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CHAPTER 48 cells and lead to profound anemia. This causes expansion of the ineffective

THE THALASSEMIAS: marrow, with severe effects on development, bone formation, and growth.
The major cause of morbidity and mortality is the effect of iron deposition in
DISORDERS OF GLOBIN the endocrine organs, liver, and heart, which results from increased intesti-
nal absorption and the effects of blood transfusion. The pathophysiology of
SYNTHESIS the α-thalassemias is different because the excess β chains that result from
defective α-chain production form β molecules, or hemoglobin H, which is
4
soluble and does not precipitate in the marrow. However, it is unstable and
precipitates in older red cells. Hence, the anemia of α-thalassemia is hemolytic
David J. Weatherall rather than dyserythropoietic.
The clinical pictures of α- and β-thalassemia vary widely, and knowledge is
gradually being amassed about some of the genetic and environmental factors
that modify these phenotypes.
Because the carrier states for the thalassemias can be identified and
SUMMARY affected fetuses can be diagnosed by DNA analysis after the ninth to tenth
week of gestation, these conditions are widely amenable to prenatal diag-
The thalassemias are the commonest monogenic diseases in man. They occur nosis. Currently, marrow transplantation is the only way in which they can
at a high gene frequency throughout the Mediterranean populations, the be cured. Symptomatic management is based on regular blood transfusion,
Middle East, the Indian subcontinent, and Myanmar, and in a line stretching iron chelation therapy, and the judicious use of splenectomy. Experimental
from southern China through Thailand and the Malay peninsula into the island approaches to their management include the stimulation of fetal hemoglobin
populations of the Pacific. They are also seen commonly in countries in which synthesis and attempts at somatic cell gene therapy.
there has been immigration from these high-frequency populations.
There are two main classes of thalassemias, α and β, in which the α- and
β-globin genes are involved, and rarer forms caused by abnormalities of other
globin genes. Some extremely rare congenital and acquired thalassemia that
have intact globin genes are caused by either mutations of nonglobin genes or DEFINITIONS AND HISTORY
factors yet to be elucidated. All thalassemias have in common an imbalanced
1
rate of production of the globin chains of adult hemoglobin, excess α chains in In 1925, Cooley and Lee first described a form of severe anemia that
β-thalassemia and excess β chains in α-thalassemia. Several hundred differ- occurred early in life and was associated with splenomegaly and bone
2
ent mutations at the α- and β-globin loci have been defined as the cause of changes. In 1932, George H. Whipple and William L. Bradford pub-
the reduced or absent output of α or β chains. The high frequency and genetic lished a comprehensive account of the pathologic findings in this dis-
ease. Whipple coined the phrase thalassic anemia and condensed it to
3,4
diversity of the thalassemias is related to past or present heterozygote resis- thalassemia, from θαλασσα (“the sea”), because early patients were all of
tance to malaria. Mediterranean background. The true genetic character of the disorder
The pathophysiology of the thalassemias can be traced to the delete- became fully appreciated after 1940. The disease described by Cooley
rious effects of the globin-chain subunits that are produced in excess. In β- and Lee is the homozygous state of an autosomal gene for which the
thalassemia, excess α chains cause damage to the red cell precursors and red heterozygous state is associated with much milder hematologic changes.
The severe homozygous condition became known as thalassemia major.
The heterozygous states, thalassemia trait, were designated according to
their severity as thalassemia minor or minima. 3,5–7 Later, the term thalas-
semia intermedia was used to describe disorders that were milder than
the major form but more severe than the traits.
Thalassemia is not a single disease but a group of disorders, each
Acronyms and Abbreviations: AATAAA, the polyadenylation signal site; ATR-16, resulting from an inherited abnormality of globin production. The
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α-thalassemia chromosome 16-linked mental retardation syndrome; ATR-X, α- conditions form part of the spectrum of diseases known collectively as
thalassemia X-linked mental retardation syndrome; BCL11A, B-cell lymphoma/leu- the hemoglobinopathies, which can be classified broadly into two types.
kemia oncogene important for γ- to β-globin switching; CAP site, a DNA site located The first subdivision consists of conditions, such as sickle cell anemia,
in or near a promoter; DNase I, an enzyme used to detect DNA-protein interaction; that result from an inherited structural alteration in one of the globin
GATA-1, a transcription factor essential for productive erythropoiesis; HPFH, hered- chains. Although such abnormal hemoglobins may be synthesized less
itary persistence of fetal hemoglobin; HS, hypersensitive site to DNase I treatment; efficiently or broken down more rapidly than normal adult hemoglobin,
IVS, intervening sequence of a gene (i.e., an intron); KLF1, erythroid Kruppel-like the associated clinical abnormalities result from the physical properties
factor; LCR, locus control region; MCS, multispecies conserved sequences; NFE-2, of the abnormal hemoglobin (Chap. 49). The second major subdivi-
“nuclear factor, erythroid 2” is a transcription factor essential for productive erythro- sion of the hemoglobinopathies, the thalassemias, consists of inherited
poiesis; PHD region, known as plant homeodomain is a DNA region with zinc finger defects in the rate of synthesis of one or more of the globin chains. The
motif commonly deleted in ATR-X α-thalassemia; RFLP, restriction fragment length result is imbalanced globin chain production, ineffective erythropoiesis,
polymorphism; TATA box, a DNA sequence (cis-regulatory element) found in the pro- hemolysis, and a variable degree of anemia.
moter region of genes. Several monographs describe the historical aspects of thalassemia
in greater detail. 5,7

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