What are the other Names for this Condition? (Also known as/Symptoms)

• Defect of Enterocyte Intrinsic Factor Receptor
• Juvenile Pernicious Anemia with Proteinuria due to Selective Intestinal Malabsorption of Vitamin B12
• Selective Cobalamin Malabsorption with Proteinuria

What is Imerslund-Gräsbeck Syndrome? (Definition/Background Information)

• Imerslund-Gräsbeck Syndrome (IGS) is a rare genetic disorder, in which the body’s ability to absorb vitamin B12 (cobalamin) is compromised
• Vitamin B12 cannot be made by the body and can only be obtained from the food one eats. This vitamin is essential for the formation of red blood cells, and for the proper functioning of the brain and spinal cord
• Imerslund-Gräsbeck Syndrome was first described in Norway and Finland in a few families. The age of onset of IGS can range from early infancy to childhood
• It is a genetic disorder, and therefore, a family history of Imerslund-Gräsbeck Syndrome is a major risk factor for being diagnosed the disorder. IGS is inherited in an autosomal recessive manner
• The disorder is caused by a mutation in either the AMN or CUBN genes, which code for amnionless or cubilin proteins, respectively. The proteins are components of vitamin B12-intrinsic factor complex in the intestinal cells, known as enterocytes, as well as the receptor complex for protein reabsorption from urine
• When either amnionless or cubilin protein is aberrant in the complex, the B12 vitamin in the intestines and the protein absorption from primary urine are both dysfunctional. This leads to the symptoms of Imerslund-Gräsbeck Syndrome
• Since vitamin B12 cannot be made by the body and can only be procured from food, its inefficient absorption leads to symptoms including megaloblastic anemia, neurological issues including numbness and tingling sensations in hands and feet, confusion, low muscle tone, and a delay in achieving developmental milestones
• About 50% of the affected individuals have proteinuria, which is the presence of protein in urine. If Imerslund-Gräsbeck Syndrome is left untreated, it can lead to brain damage and the neurological symptoms may become permanent
• Intramuscular injection of cobalamin is the treatment method for combating the condition. Tests are again conducted after beginning the injections to ensure that the deficiency has been corrected. However, the injections have to be continued lifelong in order for an affected individual to lead a normal life
• Since Imerslund-Gräsbeck Syndrome has a genetic basis, there are currently no methods or guidelines available for preventing the disorder. Prospective parents with a family history of the disorder may benefit from getting genetically tested and seeking genetic counselling
• With sustained treatment, the prognosis of Imerslund-Gräsbeck Syndrome is excellent. However, proteinuria continues to be present in the affected individuals; but, it does not worsen and there is no kidney damage reported

Who gets Imerslund-Gräsbeck Syndrome? (Age and Sex Distribution)

• Imerslund-Gräsbeck Syndrome is a rare genetic condition first described in Norway and Finland. In these countries, the estimated incidence rate is 1:200,000
• So far, approximately 300 cases have been reported in the scientific literature; but, the majority of new cases are from Eastern Mediterranean countries. The exact prevalence of the disorder in these countries is not yet known
• The age of onset of IGS can range from early infancy (4 months after birth) to early childhood
• Both male and female genders can be affected

What are the Risk Factors for Imerslund-Gräsbeck Syndrome? (Predisposing Factors)

The risk factors for Imerslund-Gräsbeck Syndrome include:

• Having a family history of IGS
• Being of Finnish and Norwegian descent, or belonging to the Eastern Mediterranean region

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases ones chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Imerslund-Gräsbeck Syndrome? (Etiology)

Imerslund-Gräsbeck Syndrome is caused by mutations in the AMN or CUBN gene, located on chromosomes 10 and 14, respectively. The condition is inherited in an autosomal recessive manner.

• Under normal circumstances,
  • The AMN gene codes for amnionless protein. This protein is membrane-bound and is located in the cells of the kidneys and the lining of the small intestine
  • The CUBN gene codes for cubilin protein, which binds to vitamin B12 in the intestinal cells
  • The amnionless and cubilin proteins are key components of vitamin B12-intrinsic factor complex in the enterocytes of small intestine, and the receptor complex for protein reabsorption from primary urine
  • The cubilin protein binds to vitamin B12 released from digested food, as it passes in the intestine. The binding of amnionless protein to cubulin enables the transport of vitamin B12 into the cell. By a similar mechanism, the amnionless-cubulin complex also brings about protein reabsorption from the primary urine in the kidneys
• When either AMN or CUBN gene is mutated, the absorption of vitamin B12 in the intestine and reabsorption of protein in the kidneys is impaired, leading to the symptoms of Imerslund-Gräsbeck Syndrome

Autosomal recessive: Autosomal recessive conditions are traits or disorders that occur when two copies of an abnormal gene have been inherited on a non-sex chromosome. If both parents have an autosomal recessive condition, there is a 100% likelihood of passing on the mutated genes to their children. If, however, only one mutant copy of the gene is inherited, the individual will be a carrier of the condition, but will not be present with any symptoms. Children, born to two carriers, have a 25% chance of being homozygous dominant (unaffected), a 50% chance of being heterozygous (carrier), and a 25% chance of being homozygous recessive (affected). 

What are the Signs and Symptoms of Imerslund-Gräsbeck Syndrome?

The common signs and symptoms of Imerslund-Gräsbeck Syndrome include:

• Megaloblastic anemia that results in the presence of large, abnormal red blood cells
• Pale appearance
• Difficulty gaining weight
• Fatigue
• Feeling of numbness or tingling in extremities
• Low or weak muscle tone
• Lack of coordination, confusion
• Vulnerability to infections
• Protein in the urine or proteinuria (observed in approximately 50% of the affected individuals)
• Rarely, structural defects in the urinary tract may be observed

How is Imerslund-Gräsbeck Syndrome Diagnosed?

Imerslund-Gräsbeck Syndrome may be diagnosed by the following tests and exams:

• Complete physical examination and assessment of symptoms
• An evaluation of one’s family medical history
• Blood test to check numbers of different blood cell types, vitamin B12 deficiency
• Examination of blood to check for large, abnormal red blood cells (megaloblasts)
• Bone marrow analysis
• Vitamin B12 absorption tests
• Exclusionary tests for other deficiencies (such as folic acid)
• Molecular genetic testing for mutational analysis of AMN and CUBN genes

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Imerslund-Gräsbeck Syndrome?

Some potential complications of Imerslund-Gräsbeck Syndrome include:

• The neurological symptoms may become permanent
• Brain injury/damage

How is Imerslund-Gräsbeck Syndrome Treated?

• Imerslund-Gräsbeck Syndrome is treated and managed by administering vitamin B12 injections
• Following diagnosis, IGS is initially treated with cobalamin injection (given intramuscularly) for a period of about 10 days
• This is followed by vitamin B12 injections every month for the entire duration of the affected individual’s life
• Symptomatic treatment to manage the signs and symptoms may be provided, as necessary

How can Imerslund-Gräsbeck Syndrome be Prevented?

Imerslund-Gräsbeck Syndrome is a genetic condition, and currently, no preventive methods or guidelines exist. However, the following may help with the understanding and management of this disorder:

• Genetic testing of the expecting parents (and related family members) and prenatal diagnosis (molecular testing of the fetus during pregnancy) may help in understanding the risks better during pregnancy
• If there is a family history of the condition, then genetic counseling will help assess risks, before planning for a child
• Active research is currently being performed to explore the possibilities for treatment and prevention of inherited and acquired genetic disorders such as Imerslund-Gräsbeck Syndrome

Regular medical screening at periodic intervals with tests and physical examinations are highly recommended.

What is the Prognosis of Imerslund-Gräsbeck Syndrome? (Outcomes/Resolutions)

• The prognosis of Imerslund-Gräsbeck Syndrome is excellent, with early diagnosis as well as with prompt and sustained treatment
• In the absence of treatment, severe and permanent neurological symptoms may develop
• Even with vitamin B12 sufficiency after treatment, the symptoms of proteinuria may persist. However, these symptoms generally do not worsen or cause any kidney damage

Additional and Relevant Useful Information for Imerslund-Gräsbeck Syndrome:

Imerslund-Gräsbeck Syndrome has been variously described as ‘Juvenile Pernicious Anemia with Proteinuria due to Selective Intestinal Malabsorption of Vitamin B12’ and ‘Defect of Enterocyte Intrinsic Factor Receptor’.