Imerslund-Gräsbeck syndrome
Encyclopedia
Imerslund-Grasbeck syndrome or Imerslund-Najman-Grasbeck syndrome or Imerslund-Grasbeck disease (IGS or INGS) is an autosomal recessive, familial form of vitamin B12 deficiency caused by malfunction of the receptor located in the terminal ileum. This receptor is referred to as "Cubam", and is composed of two proteins, amnionless
(AMN), and cubilin
. Defect in either of these protein components can cause this syndrome. This is a rare disease (prevalence about 1 in 200,000), and a rare form of macrocytic, vitamin B12 deficient anemia, and is usually seen in patients of European ancestry.
Vitamin B12 is an important vitamin needed for bone marrow functioning, the deficit of which causes 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 bowel, 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.
genotype
) need to undergo genetic counselling to identify risk of family members who might be heterozygous genetic carrier
s.
. 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 (Vit. B12) along the GI tract:
.
, a Finnish physician and clinical biochemist, Armas Ralph Gustaf Gräsbeck
, and Emil Najman, a pediatrician from Croatia.
Amnionless
Amnionless is a protein that in humans is encoded by the AMN gene.- Function :A complex of amnionless and cubilin forms the cubam receptor....
(AMN), and cubilin
Cubilin
Cubilin is a protein that in humans is encoded by the CUBN gene.- Function :Cubilin acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in...
. Defect in either of these protein components can cause this syndrome. This is a rare disease (prevalence about 1 in 200,000), and a rare form of macrocytic, vitamin B12 deficient anemia, and is usually seen in patients of European ancestry.
Vitamin B12 is an important vitamin needed for bone marrow functioning, the deficit of which causes 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
Haptocorrin
Haptocorrin also known as transcobalamin-1 is a protein that in humans is encoded by the TCN1 gene. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach.- Function :...
(R-factor), protects it in the stomach. In the small bowel, a molecule named intrinsic factor
Intrinsic factor
Intrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
(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:- AnemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
: causing fatigue, conjuctival palor, pale complexion, and in some cases, a mild icterus (yellowing of the eye). - GlossitisGlossitisGlossitis is inflammation of the tongue. It causes the tongue to swell and change color. Finger-like projections on the surface of the tongue may be lost, causing the tongue to appear smooth....
("shiny tongue"): shiny, glossy tongue. - Cheilosis(stomatitis): Inflammation of the edges of the lips and the oral mucosa.
- Tabes dorsalisTabes dorsalisTabes dorsalis is a slow degeneration of the sensory neurons that carry afferent information. The degenerating nerves are in the dorsal columns of the spinal cord and carry information that help maintain a person's sense of position , vibration, and discriminative touch.-Cause:Tabes dorsalis is...
("subacute combined degeneration of the spinal cord"): This involves the posterior section of the spinal cord and therefore involves proprioceptionProprioceptionProprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...
(sense of position), touch, sense of vibration and in severe cases the lateral corticospinal tractLateral corticospinal tractThe lateral corticospinal tract is the largest part of the corticospinal tract...
, causing spastic paralysis of the limbs. - Peripheral neuropathy: tingling sensation in the arms and legs.
- PancytopeniaPancytopeniaPancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
: decreased number of blood cells, due to decreased bone marrow production. - Methylmalonyl CoA-emia: defined as blood having and 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 MCVMCVMCV may refer to:* Medical College of Virginia, the medical campus of Virginia Commonwealth University, Richmond, Virginia* MCV Bus and Coach, a bus body builder, based in Ely, Cambridgeshire, England...
(Mean Corpuscular Volume), decreased HgbHGBHGB stands for:* hellogoodbye, a power pop band from California.* HGB Handelsgesetzbuch, the German commercial law.* Hemoglobin on a blood test....
/HctHCT-Colleges:* Higher College of Technology, a public college in Muscat,Oman* Higher Colleges of Technology, a tertiary education institution in the United Arab Emirates* Herefordshire College of Technology, a college of Further Education in Hereford, England...
(indicating anemia), and decreased value of vitamin B12 in the blood. - Proteinuria: protein found in the urine detected by analysis or by dipstickDipstickA dipstick is one of several measurement devices.Some dipsticks are dipped into a liquid to perform a chemical test or to provide a measure of quantity of the liquid....
. - Reversal of all symptoms except neurological symptoms, by IV injection of vitamin B12.
- Schilling testSchilling testThe Schilling test is a medical investigation used for patients with vitamin B deficiency. The purpose of the test is to determine whether the patient has pernicious anemia.It is named for Robert F. Schilling.-Process:The Schilling test has multiple stages...
indicating no radioactive vitamin B12 in the urine. (This test has droped 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. The suspected chromosome is 14. Due to its autosomal recessive pattern of inheritance, affected individuals (persons possessing a homozygous recessiveRecessive
In genetics, the term "recessive gene" refers to an allele that causes a phenotype that is only seen in a homozygous genotype and never in a heterozygous genotype. Every person has two copies of every gene on autosomal chromosomes, one from mother and one from father...
genotype
Genotype
The genotype is the genetic makeup of a cell, an organism, or an individual usually with reference to a specific character under consideration...
) need to undergo genetic counselling to identify risk of family members who might be heterozygous genetic carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
s.
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 the greens, and therefore one of the principal sources of vitamin B12 deficiency is a purely vegan diet. Normal daily intake of vitamin B12 is 7-30 micro gram, cooking has minimal effect on the structure of this vitamin. Minimal daily adult requirement is 1-3 micro gram, and the human body is able to store at any one time, about 2-3 microgram, 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 circulationEnterohepatic circulation
Enterohepatic circulation refers to the circulation of biliary acids from the liver, where they are produced and secreted in the bile, to the small intestine, where it aids in digestion of fats and other substances, back to the liver....
. 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:
- Deoxyadenosyl B12 or as it is sometimes referred to Ado B12: Ado B12 is essential for acid-base maintenance of the blood, simply because Ado B12 is the catalyst that assists the conversion of, Methylmalonyl CoA, into Succinyl CoA. In absence of vitamin B12, levels of Methylmalonyl CoA increase, and this is in fact a great way to distinguish folate deficiency macrocytic anemia, from vitamin B12 anemia. The following is the reaction in which Ado B12, plays a pivotal role:
Propionyl CoA → Methylmalonyl CoA → Succinyl CoA
- Methyl B12: This form of vitamin B12 is essential for conversion of Methy-THF (Methyl Tetrahydrofolate) into THF, and methyl (CH3). The methyl group, is then used to add a carbon, to homocysteineHomocysteineHomocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
, converting it into MethionineMethionineMethionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein...
. Methionine is further converted to S-adenosyl methionine, which in turn gives of the extra carbon it received from THF, now to a DNA nucleotide, becoming S-adenosyl homcysteine. S-adenosyl Homocysteine, further loses its "S-adenosyl" attachment, to become homocysteine, and the cycle repeats yet again!
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 (Vit. B12) along the GI tract:
- Oral cavity: Vitamin B12 containing food is ingested. Salivary glands produce haptocorrinHaptocorrinHaptocorrin also known as transcobalamin-1 is a protein that in humans is encoded by the TCN1 gene. The essential function of haptocorrin is protection of the acid-sensitive vitamin B12 while it moves through the stomach.- Function :...
which binds vitamin B12, creating a "Vitamin B12-Haptocorrin complex". This complex is then ingested via esophageal peristalsis into the stomach. - StomachStomachThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
: Vitamin B12-Haptocorrin, survives the low pH, highly osmotic environment of the stomach. Parietal cells produce hydrochloric acid (the effect of which Haptocorrin protects vitamin B12 from), and also intrinsic factorIntrinsic factorIntrinsic factor also known as gastric intrinsic factor is a glycoprotein produced by the parietal cells of the stomach. It is necessary for the absorption of vitamin B12 later on in the small intestine...
(IF). Intrinsic factor also has a high binding affinity for vitamin B12, but because that position is already filled by Haptocorrin, free intrinsic factor, and "Haptocorrin-vitamin B12" complex, empty from the stomach into the duodenum. - duodenumDuodenumThe duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms anterior intestine or proximal intestine may be used instead of duodenum...
: Pancreatic juicePancreatic juicePancreatic juice is a liquid secreted by the pancreas, which contains a variety of enzymes, including trypsinogen, chymotrypsinogen, elastase, carboxypeptidase, pancreatic lipase, and amylase....
, produced by the pancreas, contains pancreatic proteases that break the haptocorrin, degrading it and freeing the vitamin B12. Once free, vitamin B12, binds with intrinsic factor (IF), to produce an "IF-Vitamin B12" complex. - IleumIleumThe ileum is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine may be used instead of ileum.The ileum follows the duodenum...
: Located in the terminal portion of the ileum is a specialized receptor complex called the cubamCubamCubam, is the term used to refer to a multi-ligand receptor located in the terminal ileum, specializing in absorption of vitamin B12. Cubam is essentially composed of amnionless , and cubilin...
(or sometimed called "CUBN"). Cubam is composed of two molecules, one of which is amnionlessAmnionlessAmnionless is a protein that in humans is encoded by the AMN gene.- Function :A complex of amnionless and cubilin forms the cubam receptor....
(AMN), and the other cubilinCubilinCubilin is a protein that in humans is encoded by the CUBN gene.- Function :Cubilin acts as a receptor for intrinsic factor-vitamin B12 complexes. The role of receptor is supported by the presence of 27 CUB domains. Cubulin is located within the epithelium of intestine and kidney. Mutations in...
. Cubilin specializes in recognition of the "vitamin B12-IF" complex and attaches it, while amnionless (AMN), is responsible for initiation of the endocytosis of complex, result of which is absorption of vitamin B12. It is at this point, where the IGS syndrome causes its pathology, by preventing absorption of vitamin B12 due to a defective cubam receptor, due to mutation in either the amnionless (AMN) portion, or the cubilin portion. Mutation at either cubilin, or AMN, can cause this syndrome.
Treatment
Since the essential pathology is due to the inability to absorb vitamin B12 from the bowels, the solution is therefore injection of IV vitamin B12. Timing is essential, as some of the side effects of vitamin B12 efficiency are reversible (such as 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, proteinuria, sufficient vitamin B12 dietary intake, and no signs of pernicious anemiaPernicious anemia
Pernicious anemia is one of many types of the larger family of megaloblastic anemias...
.
History
The syndrome is the result of the collective work done by a Norwegian pediatrician, Olga ImerslundOlga Imerslund
Olga Imerslund was a renowned Norwegian pediatrician best known for her contribution to identification and naming of the Imerslund-Gräsbeck syndrome....
, a Finnish physician and clinical biochemist, Armas Ralph Gustaf Gräsbeck
Armas Ralph Gustaf Gräsbeck
Armas Ralph Gustaf Grasbeck is a Finnish physician and clinical biochemist. He is best known for his contribution to the identification and naming of the Imerslund-Gräsbeck syndrome....
, and Emil Najman, a pediatrician from Croatia.