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Description
X-linked sideroblastic anemia belongs to a group of disorders that are characterized by a shortage of healthy red blood cells (anemia). X-linked sideroblastic anemia prevents developing red blood cells from making enough hemoglobin
, which is the protein that carries oxygen in the blood. People with X-linked sideroblastic anemia have red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin. This disorder also leads to an abnormal accumulation of iron in red blood cells. The iron-loaded red blood cells, which are present in bone marrow, are called ring sideroblasts.
The signs and symptoms of X-linked sideroblastic anemia are caused by a combination of too little hemoglobin and too much iron. Common signs and symptoms include extreme tiredness (fatigue), dizziness, a rapid heartbeat, pale skin, and an enlarged liver and spleen (hepatosplenomegaly). Over time, severe health problems such as heart disease and liver damage (cirrhosis), can result from the buildup of iron in these organs.
Males with X-linked sideroblastic anemia typically have the classic signs and symptoms of the condition, while females tend to be less severely affected. Females with X-linked sideroblastic anemia usually develop features of the condition in mid to late adulthood, while affected males often first experience symptoms in adolescence to early adulthood.
Frequency
X-linked sideroblastic anemia is a rare form of anemia, and its exact prevalence is unknown. Hundreds of families with this condition have been described in the scientific literature.
Causes
Variants (also called mutations) in the ALAS2 gene cause X-linked sideroblastic anemia. The ALAS2 gene provides instructions for making an enzyme called 5-aminolevulinate synthase. This enzyme is active in the bone marrow, where it plays a critical role in the production of heme
(a component of hemoglobin).
ALAS2 gene variants lead to the production of a 5-aminolevulinate synthase enzyme that does not function properly. As a result, normal heme production is disrupted and red blood cells cannot make enough hemoglobin. Because most of the iron in red blood cells is normally used for heme, reduced heme production causes a buildup of iron
in these cells. The body compensates by absorbing more iron from the diet, which leads to an accumulation of iron in the body's organs. Low hemoglobin levels and iron accumulation lead to the characteristic features of X-linked sideroblastic anemia.
Inheritance
X-linked sideroblastic anemia is inherited in an X-linked pattern. A condition is considered X-linked if the altered gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes
in each cell. Males have only one X chromosome in each cell, and females have two. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.
Females with one altered copy of the ALAS2 gene in each cell may have mild features of the condition, or they may have no related signs or symptoms. However, some females with one altered copy of this gene have signs and symptoms of X-linked sideroblastic anemia that are similar to those seen in affected males. In these cases, the affected females may have the X chromosome with the normal copy of the ALAS2 gene turned off through a process called X-inactivation.
Early in embryonic development in females, one of the two X chromosomes is permanently inactivated in somatic cells, which are cells other than egg and sperm cells. X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each somatic cell. Usually, X-inactivation occurs randomly, so that each X chromosome is active in about half of the body's cells. Sometimes, X-inactivation is not random, and one X chromosome is active in more than half of cells. When X-inactivation does not occur randomly, it is called skewed X-inactivation.
In people with X-linked sideroblastic anemia, X-inactivation can be skewed. In females who develop signs and symptoms, the X chromosome with the normal copy of the ALAS2 may be turned off, especially in red blood cells. Skewed X-inactivation tends to increase with age. As a result, affected females produce less 5-aminolevulinate synthase over time and typically develop signs and symptoms of X-linked sideroblastic anemia later in life.
Other Names for This Condition
- ANH1
- X-linked pyridoxine-responsive sideroblastic anemia
- XLSA
Additional Information & Resources
Genetic Testing Information
Genetic and Rare Diseases Information Center
Patient Support and Advocacy Resources
Catalog of Genes and Diseases from OMIM
Scientific Articles on PubMed
References
- Ducamp S, Campagna DR, Sendamarai AK, Schmidt PJ, Tsai HK, Heeney MM, Bottomley SS, Fleming MD. X-linked sideroblastic anemia in females. Blood. 2025 Apr 3;145(14):1583-1587. doi: 10.1182/blood.2024024475. Citation on PubMed
- Fujiwara T, Harigae H. Molecular pathophysiology and genetic mutations in congenital sideroblastic anemia. Free Radic Biol Med. 2019 Mar;133:179-185. doi: 10.1016/j.freeradbiomed.2018.08.008. Epub 2018 Aug 8. Citation on PubMed
- Jove-Solavera D, Ramila M, Ferrer-Cortes X, Olivella M, Venturi V, Morado M, Hernandez-Rodriguez I, Khan A, Perez-Montero S, Tornador C, Germing U, Gattermann N, Sanchez M. The role of genetic testing in accurate diagnosis of X-linked sideroblastic anemia: novel ALAS2 mutations and the impact of X-chromosome inactivation. Sci Rep. 2025 Apr 7;15(1):11843. doi: 10.1038/s41598-025-95590-x. Citation on PubMed
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