1. Structural defects in the hemoglobin molecule. Alterations in the gene for one of the two hemoglobin subunit chains, alpha (a) or beta (b), are called mutations. Often, mutations change a single amino acid building block in the subunit. Most commonly the change is innocuous, perturbing neither the structure nor function of the hemoglobin molecule. Occasionally, alteration of a single amino acid dramatically disturbs the behavior of the hemoglobin molecule and produces a disease state. Sickle hemoglobin exemplifies this phenomenon.


2. Diminished production of one of the two subunits of the hemoglobin molecule. Mutations that produce this condition are termed "thalassemias." Equal numbers of hemoglobin alpha and beta chains are necessary for normal function. Hemoglobin chain imbalance damages and destroys red cells thereby producing anemia. Although there is a dearth of the affected hemoglobin subunit, with most thalassemias the few subunits synthesized are structurally normal.


3. Abnormal associations of otherwise normal subunits. A single subunit of the alpha chain (from the a-globin locus) and a single subunit from the b-globin locus combine to produce a normal hemoglobin dimer. With severe a-thalassemia, the b-globin subunits begin to associate into groups of four (tetramers) due to the paucity of potential a-chain partners. These tetramers of b-globin subunits are functionally inactive and do not transport oxygen. No comparable tetramers of alpha globin subunits form with severe beta-thalassemia. Alpha subunits are rapidly degraded in the absence of a partner from the beta-globin gene cluster (gamma, delta, beta globin subunits).

Types of hemoglobins

Normal Hemoglobins

• Hemoglobin A. This is the designation for the normal hemoglobin that exists after birth. Hemoglobin A is a tetramer with two alpha chains and two beta chains (a₂b₂).
• Hemoglobin A2. This is a minor component of the hemoglobin found in red cells after birth and consists of two alpha chains and two delta chains (a₂d₂). Hemoglobin A2 generally comprises less than 3% of the total red cell hemoglobin.
• Hemoglobin F. Hemoglobin F is the predominant hemoglobin during fetal development. The molecule is a tetramer of two alpha chains and two gamma chains (a₂g₂).

The genes for hemoglobin F and hemoglobin A are closely related, existing in the same gene cluster on chromosome 11. Hemoglobin F production falls dramatically after birth, although some people continue to produce small amounts of hemoglobin F for their entire lives.

Clinically Significant Variant Hemoglobins

• Hemoglobin S. This the predominant hemoglobin in people with sickle cell disease. The alpha chain is normal. The disease-producing mutation exists in the beta chain, giving the molecule the structure, a₂b^S₂. People who have one sickle mutant gene and one normal beta gene have sickle cell trait which is benign.
• Hemoglobin C. Hemoglobin C results from a mutation in the beta globin gene and is the predominant hemoglobin found in people with hemoglobin C disease (a₂b^C₂). Hemoglobin C disease is relatively benign, producing a mild hemolytic anemia and splenomegaly. Hemoglobin C trait is benign.
• Hemoglobin E. This variant results from a mutation in the hemoglobin beta chain. People with hemoglobin E disease have a mild hemolytic anemia and mild splenomegaly. Hemoglobin E trait is benign. Hemoglobin E is extremely common in S.E. Asia and in some areas equals hemoglobin A in frequency.
• Hemoglobin Constant Spring. Hemoglobin Constant Spring is a variant in which a mutation in the alpha globin gene produces an alpha globin chain that is abnormally long. The quantity of hemoglobin in the cells is low for two reasons. First, the messenger RNA for hemoglobin Constant Spring is unstable. Some is degraded prior to protein synthesis. Second, the Constant Spring alpha chain protein is itself unstable. The result is a thalassemic phenotype. (The designation Constant Spring derives from the isolation of the hemoglobin variant in a family of ethnic Chinese background from the Constant Spring district of Jamaica.)
• Hemoglobin H. Hemoglobin H is a tetramer composed of four beta globin chains. Hemoglobin H occurs only with extreme limitation of alpha chain availability. Hemoglobin H forms in people with three-gene alpha thalassemia as well as in people with the combination of two-gene deletion alpha thalassemia and hemoglobin Constant Spring.
• Hemoglobin Barts. Hemoglobin Barts develops in fetuses with four-gene deletion alpha thalassemia. During normal embryonic development, the episilon gene of the alpha globin gene locus combines with genes from the beta globin locus to form functional hemoglobin molecules. The episolon gene turns off at about 12 weeks, and normally the alpha gene takes over. With four-gene deletion alpha thalassemia no alpha chain is produced. The gamma chains produced during fetal development combine to form gamma chain tetramers. These molecules transport oxygen poorly. Most individuals with four-gene deletion thalassemia and consequent hemoglobin Barts die in utero (hydrops fetalis). The abnormal hemoglobin seen during fetal development in individuals with four-gene deletion alpha thalassemia was characterized at St. Bartholomew's Hospital in London. The hospital has the fond sobriquet, St. Barts, and the hemoglobin was named "hemoglobin Barts."

Compound Heterozygous Conditions

• Hemoglobin SC disease. Patients with hemoglobin SC disease inherit a gene for hemoglobin S from one parent, and a gene for hemoglobin C from the other. Hemoglobin C interacts with hemoglobin S to produce some of the abnormalities seen in patients with sickle cell disease. On average, patients with hemoglobin SC disease have milder symptoms than do those with sickle cell disease. This is only an average, however. Some people with hemoglobin SC disease have a condition equal in severity to that of any patient with sickle cell disease. A number other syndromes exist that involve a hemoglobin S compound heterozyous state. They are less common than hemoglobin SC disease, however. Ironically, hemoglobin SC disease is often a much more severe condition than is homozygous hemoglobin C disease. The expression of a single hemoglobin S gene normally produces no problem (i.e., sickle cell trait). The hemoglobin C molecule disturbs the red cell metabolism only slightly. However, the disturbance is enough to allow the deleterious effects of the hemoglobin S to be manifested.
• Sickle/beta-thalassemia. In this condition, the patient has inherited a gene for hemoglobin S from one parent and a gene for beta-thalassemia from the other. The severity of the condition is determined to a large extent by the quantity of normal hemoglobin produced by the beta-thalassemia gene. (Thalassemia genes produce normal hemoglobin, but in variably reduced amounts). If the gene produces no normal hemoglobin, b⁰-thalassemia, the condition is virtually identical to sickle cell disease. Some patients have a gene that produces a small amount of normal hemoglobin, called b⁺-thalassemia. The severity of the condition is dampened when significant quantities of normal hemoglobin are produced by the b⁺-thalassemia gene. Sickle/beta-thalassemia is the most common sickle syndrome seen in people of Mediterranean descent (Italian, Greek, Turkish). Beta-thalassemia is quite common in this region, and the sickle cell gene occurs in some sections of these countries. Hemoglobin electrophoresis of blood from a patient with sickle/b⁰-thalassemia shows no hemoglobin A. Patients with sickle/b⁺-thalassemia have an amount of hemoglobin A that depends of the level of function of the b⁺-thalassemia gene.
• Hemoglobin E/beta-thalassemia. The combination of hemoglobin E and beta-thalassemia produces a condition more severe than is seen with either hemoglobin E trait or beta-thalassemia trait. The disorder manifests as a moderately severe thalassemia that falls into the category of thalassemia intermedia. Hemoglobin E/beta-thalassemia is most common in people of S.E. Asian background.
• Alpha thalassemia/Hemoglobin Constant Spring. This syndrome is a compound heterozygous state of the alpha globin gene cluster. The alpha globin gene cluster on one of the two chromosomes 16 has both alpha globin genes deleted. On the other chromosome 16, the alpha1 gene has the Constant Spring mutation. The compound heterozygous condition produces a severe shortage of alpha globin chains. The excess beta chains associate into tetramers to form hemoglobin H.

Thalassemia