Selective Intestinal Cobalamin Malabsorption with Proteinuria (Imerslund‐Gräsbeck Syndrome) in Juvenile Beagles

BACKGROUND: Selective intestinal cobalamin malabsorption with mild proteinuria (Imerslund‐Gräsbeck syndrome; I‐GS), is an autosomal recessive disorder of dogs caused by mutations in AMN or CUBN that disrupt cubam function and which can present as a medical emergency. OBJECTIVES: To describe the clinical, metabolic, and genetic bases of I‐GS in Beagles. ANIMALS: Four cobalamin‐deficient and 43 clinically normal Beagles and 5 dogs of other breeds. METHODS: Clinical description and candidate gene genetic study. Urinary organic acid and protein excretion were determined by gas‐chromatography and SDS‐PAGE, respectively. Renal cubilin protein expression was assessed on immunoblots. Mutation discovery was carried out by PCR amplification and DNA sequencing of exons with flanking splice sites and cDNA of CUBN and AMN. Genotyping was performed by restriction enzyme digestion of PCR amplicons. RESULTS: Juvenile‐affected Beagles exhibited failure to thrive, dyshematopoiesis with neutropenia, serum cobalamin deficiency, methylmalonic aciduria, hyperammonemia, and proteinuria. Affected dogs' kidneys lacked detectable cubilin protein. All affected dogs were homozygous for a single‐base deletion in CUBN exon 8 (CUBN c.786delC), predicting a translational frameshift, and the 2 parents tested were heterozygous. CONCLUSIONS: The CUBN mutation in juvenile I‐GS Beagles causes a more severe cobalamin malabsorption than in Border Collies with a different CUBN defect, but is similar to I‐GS caused by AMN mutations in Giant Schnauzers and Australian Shepherds. Awareness of the disorder and breed predispositions to I‐GS is crucial to precisely diagnose and promptly treat hereditary cobalamin malabsorption and to prevent disease in those dogs at risk in future generations.