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Hemoglobin Abnormalities

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Also known as: Hemoglobinopathy; Hemoglobin Variants; Hemoglobin S; Sickle Cell Disease; Hemoglobin C Disease; Hemoglobin E Disease; Thalassemia; Hemoglobin Barts; Hereditary Persistence of Fetal Hemoglobin; HPFH

What is a hemoglobin abnormality?

A hemoglobin abnormality is a variant form of hemoglobin that is often inherited and may cause a blood disorder (hemoglobinopathy).

Hemoglobin is the iron-containing protein compound within red blood cells that carries oxygen throughout the body. It is made up of heme, which is the iron-containing portion, and globin chains, which are proteins. The globin protein consists of chains of amino acids, the "building blocks" of proteins. There are several different types of globin chains, named alpha, beta, delta, and gamma. Normal hemoglobin types include:

  • Hemoglobin A (Hb A): makes up about 95%-98% of hemoglobin found in adults; it contains two alpha (α) chains and two beta (β) protein chains.
  • Hemoglobin A2 (Hb A2 ): makes up about 2%-3% of hemoglobin found in adults; it has two alpha (α) and two delta (δ) protein chains.
  • Hemoglobin F (Hb F, fetal hemoglobin): makes up to 1%-2% of hemoglobin found in adults; it has two alpha (α) and two gamma (γ) protein chains. It is the primary hemoglobin produced by the fetus during pregnancy; its production usually falls shortly after birth and reaches adult level within 1-2 years.

Genetic changes (mutations) in the globin genes cause alterations in the globin protein, resulting in structurally altered hemoglobin, such as hemoglobin S, which causes sickle cell, or a decrease in globin chain production (thalassemia). In thalassemia, the reduced production of one of the globin chains upsets the balance of alpha to beta chains and causes abnormal hemoglobin to form (alpha thalassemia) or causes an increase of minor hemoglobin components, such as Hb A2 or Hb F (beta thalassemia).

Four genes code for the alpha globin chains, and two genes (each) code for the beta, delta, and gamma globin chains. (For general information on genetic testing, see The Universe of Genetic Testing.) Mutations may occur in either the alpha or beta globin genes. The most common alpha-chain-related condition is alpha thalassemia. The severity of this condition depends on the number of genes affected. (See Thalassemia for more information.)

Mutations in the beta gene are mostly inherited in an autosomal recessive fashion. This means that the person must have two altered gene copies, one from each parent, to have a hemoglobin variant-related disease. If one normal beta gene and one abnormal beta gene are inherited, the person is heterozygous for the abnormal hemoglobin, known as a carrier. The abnormal gene can be passed on to any children, but it generally does not cause symptoms or significant health concerns in the carrier.

If two abnormal beta genes of the same type are inherited, the person is homozygous. The person would produce the associated hemoglobin variant and may have some associated symptoms and potential for complications. The severity of the condition depends on the genetic mutation and varies from person to person. A copy of the abnormal beta gene would be passed on to any children.

If two abnormal beta genes of different types are inherited, the person is "doubly heterozygous" or "compound heterozygous." The affected person would typically have symptoms related to one or both of the hemoglobin variants that he or she produces. One of the abnormal beta genes would be passed on to children.

Red blood cells containing abnormal hemoglobin may not carry oxygen efficiently and may be broken down by the body sooner than usual (a shortened survival), resulting in hemolytic anemia. Several hundred hemoglobin variants have been documented, but only a few are common and clinically significant. Some of the most common hemoglobin variants include hemoglobin S, the primary hemoglobin in people with sickle cell disease that causes the red blood cell to become misshapen (sickle), decreasing the cell's survival; hemoglobin C, which can cause a minor amount of hemolytic anemia; and hemoglobin E, which may cause no symptoms or generally mild symptoms.

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