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 ...