Degenerative Liver Disease in Young Beagles with Hereditary Cobalamin Malabsorption Because of a Mutation in the Cubilin Gene

Cobalamin is an essential cofactor for enzyme systems, and adequate amounts are required for nucleic acid synthesis and hematopoiesis. The 2 most important reactions involving cobalamin are the conversion of methylmalonyl-coenzyme A to succinylcoenzyme A and the remethylation of homocysteine. Cobalamin deficiency leads to decreased activity of these enzyme systems, resulting in increased concentrations of urinary methylmalonic acid and total plasma homocysteine. Dogs are unable to synthesize cobalamin and rely on uptake of dietary cobalamin, which is bound in the small intestine to the secreted protein, intrinsic factor (IF). The cobalamin-IF complex binds to the membrane-bound cubam receptor, which mediates endocytosis. Cubam consists of 2 separate protein subunits, amnionless (AMN) and cubilin (CUBN). In infants, mutations in either the AMN or CUBN genes lead to Imerslund-Gr€asbeck syndrome (IGS). This is a rare autosomal recessive disorder which, if left untreated, results in failure to thrive, megaloblastic anemia, proteinuria, and neurological damage. In dogs, primary cobalamin malabsorption, which is analogous to IGS in humans, has been reported in young Australian Shepherds, a Beagle, Border Collies, and Giant Schnauzers. The genetic defects in affected Border Collies and Beagles recently have been identified as 2 independent mutations in the CUBN gene. Similar to human patients, dogs typically present at a young age with inappetence, weakness, and failure to thrive. Although liver disease is recognized in cobalamin-deficient farm animals, especially lambs, it has not been reported in dogs suffering from hereditary cobalamin malabsorption. The aim of the present case series was to describe the clinical and histopathologic findings of liver disease in 2 client-owned beagles suffering from genetically confirmed cobalamin malabsorption.