Megaloblastic anemia syndrome Imerslund-Gräsbeck (megaloblastic anemia, Imerslund-Gräsbeck syndrome) - Genes AMN or CUBN.

Syndrome Imerslund-Gräsbeck is a disorder caused by low concentrations of vitamin B12 (cobalamin). The main feature of this disease is megaloblastic anemia. In this form of anemia, red blood cells are abnormally large. About half of those affected also have proteinuria. Although proteinuria may be an indication of kidney problems, people with the syndrome Imerslund-Grasbeck seem to have a normal renal function.

The disease usually begins in early childhood. The blood disorder results in many of the signs and symptoms of the disease, including growth retardation, pallor, fatigue and gastrointestinal infections or frequent respiratory. Other features of the syndrome include mild neurological problems, hypotonia, numbness or tingling in the hands or feet, movement problems, developmental delay, or confusion. Rarely, affected individuals have abnormalities in organs or tissues that make up the urinary tract such as the bladder or ureters.

Syndrome Imerslund-Gräsbeck is due to mutations in genes CUBN or AMN. The AMN gene, located on the long arm of chromosome 14 (14q32.3), encodes a protein called "amnionless". The CUBN gene, located on the short arm of chromosome 10 (10p12.31), encodes a protein called cubilin. Together, these proteins play a role in the absorption of vitamin B12 from food. Vitamin B12 is essential for the formation of DNA and proteins, cellular energy production, and fat breakdown. This vitamin is involved in the formation of erythrocytes and maintenance of the central nervous system.

The amnionless protein is mainly localized in the membrane of kidney cells and cells of the small intestine mucosa. During digestion, the vitamin B12 is released from food. When vitamin passes through the small intestine, cubilin joins her. The amnionless protein helps transfer complex cubilin-B12 in the intestinal cell. From there, the vitamin is released into the blood and transported throughout the body. In the kidney, and cubilin amnionless proteins are involved in the reabsorption of certain proteins that otherwise would be released into the urine.

They have identified at least 30 mutations in the gene AMN people with Imerslund-Gräsbeck syndrome. Mutations in the gene AMN cubilin keep protein adhering to the cells in the small intestine and kidneys. Without this feature, vitamin B12 is not absorbed in the body, which impairs the proper development of red blood cells, resulting in megaloblastic anemia. Low concentrations of vitamin B12 can also affect the central nervous system causing neurological problems. Moreover, without the function of cubilin kidney, proteins are not reabsorbed and instead released into the urine, resulting in proteinuria.

Meanwhile, they have identified at least 35 mutations in the gene CUBN in people with Imerslund-Gräsbeck syndrome. The most common mutation CUBN gene found in people of Finnish origin, replaces the amino acid proline in the amino acid leucine position 1297 (Pro1297Leu or P1297L). Like AMN gene mutations, mutations in the gene CUBN cubilin alter the function of both the small intestine and kidneys, leading to deficiency of vitamin B12 and proteinuria. Other mutations in the gene CUBN affect the function of cubilin only in the small intestine, impairing absorption of vitamin B12 in intestinal cells. Individuals with these mutations have a deficiency of vitamin B12, which can lead to megaloblastic anemia and neurological problems, but no proteinuria.

This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with syndrome Imerslund-Gräsbeck, by complete PCR amplification of the exons of AMN and CUBN genes, respectively, and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).