Canis ISSN: 2398-2942

Imerslund-Gräsbeck syndrome

Synonym(s): Hereditary cobalamin syndrome

Contributor(s): James Simpson, Kenneth Simpson, Kevin Murtagh

Introduction

  • Imerslund-Gräsbeck syndrome (IGS) is an inherited disorder characterized by selective intestinal cobalamin malabsorption and mid-low molecular weight proteinuria.
  • A genetic defect has been characterized in the Australian Shepherd, Border collie, Giant Schnauzer and Beagle. The Chinese Shar Pei has also been shown to be at risk for hypercobalaminemia however a genetic cause has not been identified. This disease is seen in young growing dogs, however, Border collies can present in later life.

Pathogenesis

Etiology

  • Intestinal absorption of cobalamin is complex and mediated by cubam, expressed on enterocytes in the ileum, which recognizes B12 complexed with intrinsic factor. Cubam is a multi-ligand endocytic receptor composed of two subunits: cubilin (CUBN) and amnionless (AMN). CUBN is found also in proximal renal tubular epithelium providing binding sites for various ligands, including albumin. AMN is a transmembrane protein that provides membrane anchorage and endocytic signals. Both subunits are essential for normal function of cubam. An abnormality in this cubam (cubilin in Beagles and Border collies and amnionless in Giant Schnauzers and Australian shepherds) receptor leads to cobalamin malabsorption and proteinuria with clinical signs associated with cobalamin deficiency.

Predisposing factors

General
  • Genetic predisposition.

Specific

  • Genetic predisposition.

Pathophysiology

  • Affected breeds lack the apical brush border expression of intrinsic factor-cobalamin receptors, called cubam receptors, which are normally found on the ileum enterocytes. This leads to a deficiency in cobalamin which is an essential co-factor for the enzymes methionine synthase and methylmalonyl-CoA mutase. Methionine synthase is required for the conversion of homocysteine to methionine and for the generation of folate co-factors that are required for nucleic acid synthesis. Decreased activity of methylmalonyl-CoA mutase can be associated with urea cycle dysfunction, through increased production of methylmalonic acid which can cause inhibition of carbomyl phosphate synthetase, resulting in hyperammonemia. Reduced activity of these two enzymes can cause the biochemical signatures of cobalamin deficiency, methylmalonic acidemia/uria (MMA), hyperhomocysteinemia, hyperammonemia and proteinuria. Rapidly dividing cells in the bone marrow are most often characterized by with neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, thrombocytopenia and megaloblastic changes of the bone marrow developing in affected dogs.

Timecourse

  • Variable; but is generally seen in young growing dogs.
  • Border collies have presented later in life (3 years).

Diagnosis

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Treatment

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Outcomes

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Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Kook P H, Drogemuller M, Leeb T et al (2015) Hepatic fungal infection in a young beagle with unrecognised hereditary cobalamin deficiency (Imerslund-Gräsbeck syndrome). JSAP 56 (2), 131-141 PubMed.
  • Fyfe J C, Hemker S L, Venta P J et al (2014) Selective intestinal cobalamin malabsorption with proteinuria (Imerslund-Gräsbeck) syndrome in juvenile Beagles. JVIM 28 (2), 356-363 PubMed.
  • Kook P H, Drogemuller M, Leeb T et al (2014) Degenerative liver disease in young Beagles with hereditary cobalamin malabsorption because of a mutation in the cubulin gene. JVIM 28 (2), 666-671 PubMed.
  • Lutz S, Sewell A C, Reusch C E & Kook P H (2013) Clinical and laboratory findings in Border collies with presumed hereditary juvenile cobalamin deficiency. JAAHA 49 (3), 197-203 PubMed.
  • Owczarek-Lipska M, Jagannathan V, Drogemuller C et al (2013) A frameshift mutation in the cubilin gene (CUBN) in Border collies with Imerslund-Gräsbeck syndrome (selective cobalamin malabsoprtion). Plos One 8 (4), e61144 PubMed.
  • Bishop M A et al (2012) Partial characterization of cobalamin deficiency in Chinese Shar Peis. Vet J 191 (1), 41-45 PubMed.
  • Nielson M J, Rasmussen M R, Anderson C B F et al (2012) Vitamin B12 transport from food to the body's cells-a sophisticated, multistep pathway. Nature Reviews Gastroenterology & Hepatology 9 (6), 345-354 PubMed.
  • Dali-Youcef N & Andres E (2009) An update on cobalamin deficiency in adults. QJM 102 (1), 17-28 PubMed.
  • Battersby I A, Giger U & Hall E J (2005) Hyperammonaemic encephalopathy secondary to selective cobalamin deficiency in a juvenile Border collie. JSAP 46 (7), 339-344 PubMed.
  • Fordyce H H, Callan M B & Giger U (2000) Persistent cobalamin deficiency causing failure to thrive in a juvenile beagle. JSAP 41 (9), 407-410 PubMed.
  • Morgan L W & McConnell J (1999) Cobalamin deficiency associated with erythroblastic anemia and methylmalonic aciduria in a Border collie. JAAHA 35 (5), 392-395 PubMed.


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