Imerslund-Gräsbeck syndrome

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),[1] 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.

Contents

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. The suspected chromosome is 14.[1] Due to its autosomal recessive pattern of inheritance, affected individuals (persons possessing a homozygous recessive genotype) need to undergo genetic counselling to identify risk of family members who might be heterozygous genetic carriers.

Pathogenesis

Vitamin B12, is an essential water soluble vitamin found in animal products (such as liver, meat, fish, and dairy products).[2] 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 circulation.[2] 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 [2]

                              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:

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 deficiency 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 anemia.

History

The syndrome is the result of the collective work done by a Norwegian pediatrician, Olga Imerslund,[5] a Finnish physician and clinical biochemist, Armas Ralph Gustaf Gräsbeck,[6] and Emil Najman, a pediatrician from Croatia.[7]

References

  1. ^ a b c Grasbeck R (2006). "Imerslund-Gräsbeck syndrome (selective vitamin B12 malabsorption with proteinuria". Orphanet Journal of Rare Diseases 19 (1): 17. doi:10.1186/1750-1172-1-17. PMC 1513194. PMID 16722557. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1513194. 
  2. ^ a b c Pettit, John D.; Paul Moss (2006). Essential Haematology 5e (Essential). Blackwell Publishing Professional. pp. 44–6. ISBN 1-4051-3649-9. 
  3. ^ Pedersen GA, Chakraborty S, Steinhauser AL, Traub LM, Madsen M (May 2010). "AMN directs endocytosis of the intrinsic factor-vitamin B(12) receptor cubam by engaging ARH or Dab2". Traffic 11 (5): 706–20. doi:10.1111/j.1600-0854.2010.01042.x. PMC 2964065. PMID 20088845. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2964065. 
  4. ^ Quadros EV (January 2010). "Advances in the understanding of cobalamin assimilation and metabolism". Br. J. Haematol. 148 (2): 195–204. doi:10.1111/j.1365-2141.2009.07937.x. PMC 2809139. PMID 19832808. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2809139. 
  5. ^ "Who named it --Olga Imerslund"
  6. ^ "Who named it --Armas Ralph Gustaf Gräsbeck"
  7. ^ "Who named it --Emil Najman"