Anemia, sideroblastic X-linked Health Article

Definition

X-linked sideroblastic anemia is a hereditary enzyme disorder in which the body has adequate iron but is unable to incorporate it into hemoglobin.

Description

X-linked sideroblastic anemia is the hereditary form of sideroblastic anemia, also known as iron overload anemia or sideroblastosis. Another, more common type of sideroblastic anemia is called acquired sideroblastic anemia.

In sideroblastic anemia, iron enters a developing red blood cell and is not incorporated properly into the hemoglobin molecule (the cell's oxygen carrier). This causes iron to accumulate in the mitochondria and sideroblasts. The defective hemoglobin then transports oxygen poorly, resulting in decreased tissue oxygenation.

This build–up of iron gives the cell nucleus its ringed appearance, called ringed sideroblast, which is the primary sign of siderblastic anemia.

Sideroblastic anemia is often mistaken for iron deficiency anemia, but tests usually reveal normal or increased levels of iron.

X-linked sideroblastic anemia

The hereditary form of the disorder is rare. The primary type of inherited sideroblastic anemia was first described in 1945 by Thomas Cooley. He identified cases of X-linked sideroblastic anemia in two brothers from a family with a six-generational history of the inherited disease. The genetic abnormality that causes X-linked sideroblastic anemia was identified almost 40 years later. Identification has aided diagnosis of this disorder.

X-linked sideroblastic anemia nearly always mani fests in infancy or childhood.

Other inherited forms of sideroblastic anemia

There are other inherited forms of sideroblastic anemia, which are also rare. A rare autosomal recessive form of inherited sideroblastic anemia occurs in both males and females of affected families. Autosomal dominant inheritance has also been reported. The abnormalities that cause these anemias are not yet identified. Also, Pearson's syndrome, an inherited disorder caused by abnormal mitochondria, is sometimes called sideroblastic anemia with marrow cell vacuolization and exocrine pancreatic dysfunction.

Acquired sideroblastic anemia

Acquired sideroblastic anemia often results from prolonged exposure to toxins (such as alcohol, lead, or drugs), or nutritional imbalances (such as deficiency in folic acid or copper or excess in zinc). Other causes may be inflammatory disease, cancerous conditions, or kidney, endocrine, or metabolic disorders. Acquired sideroblastic anemia sometimes surfaces in the context of a myelodysplastic syndrome.

Removal of the toxin or treatment of the underlying disease will reverse this type of sideroblastic anemia.

Acquired anemia is usually seen in patients over 65, particularly in those cases associated with myelodysplasia. The disorder can appear as early as the mid-fifties.

Genetic profile

Hereditary sideroblastic anemia is most commonly inherited as an X-linked recessive trait.

Typical X-linked genetics

The following concepts are important to understanding the inheritance of an X-linked disorder. All humans have two chromosomes that determine their gender: females have XX, males have XY. X-linked recessive, also called sex-linked, inheritance affects the genes located on the X chromosome. It occurs when an unaffected mother carries a disease-causing gene on at least one of her X chromosomes. Because females have two X chromosomes, they are usually unaffected carriers. The X chromosome that does not have the disease-causing gene compensates for the X chromosome that does. For a woman to show symptoms of the disorder, both X chromosomes would need to have the disease-causing gene. That is why women are less likely to show such symptoms than males.

If a mother has a female child, the child has a 50% chance of inheriting the disease gene and being a carrier who can pass the disease gene on to her sons. On the other hand, if a mother has a male child who inherits the disease-causing gene, he will be affected and has a 100% chance of passing the disease gene on to his children. Since the gene is defective and in the XY state there is no normal gene, the singular flawed gene is expressed.

Genetics of X-linked sideroblastic anemia

The genetic abnormality that causes X-linked sideroblastic anemia is a mutation in the erythroid (red blood cell) specific form of delta-aminolevulinate synthase (ALAS2). ALAS2 is the first enzyme in the heme biosynthetic pathway and the mutation, when present, results in the inability to transport the heme (iron) into the hemoglobin, making it ineffective.

The ability to test for this genetic disorder has improved diagnosis.

Demographics

X-linked sideroblastic anemia occurs in young men. It may be seen in maternal uncles and male cousins of men with the disorder.

Autosomal transmitted forms of the disease may occur in both men and women.

Hereditary sideroblastic anemia generally occurs during the first three decades of life especially during adolescence, but it has been diagnosed in patients over 70 years old.