Imerslund–Gräsbeck syndrome

Imerslund–Gräsbeck syndrome is a 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:
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&gt;T; p.Pro1297Leu, was considered to be a Finnish founder mutation presenting mostly in homozygous status, while an "AMN" mutation c.208-2A&gt;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.
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. This is in general a principal characteristic of water-soluble vitamins, in that no matter the oral intake, there is a certain threshold for intestinal absorption hence, low or non-existent chance of intoxication, as opposed to fat-soluble vitamins.
Vitamin B12 has a major function in the nuclear replication of the DNA. It is therefore logical that its deficiency causes decrease bone marrow production, one of the most common manifestations of which is decreased red blood cell production or as it is referred to medically, anemia. Vitamin B12 however has two major forms in the human body:
Propionyl CoA → Methylmalonyl CoA → Succinyl CoA 
 Methyl THF → CH3 + THF
 Homocysteine → Methionine
 S-adenosyl ← ↑ ↓ ← S-adenosyl
 S-adenosyl Homocysteine ← S-adenosyl Methionine
 CH3
 DNA → Methyl-DNA
It is therefore understood that vitamin B12 is involved in complex DNA synthesis, along with folate, as well as in acid-base metabolism. To understand the basic pathophysiology of Imerslund–Gräsbeck syndrome, it is imperative to understand the absorption of vitamin B12. The following lists principal events that lead to absorption of vitamin B12 along the GI tract:
Cubam is composed of two molecules, amnionless (AMN) and cubilin. 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.
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. Timing is essential, as some of the side effects of vitamin B12 deficiency are reversible (such as red blood cell (RBC) indices, peripheral RBC smear findings such as hypersegmented neutrophils, or even high levels of methylmalonyl CoA), but some side effects are irreversible as they are of a neurological source (such as tabes dorsalis, and peripheral neuropathy). High suspicion should be exercised when a neonate, or a pediatric patient presents with anemia, protein in the urine, sufficient vitamin B12 dietary intake, and no signs of pernicious anemia.
Epidemiology.
This is a rare disease with prevalence about 1 in 200,000 to 1 in 600,000. 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.