The thalassemias are the commonest monogenic diseases
in man. They occur at a high gene frequency throughout the Mediterranean
populations, the Middle East, the Indian subcontinent, and Myanmar,
and in a line stretching from southern China through Thailand and
the Malay peninsula into the island populations of the Pacific.
They are also seen commonly in countries in which there has been
immigration from these high-frequency populations.
There are two main classes of thalassemia, α and β,
in which the α- and β-globin genes
are involved, and rarer forms caused by abnormalities of other globin
genes. These conditions all have in common an imbalanced rate of
production of the globin chains of adult hemoglobin, excess α chains
in β-thalassemia and excess β chains
in α-thalassemia. Several hundred
different mutations at the α- and β-globin
loci have been defined as the cause of the reduced or absent output
of α or β chains. The high frequency
and genetic diversity of the thalassemias is related to past or
present heterozygote resistance to malaria.
The pathophysiology of the thalassemias can be traced
to the deleterious effects of the globin-chain subunits that are
produced in excess. In β-thalassemia,
excess α chains cause damage to the red cell precursors
and red cells and lead to profound anemia. This causes expansion
of the ineffective marrow, with severe effects on development, bone
formation, and growth. The major cause of morbidity and mortality
is the effect of iron deposition in the endocrine organs, liver,
and heart, which results from increased intestinal absorption and
the effects of blood transfusion. The pathophysiology of the α-thalassemias
is different because the excess β chains that result
from defective α-chain production form β4 molecules,
or hemoglobin H, which is 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 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 affected fetuses can be diagnosed by DNA analysis
after the ninth to tenth week of gestation, these conditions are
widely amenable to prenatal diagnosis. Currently, marrow transplantation
is the only way in which they can be cured. Symptomatic management
is based on regular blood transfusion, iron chelation therapy, and
the judicious use of splenectomy. Experimental approaches to their
management include the stimulation of fetal hemoglobin synthesis
and attempts at somatic cell gene therapy.
Acronyms and Abbreviations
Acronyms and abbreviations
that appear in this chapter include: ATP, adenosine triphosphate;
ATR-16, α-thalassemia chromosome
16-linked mental retardation syndrome; ATR-X, α-thalassemia
X-linked mental retardation syndrome; bp, base pairs; DNase I, an
enzyme used to detect DNA-protein interaction; EKLF, a transcription
factor erythroid Kruppel-like factor; HPFH, hereditary persistence
of fetal hemoglobin; HS, hypersensitive site to DNase I treatment;
LCR, locus control region; MCS, multispecies conserved sequences;
PCR, polymerase chain reaction; PHD region, a DNA region with zinc
finger motif commonly deleted in ATR-X α-thalassemia;
RFLP, restriction fragment length polymorphism.
In 1925, Cooley and Lee1 first described a form
of severe anemia that occurred early in life and was associated
with splenomegaly and bone changes. In 1932, George H. Whipple and
William L. Bradford2 published a comprehensive
account of the pathologic findings in this disease. Whipple coined
the phrase thalassic anemia3,4 and
condensed it to thalassemia, from θαλασσα (“the
sea”), because early patients were all of Mediterranean
background. The true genetic character of the disorder became fully
appreciated after 1940. The disease described by Cooley and Lee
is the homozygous state of an autosomal gene for which the 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 thalassemia intermedia was used to describe
disorders that were milder than the major form but more severe than
Thalassemia is not a single disease but a group of disorders,
each resulting from an inherited abnormality of globin production.7 The
conditions form part of the spectrum of diseases known collectively
as the hemoglobinopathies, which can be classified
broadly into two types. The first subdivision consists of conditions, such
as sickle cell anemia, that result from an inherited structural
alteration in one of the globin chains. Although such abnormal hemoglobins
may be synthesized less efficiently or broken down more rapidly
than normal adult hemoglobin, the associated clinical abnormalities
result from the physical properties of the abnormal hemoglobin (see Chap. 48). The second major subdivision of
the hemoglobinopathies, the thalassemias, consists of inherited
defects in the rate of synthesis of one or more of the globin chains.
The result is imbalanced globin chain production, ineffective erythropoiesis,
hemolysis, and a variable degree of anemia.
Several monographs describe the historical aspects of thalassemia
in greater detail.5,7
Thalassemia can be defined as a condition in which a reduced
rate of synthesis of one or more of the globin chains leads to imbalanced
globin-chain synthesis, defective hemoglobin production, and damage
to the red cells or their precursors from the effects of the globin
subunits that are produced in relative excess.7,8 Table 47–1 summarizes the main varieties
of thalassemia that have been defined with certainty.
Table 47–1. Thalassemias and Related
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Table 47–1. Thalassemias and Related
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