Imerslund–Gräsbeck syndrome

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. ==Pathogenesis==

Vitamin B12, is an essential water-soluble vitamin found in animal products (such as liver, meat, fish, and dairy products). Vitamin B12 is not found in plant sources; a vegetarian diet can be a risk factor for vitamin B12 deficiency. Normal daily intake of vitamin B12 is 7–30 micro gram, cooking has minimal effect on the structure of this vitamin. The minimal daily adult requirement is 1–3 micro gram, and the human body is able to store at any one time about 2–3 milligram, which is sufficient for at least 2 years of impeccable functioning before the source is depleted. In terms of absorption, no more than 2–3 microgram of vitamin B12 can be absorbed on a daily basis, with some 5–10 microgram of the vitamin B12 involved in enterohepatic circulation. The following lists principal events that lead to absorption of vitamin B12 along the GI tract: • Oral cavity: vitamin B12 containing food is ingested. Salivary glands produce haptocorrin, which binds vitamin B12, creating a "vitamin B12-Haptocorrin complex". This complex is then ingested via esophageal peristalsis into the stomach. Cubilin is a multi-ligand protein that contains eight epidermal growth factor (EGF) repeats and 27 CUB domains, from which the four active domains (CUB5-8) collectively get involved in binding interaction with the IF-Cbl complex. Whereas, amnionless is an apical transmembrane protein which is expressed in both intestine and kidney, and it seems to assist the subcellular localization and endocytosis of the cubilin by binding to its amino-terminal residues. Cubilin specializes in recognition of the "vitamin B12-IF" complex and attaches to it, while amnionless (AMN) is responsible for initiation of the endocytosis of complex and the subsequent absorption of vitamin B12. It is at this point that the pathology of IGS syndrome occurs by preventing the absorption of vitamin B12, and can be caused by a mutation in either the amnionless (AMN) portion or the cubilin portion of the receptor. ==Diagnosis==

Diagnosis of Imerslund–Gräsbeck syndrome can be suspected by macrocytic anemia, vitamin B12 defieciency, and persistent proteinuria. Also, thrombocytopenia, high levels of homocysteine and methylmalonic acid in serum or urine, and moderate leukopenia and neutropenia can also be a diagnostic marker. The diagnosis gets confirmed by molecular testing of AMN and CUBN gene; Schilling test can be used. ==Treatment==

Since the essential pathology is due to the inability to absorb vitamin B12 from the bowels, the solution is, therefore, intramuscular injections of vitamin B12. ==Epidemiology==

This is a rare disease with prevalence about 1 in 200,000 Studies showed that mutations in CUBN or AMN clustered particularly in the Scandinavian countries and the Eastern Mediterranean regions. Founder effect, higher clinical awareness to IGS, and frequent consanguineous marriages all play a role in the higher prevalence of IGS among these populations. ==History==

The discovery and research of the syndrome is the result of the collective work done by a Norwegian pediatrician, Olga Imerslund, a Finnish physician and clinical biochemist, Armas Ralph Gustaf Gräsbeck, and Emil Najman, a pediatrician from Croatia. ==References==