Imerslund–Gräsbeck syndrome is –Gräa rare autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the "Cubam" receptor located in the terminal ileum. This receptor is composed of two proteins, amnionless (AMN), and cubilin. A defect in either of these protein components can cause this syndrome. This is a rare disease, with a prevalence about 1 in 200,000, and is usually seen in patients of European ancestry.
Vitamin B12 is an important vitamin needed for proper functioning of the bone marrow; if deficient, this may lead to decreased marrow output and anemia. Vitamin B12 has two forms, one of which, along with folate, is important in DNA synthesis. Vitamin B12 is sensitive to acid deformation in the stomach, so a molecule called haptocorrin (R-factor), protects it in the stomach. In the small intestine, a molecule named intrinsic factor (IF), allows vitamin B12 to be absorbed in the ileum. IGS is caused by a mutation in the receptors located in the terminal portion of ileum. This is a very rare, and unlikely cause of vitamin B12 deficiency but is a cause nonetheless.
Signs and symptoms
Defined as those seen in any macrocytic, megaloblastic anemia: Anemia: causing fatigue, conjuctival pallor, pale complexion, and in some cases, a mild icterus (yellowing of the eye). Glossitis ("shiny tongue"): shiny, glossy tongue. Cheilosis (stomatitis): Inflammation of the edges of the lips and the oral mucosa. Tabes dorsalis ("subacute combined degeneration of the spinal cord"): This involves the posterior section of the spinal cord and therefore involves proprioception (sense of position), touch, sense of vibration and in severe cases the lateral corticospinal tract, causing spastic paralysis of the limbs. Peripheral neuropathy: tingling sensation in the arms and legs. Pancytopenia: decreased number of blood cells of all lineages (RBCs, leucocytes, platelets), due to decreased bone marrow production. Methylmalonic acidemia: defined as blood having an unusually high concentration of methylmalonyl CoA. Peripheral findings such as hypersegmented neutrophils and large RBCs on high field view of the blood smears. Laboratory findings indicating increased MCV (Mean Corpuscular Volume), decreased Hgb/Hct (indicating anemia), and decreased value of vitamin B12 in the blood. Proteinuria: protein found in the urine detected by analysis or by dipstick. Reversal of all symptoms except neurological symptoms, by intramuscular injection of vitamin B12. Schilling test indicating no radioactive vitamin B12 in the urine. (This test has dropped out of favor and should not be tried in patients with any form of renal failure).
Genetics
The disease is autosomal recessive, and can therefore skip generations. Mutations in either amnionless (AMN) or cubilin can be the culprit. Due to its autosomal recessive pattern of inheritance, affected individuals (persons possessing a homozygous recessive genotype) need to undergo genetic counseling to identify the risk of family members who might be heterozygous genetic carriers. Certain mutations on the CUBN or AMN (genes that encode cubilin and amnionless respectively) have been identified through genetic analysis, and ethnic susceptibility of some of the mutations was indicated from the current research. It has been further suggested that mutations on CUBN were restricted to exon 1-28 which encoded amnionless binding domains (EGF) and IF-Cbl binding region of cubilin, while AMN mutations primarily clustered in intron 8-11 and transmembrane domain in exon 10. Some interesting aspects of particular mutations were also elucidated by the researchers, for example, CUBN mutation c.3890C>T; p.Pro1297Leu, was considered to be a Finnish founder mutation presenting mostly in homozygous status, while an AMN mutation c.208-2A>G, which was thought to account for 15% IGS cases around the world, was postulated as an ancient founder mutation that can trace back to approximately 13,600 years ago.