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determines the MPD phenotypes in transgenic mice.

Alpha-thalassemia

Patients with a single alpha + allele (alpha/alpha;alpha/–) are clinically normal and are called silent carriers.

Heterozygotes with defects in 2 of the 4 genes such as two alpha + alleles (alpha/–;alpha/–) or one alpha 0 allele (alpha/alpha;–/–) tend to develop mild to moderate microcytic anemia but no symptoms. These patients have alpha-thalassemia trait.

Defects in 3 of the 4 genes caused by coinheritance of both alpha + and alpha 0 (alpha/–;–/–) severely impair alpha-chain production. This results in the formation of tetramers of excess beta-chains termed Hb H or, in infancy, gamma-chains termed Bart’s hemoglobin. Patients with Hb H disease often have symptomatic hemolytic anemia and splenomegaly.

Defects in all 4 genes via two alpha 0 alleles (–/–;–/–) is a lethal condition in utero (hydrops fetalis), because hemoglobin that lacks alpha chains does not transport oxygen.

Beta-thalassemia

In beta-thalassemia, clinical phenotypes are classified into 3 groups based on the degree to which beta globin production is impaired:

  • Minor (or trait)
  • Intermedia
  • Major

Beta-thalassemia minor (trait) occurs in heterozygotes (beta/beta + or beta/beta 0), who are usually asymptomatic with mild to moderate microcytic anemia. This phenotype may also occur in mild cases of beta +/beta +.

Beta-thalassemia intermedia is a variable clinical picture that is intermediate between thalassemia major or minor, caused by inheritance of 2 beta thalassemia alleles (beta +/beta 0 or severe cases of beta +/beta +).

Beta-thalassemia major (or Cooley anemia) occurs in homozygotes (beta 0/beta 0) or severe compound heterozygotes (beta 0/beta +) and results from severe beta globin deficiency. These patients develop severe anemia and bone marrow hyperactivity. Beta-thalassemia major manifests by age 1 to 2 years with symptoms of severe anemia and transfusional and absorptive iron overload. Patients are jaundiced, and leg ulcers and cholelithiasis occur (as in sickle cell disease). Splenomegaly, often massive, is common. Splenic sequestration may develop, accelerating destruction of transfused normal red blood cells. Bone marrow hyperactivity causes thickening of the cranial bones and malar eminences. Long bone involvement predisposes to pathologic fractures and impairs growth, possibly delaying or preventing puberty.