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Description
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 (failure to thrive), 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.
Frequency
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.
Causes
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
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.
Other Names for This Condition
- Enterocyte cobalamin malabsorption
- Gräsbeck-imerslund disease
- Imerslund's syndrome
- Imerslund-Grasbeck anemia
- Imerslund-grasbeck disease
- Imerslund-najman-grasbeck syndrome
- Juvenile pernicious anemia with proteinuria due to selective intestinal malabsorption of vitamin B12
- Selective cobalamin malabsorption with proteinuria
Additional Information & Resources
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
- Grasbeck R. Imerslund-Grasbeck syndrome (selective vitamin B(12) malabsorption with proteinuria). Orphanet J Rare Dis. 2006 May 19;1:17. doi: 10.1186/1750-1172-1-17. Citation on PubMed or Free article on PubMed Central
- Kingma SDK, Neven J, Bael A, Meuwissen MEC, van den Akker M. Imerslund-Grasbeck syndrome: a comprehensive review of reported cases. Orphanet J Rare Dis. 2023 Sep 14;18(1):291. doi: 10.1186/s13023-023-02889-x. Citation on PubMed
- Kozyraki R, Cases O. Vitamin B12 absorption: mammalian physiology and acquired and inherited disorders. Biochimie. 2013 May;95(5):1002-7. doi: 10.1016/j.biochi.2012.11.004. Epub 2012 Nov 20. Citation on PubMed
- Kristiansen M, Aminoff M, Jacobsen C, de La Chapelle A, Krahe R, Verroust PJ, Moestrup SK. Cubilin P1297L mutation associated with hereditary megaloblastic anemia 1 causes impaired recognition of intrinsic factor-vitamin B(12) by cubilin. Blood. 2000 Jul 15;96(2):405-9. Citation on PubMed
- Tanner SM, Sturm AC, Baack EC, Liyanarachchi S, de la Chapelle A. Inherited cobalamin malabsorption. Mutations in three genes reveal functional and ethnic patterns. Orphanet J Rare Dis. 2012 Aug 28;7:56. doi: 10.1186/1750-1172-7-56. Citation on PubMed or Free article on PubMed Central
- Udagawa T, Harita Y, Miura K, Mitsui J, Ode KL, Morishita S, Urae S, Kanda S, Kajiho Y, Tsurumi H, Ueda HR, Tsuji S, Saito A, Oka A. Amnionless-mediated glycosylation is crucial for cell surface targeting of cubilin in renal and intestinal cells. Sci Rep. 2018 Feb 5;8(1):2351. doi: 10.1038/s41598-018-20731-4. Citation on PubMed
- Watkins D, Rosenblatt DS. Inherited defects of cobalamin metabolism. Vitam Horm. 2022;119:355-376. doi: 10.1016/bs.vh.2022.01.010. Epub 2022 Feb 21. Citation on PubMed
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