for the output of one a-globin gene), apparently because
the mRNA is unstable. Because of the low rate of synthe-
sis of Hb Constant Spring, when a chromosome carrying
this mutation is present along with one lacking a-globin
genes, HbH disease results. Extended a chains also result
from frameshift mutations (Hb Wayne) and duplications
(Hb Grady).
Other a-globin mutants have a mutation at the intron-
exon boundary (mRNA splice boundary) that prevents
RNA processing or a mutation in the recognition sequence
needed for polyadenylation of the mRNA during RNA
maturation. In other a +-thalassemias with both
present but active only at a reduced level, the defect has
not been identified.
Thalassemias of the /3-Globin Gene Family
In thalassemias of the /3-globin gene family, there is re-
duced synthesis of /3 chains, with or without reduced syn-
thesis of
or <5
chains. An isolated decrease in
5-globin synthesis would probably be benign and likely
to be detected only by chance. Hemoglobin Lepore is usu-
ally included with the /3-thalassemias, since synthesis of
normal /3 chains is reduced or absent.
The /3-thalassemias are more important in terms of pa-
tient suffering and expense than the a-thalassemias. Be-
cause all of the normal hemoglobins of fetal and adult life
require a-globin chains for normal function, homozygous
a-thalassemia (hydrops fetalis) is usually fatal
in utero
the third trimester of pregnancy. When (/-chain synthesis
is unusually prolonged and a living fetus is born, death in-
variably occurs soon after delivery. In the a-thalassemias,
even a single a-locus seems sufficient to preclude serious
morbidity. In contrast, the /3-globin chain is not needed
until after birth. Except for the rare instances in which
and /1-chain syntheses are all absent, /3-thalassemic
fetuses are delivered normally at term. In homozygous
/3-thalassemia, problems begin about 4-6 months postna-
tally, when
-chain synthesis has declined and /3-chain
synthesis should have taken over. Thus, /3-thalassemia is
a crippling disease of childhood.
Characteristics of the more common /3-thalassemia
syndromes are summarized in Table 28-4. Not included
are two different abnormal heterozygotes. Anemia re-
sults from precipitation of excess a-globin chains, pre-
mature red cell destruction in bone marrow and the circu-
lation, and deficiency of functional hemoglobin tetramer.
/3-Thalassemia major, or Cooley’s anemia, occurs when
/3-globin synthesis is markedly depressed or absent. The
ineffective erythropoiesis causes massive erythroid prolif-
eration, skeletal deformities, and extramedullary erythro-
poiesis. The usual treatment is frequent blood transfusion.
However, this treatment leads to iron overload, usually
by the early teenage years, and death due to iron de-
position cardiomyopathy by the second decade. Treat-
ment with chelating agents, particularly deferoxamine, has
been of considerable value (Chapter 29). Transfusions also
put these patients at risk for viral hepatitis and acquired
immunodeficiency syndrome (AIDS). Immunization with
the hepatitis B virus vaccine reduces the risk for hepatitis
B infection. Two other therapeutic approaches in the treat-
ment of severe ^-thalassemia have been employed. These
include bone marrow transplantation from HLA identi-
cal donors and augmentation of HbF synthesis by using
hydroxyurea, butyric acid analogues or acylating agents
(discussed later).
Thalassemia intermedia occurs in homozygotes for a
3 deletion chromosome (5°-/3°-thalassemia). Because
the production of HbF is greater than in /3°-thalassemia,
it is a milder clinical form of homozygous /3-thalassemia.
The increased y -chain synthesis in thalassemia interme-
dia and the increased synthesis of
and 5-globins in /3°-
and /3+-thalassemias suggest that some site downstream
from the
genes normally prevents their expres-
sion. Thalassemia intermedia also is seen in homozygous
+-thalassemia if the reduction in /J-globin synthesis is
not severe. Under oxidative stress or following a febrile
illness, transfusion may be needed. Because these patients
are anemic, they have increased intestinal iron absorption
and may develop secondary hemochromatosis in later life.
-Thalassemia trait is usually asymptomatic.
The molecular defects of /
-thalassemias and related
disorders are heterogeneous and nearly
have been identified. Many of the mutations are single-
nucleotide substitutions affecting critical
loci in the
expression of /3-globin-like genes. For example muta-
tions in the promoter region A—>-G at position —29
or C—>-T at position
cause defects in binding of
transcription factors leading to decreased synthesis of
-globin mRNA. The same mutations however promote
transcription of (5-globin gene, leading to increased syn-
thesis of hemoglobin A
. These mutations have been noted
in African-Americans.
Thalassemias, Lepore Hemoglobins,
and Hereditary Persistence of Fetal
Hemoglobin (HPFH)
<3-/8-Thalassemias, Lepore hemoglobin thalassemia, and
HPFH are characterized by lack of /
-globin synthesis and
are caused by deletions in the /3-gene family on chromo-
some 11 (Figure 28-14).
Hemoglobin Lepore contains abnormal 5-/3 fusion
polypeptides. The N-terminal sequence in the non-/3
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