Anemia, sideroblastic X-linked

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 sideroblastic 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 manifests 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 myelo-dysplasia. The disorder can appear as early as the midfifties.

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 side-roblastic 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.

Signs and symptoms

General weakness, fatigue, dizziness, and difficulty breathing are associated with the disorder. Exertion may cause chest pains similar to angina.

The mucous membranes and skin of hands and arms may be pale, possibly with a lemon-yellow cast. Subcutaneous bleeding may occur, causing a brownish-red effect.

Excess iron accumulation, known as hemochromatosis , accumulates over years in the bone marrow, liver, heart, and other tissues. This progressive deposition of toxic iron may result in an enlarged spleen or liver, liver disease, diabetes , impotence, arthritic signs, and heart disease, particularly cardiac arrhythmia.

Diagnosis

Using Prussian blue staining, sideroblasts are visible under microscopic examination of bone marrow.

A blood test can indicate sideroblastic anemia. Indicative laboratory results of an iron panel test include:

• High levels for serum iron, serum ferritin, and transferrin iron saturation percentage.
• Low levels for total iron binding capacity and transferrin.
• Normal to high levels for serum transferrin receptor.

Additionally, other signs of sideroblastic anemia include:

• Hemoglobin is generally less than 10.0g/dL.
• Hypochromic (reduced color) cells coexist with normal cells.
• Stainable marrow and hemosiderin is increased.
• Ringed sideroblasts are visible with Prussian blue staining and observable under microscopic examination of bone marrow.
• Red cell distribution width is increased.
• White blood cells and platelets are normal.

Treatment and management

The main objective in treatment of X-linked sideroblastic anemia is to prevent the development of diabetes, cirrhosis, and heart failure from iron overload (hemochromatosis).

X-linked sideroblastic anemia often improves with pyridoxine (vitamin B6) therapy. Dosage is 50–200 mg, however, pregnant or nursing mothers may wish to limit intake to 100 mg daily.

In cases of extreme anemia, whole red blood cell transfusion may be required. Repeated whole red blood cell transfusion, however, will contribute significantly to existing iron burden in sideroblastic anemia patients. It will likely require chelation therapy with desferrioxamine (Desferal), a drug with iron chelating properties. Desferrioxamine binds excess body iron and promotes excretion by the liver and kidneys. It is administered by intravenous infusion from a small portable pump. The pump is worn nine to twelve hours daily, usually at night while sleeping. Side effects vary and include pain and swelling at injection site.

Certain drugs are sometimes associated with acquired sideroblastic anemia: progesterone (found in oral contraceptives and hormone replacement therapy); copper chelating drugs like trientine, which is used in treating Wilson disease ; and anti-tuberculosis drugs like isoniazid (a type of antibiotic), among others. In other cases, acquired sideroblastic anemia may be secondary to another disorder or disease. Other predisposing causes may be inflammatory disease such as rheumatoid arthritis , cancerous conditions such as leukemia and lymphoma, kidney disorders causing uremia, endocrine disorders such as hyperthyroidism, and metabolic disorders such as porphyria cutanea tarda. In these cases, it is important to treat the primary disease or disorder in order to reverse the anemia.

Development of leukemia is associated with the acquired form of the disease, often first showing up in the form of a myeloproliferative disorder. These disorders are characterized by abnormal growth of bone tissue and related cells.

Prognosis

The disorder can often be kept in check with regular medical supervision. Many individuals with X-linked sideroblastic anemia require chronic transfusion to maintain acceptable hemoglobin levels. Over a lifetime, problems related to iron overload, including congestive heart failure and cirrhosis, can become life-threatening issues.

Death can result from hemochromatosis (iron-over-load) if the disease is untreated or if blood transfusions are inadequate to account for the iron overload.

Resources

BOOKS

Current Medical Diagnosis & Treatment. Edited by Tierney, Lawrence M., Jr., et al. Stamford, CT: Appleton & Lange, 1998.

PERIODICALS

Sheth, Sujit, and Gary M. Brittenham. "Genetic disorders affecting proteins of iron metabolism: Clinical implications." Annual Review of Medicine 51 (2000): 443+.

ORGANIZATIONS

Leukemia & Lymphoma Society. 1311 Mamaroneck Ave., White Plains, NY 10605. (914) 949-5213. <http://www.leukemia-lymphoma.org>.

National Heart, Lung, and Blood Institute. PO Box 30105, Bethesda, MD 20824-0105. (301) 592-8573. nhlbiinfo@rover.nhlbi.nih.gov. <http://www.nhlbi.nih.gov>.

National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.

WEBSITES

Iron Disorders Institute. <http://www.irondisorders.org>.

National Center for Biotechnology Information. <http://www.ncbi.nlm.nih.gov>.

Jennifer F. Wilson, MS