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

Abstract

BackgroundSelective 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.ObjectivesTo describe the clinical, metabolic, and genetic bases of I‐GS in Beagles.AnimalsFour cobalamin‐deficient and 43 clinically normal Beagles and 5 dogs of other breeds.MethodsClinical 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.ResultsJuvenile‐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.ConclusionsThe 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.

Congenital cobalamin malabsorption (Imerslund‐Gräsbeck syndrome) in two Beagles in the UK

“…Both cases presented with normocytic, normochromic, non-regenerative anaemia, compatible with previous reports in hypocobalaminaemic Beagles (Fordyce and others 2000, Fyfe and others 2014) and Border collies (Battersby and others 2005, Lutz and others 2013). Case 1 also had thrombocytopenia with hypersegmented neutrophils seen on examination of mesenteric lymph node aspirates.…”

“…To the authors' knowledge, this is the first report of this syndrome, confirmed by the commercially available genetic test, in Beagles from the UK that were successfully treated with parenteral cobalamin supplementation. The authors recognise that this disease has been seen in Beagles previously (Fordyce and others 2000, Barron and Wouda 2008, Fyfe and others 2014, Kook and others 2014, Kook and others 2015). …”

“…Both cases showed hypoalbuminaemia and hypoglobulinaemia, described in IGS in Beagles (Fyfe and others 2014). Both variables may have been the result of GI disease secondary to hypocobalaminaemia.…”

“…The cause of vomiting and diarrhoea seen in IGS is incompletely understood, but one possible explanation could be that impaired DNA synthesis associated with hypocobalaminaemia affects rapidly diving cells, including intestinal epithelial cells, and thus contribute to the development of GI signs. Alternatively, there might be concurrent pathological change within the GI tract and, in this regard, one affected Beagle died of necrotising enteropathy in a previous study of this disease (Fyfe and others 2014). Case 1 also presented with a history of cervical pain (however, this was not present on examination at the referral institute and therefore was resolved before cobalamin supplementation) and oral ulceration.…”

Prospective long‐term evaluation of parenteral hydroxocobalamin supplementation in juvenile beagles with selective intestinal cobalamin malabsorption (Imerslund‐Gräsbeck syndrome)

“…It is an autosomal recessive trait caused by 2 distinct AMN mutations in Giant Schnauzers and Australian Shepherds . Our group and others recently identified 2 independent CUBN mutations in Border Collies and Beagles . Although the disease is rare, substantial carrier frequency has been noted in affected breeds and thus disease occurrence is more common regionally .…”