and under oxidant stress, such as when the patient is treated for malaria with
primaquine. A total absence of a A-globin gene results in the lethal in utero
condition, hydrops fetalis.
Some mutations that produce thalassemia are referred to as nondeletion
mutations. The mutation occurs in the STOP codon for the A-chain,
consequently translation continues beyond the normal end point to the next
STOP codon, extending the polypeptide by 31 residues. An example of this
produces Hb Constant Spring, the incidence of which is fairly common in
southeastern Asian populations where the usual STOP codon UAA is mutated
to CAA. It appears that the extended mRNA for the A-chain is unstable and
leads to a reduced rate of Hb synthesis. If this mutation is present together
with a lack of one of the A-globin genes, then HbH disease results. However, in
heterozygotes only about 1% of the A-globin produced is the Constant Spring
mutant type.
B-Thalassemias result from mutations in the B-globin genes. In some ways,
it would be more appropriate to call them ‘thalassemias of the B-globin gene
family’ because the genes for D-, and G-globins and the single B-globin are
all grouped together on chromosome 11. In B-thalassemia there is reduced
synthesis of B-globin with or without a reduced synthesis of D- or G-globins.
B-Thalassemia is not a single disease. The molecular defects in this and
related disorders are highly heterogeneous, with about 200 mutations having
been identified to date. These include many single nucleotide substitutions
that affect the expression of B-globin genes. Examples include nonsense and
frameshift mutations in the exons, point mutations in the intron–exon splice
junctions and mutations in the 5 region and the 3-polyadenylation sites. The
latter are extended sequences of adenine nucleotides at the 3_ end of mRNA
molecules that stabilize the mRNA molecules and help in their transport from
the nucleus to the cytoplasm. A number of heterozygous states are also known
but these usually only give rise to mild clinical symptoms. In some forms of
B-thalassemia, abnormal D-B fusion polypeptides may be formed. For example,
in Hb Lepore there is a fusion gene caused by nonhomologous crossing over
between the D-gene on one chromosome and the B-gene on the other. Thus
normal B- and D-genes are absent.
B-Globin chains are not required until after birth (Figure 13.9) and
B-thalassemia infants are usually born normally at term. Clinical problems
begin two to six months later, when G-globin synthesis, and therefore the
amount of HbF, has declined. Consequently B-thalassemia is a crippling
disease of childhood, characterized by the precipitation of excess A-globin
chains, destruction of erythrocytes in the bone marrow and circulation,
and deficiency of functional Hb tetramers. In B-thalassemia major, formerly
Cooley’s anemia, B-globin synthesis is strongly depressed or absent causing
massive erythroid proliferation and skeletal deformities.
Thalassemias can be diagnosed from their general clinical symptoms and the
anemia, including the precipitation of excess free globin chains. Hypochromic
erythrocytes with a clear center and a darker rim containing the Hb are
visible in blood smears as are poikilocytes, which are abnormally shaped cells
produced by the spleen when it removes target cells. There is also splenomegaly.
Electrophoresis of hemolyzed erythrocytes will provide information about the
relative proportions of A, A 2 and F globins. In HbH disease, the Hb (tetramer
ofB-globin) is detected as a rapidly moving band at pH 8.4.
The treatment for thalassemias, as with sickle cell disease, is to give repeated
blood transfusions combined with chelation therapy to remove the iron with,
for example, desferrioxamine. The latter is necessary because the body has
no real excretion route for iron, and an iron overload may be fatal due to
deposition cardiomyopathy by the second decade of life. Transfusions may
also put the patient at risk from hepatitis and AIDS, especially in developing
HEMOGLOBINOPATHIESCZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY (+,