Thalassemia includes a number of different forms of anemia (red blood cell deficiency). The two main types are called alpha and beta thalassemias, depending on which part of an oxygen-carrying protein (called hemoglobin) is lacking in the red blood cells. Humans normally have 4 functional alpha globin genes (2 from each parent) and 2 functional beta globin genes.

Alpha-thalassemia ( alpha-thalassemia), due to faulty alpha globin genes, has two clinically significant forms. Hb Bart hydrops fetalis (Hb Bart) syndrome, resulting from all four alpha globin genes being nonfunctional, is the most severe form and is characterized by fetal onset of generalized edema, pleural and pericardial effusions, severe hypochromic anemia, and death in the neonatal period. Hemoglobin H (HbH) disease, resulting from three of four alpha globin genes being nonfunctional, is characterized by microcytic hypochromic hemolytic anemia, hepatosplenomegaly, mild jaundice, and sometimes thalassemia-like bone changes. Carriers of alpha thalassemia may have some clinical manifestations. alphaº-thalassemia ( alpha-thalassemia trait), results from 2 nonfunctional alpha globin genes and is characterized by microcytosis (low MCV), hypochromia (low MCH), and normal percentages of HbA2 and F. alpha+-thalassemia ( alpha-thalassemia silent carrier), resulting from 1 nonfunctional alpha globin gene, is characterized by either no clinical symptoms or a moderate thalassemia-like hematologic picture. Individuals from Asian descent are at increased risk of carrying abnormal alpha thalassemia genes

Beta-thalassemia is characterized by reduced synthesis of the hemoglobin beta chain that results in microcytic hypochromic anemia, an abnormal peripheral blood smear with nucleated red blood cells, and reduced amounts of hemoglobin A. There may be a range of clinical symptoms. Individuals with thalassemia major generally have clinical symptoms within the first 2 years of life. They have severe anemia and hepatosplenomegaly. Untreated children have severe failure to thrive and shortened life expectancy. Transfusion programs and chelation therapy allow for normal growth and development. Life expectancy can be into the fifth decade for treated individuals. The presentation of Thalassemia intermedia is at a later age with milder anemia that only rarely requires transfusion. Heterozygotes may be slightly anemic but are clinically asymptomatic. Carriers are often referred to as having thalassemia minor (or -thalassemia minor). Beta-thalassemia is seen more commonly in individuals of Mediterranean descent.

A couple presents to you for preconceptional counseling and would like to know whether they can both have genetic screening for thalassemia to make sure they aren't carriers.

  1. Should you order both alpha and beta thalassemia genetic testing for the couple?
  2. What ethnic groups would be at highest risk?
  3. What is the molecular basis for the clinical difference between beta thalassemia major and intermedia?