Imerslund-Gräsbeck syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Imerslund-Gräsbeck syndrome is an inherited condition that is characterized by problems with the body's ability to take in (absorb) vitamin B12 (also called cobalamin). Most people with Imerslund-Gräsbeck syndrome have a blood disorder called megaloblastic anemia, which occurs when a person has a low number of red blood cells (anemia) and the remaining red blood cells are larger than normal (megaloblastic). Many people with Imerslund-Gräsbeck syndrome have a high level of protein in the urine (proteinuria), but this is less common in affected individuals from Finland. Although proteinuria can be an indication of kidney problems, people with Imerslund-Gräsbeck syndrome typically have normal kidney function.

The signs and symptoms of Imerslund-Gräsbeck syndrome usually begin in early childhood. Megaloblastic anemia leads to many of these signs and symptoms, including an inability to grow and gain weight at the expected rate (faltering weight), pale skin (pallor), and fatigue. Additional signs and symptoms can include mouth ulcers and gastrointestinal problems, such as vomiting and diarrhea. Affected individuals may also have recurring respiratory infections.

Imerslund-Gräsbeck syndrome can also cause neurological problems, such as a lack of energy (lethargy); weak muscle tone (hypotonia); developmental delays; problems with movement and balance (ataxia); or abnormal sensations, such as numbness or tingling in the hands and feet. Some affected individuals have more severe neurological signs and symptoms, such as seizures or a decline in intellectual abilities.

Abnormalities of the organs or tissues that make up the urinary tract have been reported in some individuals with Imerslund-Gräsbeck syndrome, but the cause of these problems is not well understood.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Changes in the AMN or CUBN gene cause Imerslund-Gräsbeck syndrome. Genetic changes that cause disease are called pathogenic variants. The AMN gene provides instructions for making a protein called amnionless, and the CUBN gene provides instructions for making a protein called cubilin. Together, these proteins help the body absorb vitamin B12 from food, which is especially important since the body cannot make this vitamin. Vitamin B12 is essential for the formation of DNA and for the chemical reactions that are involved in converting food into energy (energy metabolism). Vitamin B12 also plays a key role in making red blood cells and maintaining the nerve cells in the brain and spinal cord (central nervous system).

Amnionless and cubilin form a complex called the cubam receptor, which helps the body absorb vitamin B12 in the intestines. Within the small intestine, amnionless anchors cubilin to the cell membrane, which allows cubilin to interact with vitamin B12. During digestion, vitamin B12 and another protein called intrinsic factor bind to cubilin as they pass through the small intestine. Amnionless helps transfer this whole complex into the intestinal cells. Vitamin B12 is then released into the blood and travels throughout the body. In the kidneys, amnionless and cubilin are involved in returning proteins to the bloodstream (reabsorption) that would otherwise be released in the urine.

Many of the pathogenic variants in the AMN or CUBN genes lead to changes in the amnionless and cubilin proteins that prevent these proteins from reaching the cell membrane. This impairs the absorption of vitamin B12 from the intestine, which disrupts red blood cell development and leads to megalobalastic anemia. Low levels of vitamin B12 can also affect the central nervous system, which causes neurological problems. In the kidneys, these changes can disrupt the reabsorption of proteins, which leads to proteinuria.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a pathogenic variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Imerslund-Gräsbeck syndrome is a rare condition. It affects approximately 6 in 1 million individuals. More than 300 affected individuals have been described in the scientific literature. Imerslund-Gräsbeck syndrome is more common in Finland, Norway, and certain Mediterranean and Middle Eastern countries.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Abnormal blood 5-methyltetrahydrofolate level · Obligate (100%)

An abnormal concentration of 5-methyltetrahydrofolate (5-MTHF) in the blood.

Decreased circulating vitamin B12 concentration · Obligate (100%)

The concentration of vitamin B12 in the blood circulation is below the lower limit of normal.

Hypersegmentation of neutrophil nuclei · Very frequent (99-80%)

An excessive division of the lobes of the nucleus of a neutrophil.

Macrocytic anemia · Very frequent (99-80%)

A type of anemia characterized by increased size of erythrocytes with increased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin (MCH).

Megaloblastic anemia · Very frequent (99-80%)

Anemia characterized by the presence of erythroblasts that are larger than normal (megaloblasts).

Malabsorption of Vitamin B12 · Obligate (100%)

Abnormal hemoglobin concentration · Frequent (79-30%)

Any deviation from the normal concentration of hemoglobin in the blood.

Anisopoikilocytosis · Frequent (79-30%)

A type of poikilocytosis characterized by the presence in the blood of erythrocytes of varying sizes and abnormal shapes.

Other findings in the same source

From: Orphanet

Additional reported features include Decreased total neutrophil count (Frequent (79-30%)); Oval macrocytosis (Frequent (79-30%)); Pallor (Frequent (79-30%)); Proteinuria (Frequent (79-30%)); Reticulocytosis (Frequent (79-30%)); Abnormal bleeding (Occasional (29-5%)); Abnormality of the nervous system (Occasional (29-5%)); Angular cheilitis (Occasional (29-5%)); Constipation (Occasional (29-5%)); Delayed ability to walk (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Imerslund-Gräsbeck syndrome is Haematology, with a haematologist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Which blood-cell, marrow, bleeding or clotting finding matters most?
• Does the diagnosis need confirmation or a more precise subtype?
• Which symptoms or laboratory changes should trigger earlier review?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Imerslund-Gräsbeck syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.