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CHAPTER 28
Hemoglobin
P ro te in
F I G U R E 2 8 - 1 3 (
Continued
)
of abnormal cells by the spleen and the reticuloendothelial
hyperplasia caused by hemolysis lead to splenomegaly.
The thalassemias are classified according to which
chains are deficient. The most important types are the
a-
and ^-thalassemias. In each type, globin chain syn-
thesis may be reduced (
a
+,
fi+)
or absent (a0, /3°). By
the use of probes to detect the presence or absence of spe-
cific globin genes, thalassemias due to deletion of globin
genes have been distinguished from nondeletion varieties.
<5-, <5-/1-, and y-<5-/l-Thalassemias are extremely rare.
a-Thalassemias
In order of increasing severity, the four clinical entities are
1
. the
silent carrier state
(a-thalassemia-
2
),
2
.
a-thalassemia trait
(«-thalassemia-
1
),
3.
HbH disease,
and
4.
hydrops fetalis with Hb Barts,
or
homozygous
a-thalassemia.
The first three are
a
1
-thalassemias, and the last is an
«' -thalassemia. Since non-a-globin synthesis is not af-
fected
in
a-thalassemia,
the
relative
proportions
of
hemoglobins A, A2, and F are unchanged, although all
three are reduced in concentration.
These conditions are produced by deletion of one, two,
three, or four copies of the «-globin gene; the more copies
missing, the more severe the disease. Although deletion
is probably the most common cause of the a-thalassemias
(and is the
only
cause identified for a°-thalassemias), a
number of nondeletion mutations are known. Most Asian
cases of a-thalassemia trait result from heterozygosity for
a double-deletion chromosome. The defective chromo-
somes and other data relevant to a-thalassemias are listed
in Table 28-2. Since deletion mutations remove variable
amounts of DNA on the 5' and 3r sides of the affected
genes, single- and double-deletion chromosomes resulting
from different mutations will not, in general, lack identical
pieces of DNA. The deletion may extend to the f genes,
in which case synthesis of embryonic hemoglobins is af-
fected.
Decreased a-chain synthesis leads to formation of two
abnormal hemoglobin tetramers. Hemoglobin Barts (y4)
is found in the cord blood in association with all of the
a-thalassemias. It arises from normal
production of
ychains in association with a lack of
a
chains. After
birth, if the infant survives, the ychain is replaced by the
/3
chain. If a-chain production is severely depressed, ex-
cess /5 chains form and self-associate
(f4).
Neither Hb
Barts nor HbH shows cooperativity, and their oxygen bind-
ing curves resemble that of myoglobin. Consequently, they
bind oxygen very tightly, do not release it to the tissues,
and are almost useless for oxygen transport.
In HbH disease, 5-30% of the hemoglobin in adults is
HbH, which is detected as a rapidly moving hemoglobin
during electrophoresis at pH 8.4. In some patients, a
