic radiographs revealed a mildly enlarged right heart and mild interstitial pulmonary infiltrates. There was no history of coughing, sneezing, collapse, syncope, exercise intolerance, or respiratory distress at home, and the dog had no known access to toxins including acetaminophen. He was fed a commercial adult canine food diet. The dog was adopted approximately 2–3 years before presentation and had suffered only chronic skin allergies until the cranial cruciate ligament rupture occurred. The owner reported that the dog’s tongue and gums had always had a bluish discoloration. The patient was receiving carprofen, monthly milbemycin oxime—lufenuron, and spinosad. A course of antibiotic treatment with cefpodoxime had recently been discontinued. Relevant physical examination findings included cyanotic mucous membranes including the tongue, gums, and penis (Fig 2). There was no noted improvement in the color of the mucous membranes with administration of supplemental oxygen. Thoracic auscultation was normal with no evidence of a heart murmur or arrhythmia and clear lungs sounds. The dog was panting but eupneic. A lameness of the right pelvic limb was noted. A CBC, serum chemistry panel, urinalysis, and coagulation profile with D-dimer concentration were submitted for analysis. Abnormalities included erythrocytosis (HCT = 58%, reference interval 37–55%), increased total hemoglobin concentration (21.6 g/dL, reference interval 12–18 g/dL), mild hypokalemia (3.7 mEq/L, reference interval 4.0–5.6 mEq/L), hypercholesterolemia (412 mg/dL, reference interval 112– 328 mg/dL), elevated aspartate aminotransferase (115 U/L, reference interval 5–55 U/L), and increased creatine kinase (890 U/L, reference interval 10–200 U/L). Coagulation parameters and D-dimer concentration were within normal limits. Arterial and venous blood From the Department of Emergency and Critical Care, Advanced Critical Care, Emergency & Specialty Services – Los Angeles, Culver City, CA (McKenna, Son); the Department of Medical Sciences, School of Veterinary Medicine, University of Wisconsin, Madison, WI (Sacco, Trepanier); the Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA (Callan); the Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL (Harvey); and the Department of Cardiology, Advanced Critical Care, Emergency & Specialty Services – Los Angeles, Culver City, CA (Arndt). The work contributing to this case report was performed at Advanced Critical Care, Emergency & Specialty Services, and the veterinary schools of the University of Florida, University of Wisconsin and University of Pennsylvania. Corresponding author: J.A. McKenna, DVM, Advanced Critical Care, Emergency & Specialty Services – Los Angeles, 9599 Jefferson Boulevard Culver City, CA 90066; e-mail: jmckenna@accla.net. Submitted December 31, 2013; Revised May 1, 2014; Accepted June 23, 2014. Copyright © 2014 by the American College of Veterinary Internal Medicine DOI: 10.1111/jvim.12423 Abbreviations: