Inherited Selective Intestinal Cobalamin Malabsorption and Cobalamin Deficiency in Dogs

Abstract

ABSTRACT. Inherited selective intestinal malabsorption of cobalamin (Cbl) was observed in a family of giant schnauzer dogs. Family studies and breeding experiments demonstrated simple autosomal recessive inheritance of this disease. Affected puppies exhibited chronic inappetence and failure to thrive beginning between 6 and 12 wk of age. Neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, and megaloblastic changes of the bone marrow were present. Serum Cbl concentrations were low, and methylmalonic aciduria and homocysteinemia were present. Parenteral, but not oral, cyanocobalamin administration rapidly eliminated all signs of Cbl deficiency except for low serum Cbl concentrations. Cbl malabsorption in affected dogs was documented by oral administration of [57Co]cyanocobalamin with or without simultaneous oral administration of intrinsic factor or normal dog gastric juice. Quantitation and function studies of intrinsic factor and transcobalamin-I1 from affected dogs revealed no abnormality. Other gastrointestinal functions and ileal morphology were normal, indicating a selective defect of Cbl absorption at the level of the ileal enterocyte. Immunoelectron microscopy of ileal biopsies showed that the receptor for intrinsic factor-Cbl complex was absent from the apical brush border microvillus pits of affected dogs. This canine disorder resembles inherited selective intestinal Cbl malabsorption (Imerslund-Grasbeck syndrome)

Mouse amnionless, which is required for primitive streak assembly,mediates cell-surface localization and endocytic function of cubilin on visceral endoderm and kidney proximal tubules

“…A canine model for MGA1 provides a further clue to the nature of this interaction. While affected dogs do not bear mutations in Cubn, Cubn itself is mislocalized, suggesting that another protein is required to insert Cubn on the apical membrane (Fyfe et al, 1991a;Fyfe et al, 1991b). As shown in Fig.…”

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

“…This is a rare autosomal recessive disorder which, if left untreated, results in failure to thrive, megaloblastic anemia, proteinuria, and neurological damage 2. In dogs, primary cobalamin malabsorption, which is analogous to IGS in humans, has been reported in young Australian Shepherds,3 a Beagle,4 Border Collies,5, 6, 7 and Giant Schnauzers 8. The genetic defects in affected Border Collies and Beagles recently have been identified as 2 independent mutations in the CUBN gene 9, 10.…”

“…The genetic defects in affected Border Collies and Beagles recently have been identified as 2 independent mutations in the CUBN gene 9, 10. Similar to human patients, dogs typically present at a young age with inappetence, weakness, and failure to thrive 4, 5, 6, 8, 11. Although liver disease is recognized in cobalamin‐deficient farm animals, especially lambs,12, 13 it has not been reported in dogs suffering from hereditary cobalamin malabsorption.…”

Inherited metabolic disease in companion animals: Searching for nature’s mistakes

“…As previously reported by Fordyce et al (2000), this patient was successfully treated by parenteral vitamin B12 administration every 2-4 weeks. Cobalamin malabsorption has also been described in giant Schnauzers (Fyfe et al, 1991), Border collies (Battersby et al, 2005), and Australian shepherd dogs (He et al, 2005). Investigations of affected Giant schnauzers and Australian shepherd dogs at the molecular level (Fyfe et al, 2004;He et al, 2005) have confirmed that this disease is a true homologue of congenital megaloblastic anaemia due to vitamin B12 deficiency because of a defect in the vitamin B12/intrinsic factor receptor (Imerslund-Gräsbeck syndrome) in humans.…”

“…Nevertheless, there have been occasional reports of 'classical' organic acidurias (lactic aciduria and methylmalonic aciduria) in dogs with predominantly neurological signs (Podell et al, 1996). Isolated methylmalonic aciduria is characteristic of vitamin B12 malabsorption (Fyfe et al, 1991) in which patients present with a triad of failure-to-thrive, lethargy, and anorexia. If untreated, patients develop neurological signs of tremor, anxiety, and convulsions.…”