Division of Genetics: Hemoglobinopathies 2,3,4, URMC

Hemoglobinopathies^2,3,4

Hemoglobinopathies are inherited disorders of hemoglobin and could involve either the heme or globin part of the molecule.

The most common hemoglobinopathies include the sickling disorders resulting from structural changes in the globin gene, and the thalassemias, resulting from the reduced rate of production of one or more globin chains.

An individual with one normal globin gene and one globin variant gene is referred to as being a carrier or having a trait. Trait individuals are asymptomatic. For example: An individual with one gene for normal hemoglobin (HbA) and one gene for sickle hemoglobin (HbS) will have sickle cell trait.(AS)

Sickle cell trait is rarely associated with any clinical abnormality.⁵

Hemoglobin Variants

There are over 400 structural variants of normal hemoglobin. The 4 most common structural variants (all chain variants) are:

Sickle hemoglobin - the first variant to be discovered (1949)¹. Its main reservoir is Central Africa where the carrier rate approximates 20%. Approximately 8% of African-Americans will carry one sickle gene. Persons from Mediterranean countries, the Middle East or East India less frequently carry the gene.

Hemoglobin E - a variant hemoglobin commonly found in people from Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. It is also seen in people from southern China, the Philippines, India and Turkey.

Hemoglobin C - concentrated in Western Africa. It occurs in approximately 2% of African Americans.

Hemoglobin D - common in Pakistan and North West India. It is also found occasionally found in Europeans, especially among the British and Irish.

Other chain variants not as widely seen as the common variants are hemoglobin O Arab and hemoglobin Lepore (a delta fusion chain).

Variations in the alpha chain are relatively uncommon. Two variants occasionally seen are hemoglobin G_Philadelphia, found in African-Americans, and hemoglobin J_Tongariki, found in Melanesians.

The Sickling Disorders

Sickle cell anemia (SS) results from the homozygous state for the sickle gene while sickle cell disease includes also those disorders which result from the compound heterozygous state for the sickle gene and other -globin chain variants such as hemoglobins C, D, E, or thalassemia.

Hemoglobin S differs from hemoglobin A by the substitution of a valine for glutamic acid at position 6 of the globin chain. This substitution leads to polymerization in concentrated hemoglobin solutions that are partially or fully deoxygenated. The polymerized chains form intracellular fibers that deform the cell. The deformed cells occlude the microcirculation.

Clinical manifestations of the disease include anemia and acute and chronic tissue injury. Complications include painful crisis involving soft tissues and bones, acute chest syndrome, priapism, cerebral vascular accidents and both splenic and renal dysfunction. The most serious infections and complications in infants with sickle cell disease are pneumococcal sepsis and meningitis. The landmark study by Gaston⁶ et al. demonstrated the value of oral penicillin in preventing these infections in children. The results were so striking that the trial was terminated eight months before its planned ending date. It is now recommended that infants born with sickle cell disease should be placed on oral prophylactic penicillin at 2 months of age.

Patients with sickle cell disease can be referred to the Sickle Cell Clinic at Strong Memorial Hospital in Rochester NY. The clinic is a specialized service designed to assist the primary care provider with periodic assessments and ancillary services.

The Thalassemias

The thalassemias, the most common genetic disorder in the world, are inherited disorders of hemoglobin synthesis characterized by the absence or reduced amount of one or more of the globin chains of hemoglobin. The most common forms are alpha

-, - and

-thalassemia. There are two alpha

globin loci and therefore 4 variations of alpha

-thalassemia due to deletions of one, two, three or four of the alpha genes. The clinical picture of alpha

-thalassemia ranges from asymptomatic for the 1- and 2-gene deletion types, to moderate to severe anemia for the 3-gene deletion type also known as Hemoglobin H disease, to the fatal hydrops fetalis for the 4-gene deletion type.

Of the >125 point mutations causing -thalassemia, about 15 account for the vast majority of affected patients.⁷

An individual with one normal globin gene and one -thalassemia gene has -thalassemia trait, (-thalassemia minor, -thalassemia carrier). Trait individuals may have a mild anemia. The mean corpuscular volume (MCV) in -thalassemia trait is usually below 78 fl and the mean hemoglobin level is 9-16 g/100ml in males and 8-13 g/100ml in females. The red blood cells on a stained blood smear may contain numerous black dots (basophilic stippling.)²

An individual with two -thalassemia genes has -thalassemia major (Cooley's anemia, Mediterranean anemia).

Infants born with thalassemia major usually present with severe anemia during the first two years of life during which time fetal hemoglobin production declines and adult hemoglobin fails to rise normally. With frequent transfusions to maintain a hemoglobin level above 11g/dl, normal growth and development can occur. Accumulation of iron from transfusion however must be controlled by chelation therapy. Progressive splenomegaly occurs in both alpha - and -thalassemia. Splenectomy is often necessary.

Structural Hemoglobin Variants and Thalassemia

The coinheritance of a gene for a hemoglobin structural variant and a thalassemia gene generates a wide spectrum of clinical disorders, which can range in clinical severity from severe (e.g. hemoglobin E/-thalassemia) to asymptomatic (e.g. hemoglobin C/-thalassemia).

Links to other Sites

Cooley's Anemia Foundation
Thalassemia: Children's Hospital Oakland CA
Joint Center for Sickle Cell and Thalassemic Disorders.-Brigham and Women's Hospital and the Massachusetts General Hospital
The Sickle Information Center at Emory University.

References

¹ Pauling L., Itano HA, Singer SJ, Wells JG: Sickle-cell anemia, a molecular disease. Science 110:543, 1949.
² Huntsman RG, Sickle-Cell Anemia and Thalassemia, St. John's, Newfoundland, Canada. The Canadian Sickle Cell Society. 1987
³ Scriver, Charles R. et al. The Metabolic Basis of Inherited Disease. New York, McGraw Hill, 1995.
⁴ Weatherall DJ and Clegg JB. The Thalassemia Syndromes. Third Edition. Oxford, Blackwell Scientific Publications, 1981
⁵ Heller P, Proc First Natl Symposium on Sickle Cell Disease, Dept HEW Pub No. 75-723 (NIH) Bethesda MD 1974
⁶ Gaston MH, Verter JL, Woods G. et al. N Engl J Med 1986;314:1593-9
⁷ Hoffman R. et al. Hemotology Basic Principles and Practice, New York, Churchill Livingston Inc. 1995

Comments/Suggestions to: Mary_True@urmc.rochester.edu

Hemoglobinopathies2,3,4