section 28.3
Inherited Disorders of Hemoglobin Structure and Synthesis
661
T A B L E 2 8 -2
Characteristics of the a-Thalassemia Syndromes
Syndrome
(or Phenotype)
Genotype
No. of
a-Genes
Present
Possible
Parental
Genotypes*
Frequency^
Clinical
Severity
Hemoglobin
Pattern
Hydrops fetalis
0
a-Thalassemia trait
0.25
Lethal (death
Cord blood: mostly Hb
with Hb Bart’s
X
in utero)
Bart’s (y4); small
a-Thalassemia trait
amounts of HbH (j34)
and Hb Portland
Hemoglobin H disease
-l-a
1
a-Thalassemia trait
0.25
Severe to
Cord blood: about 25%
X
moderate
Hb Bart’s; adult blood:
silent carrier
microcytosis;
5-30% HbH.
hemolysis
'
(I) -/a a
a-Thalassemia trait
normal
0.50
Cord blood: about 5%
a-Thalassemia trait
+
or
2
Mild
Hb Bart’s; adult
(a-thalassemia
1
)
or
microcytosis
blood: normal
composition.
(II) -a/-a
Silent carrier
0.25
Silent carrier
Silent carrier
-a/a a
3
Silent carrier
0.50
None
Cord blood: about
(a-thalassemia
2
)
X
1-2% Hb Bart’s;
normal
adult blood:
normal composition.
*The parental genotypes are only representative examples. Matings of HbH genotypes with other genotypes are not shown.
TThe probability that a child from the indicated mating will have this thalassemia syndrome.
slow-moving, minor band of Hb Constant Spring may also
be detected. HbH is unstable and precipitates in older red
cells and under oxidant stress (e.g., treatment of the patient
with primaquine) as Heinz bodies, which are removed by
the spleen. Following splenectomy, these inclusions can
be seen in peripheral blood after staining with methylene
blue. In erythrocytes from unsplenectomized patients, fine
inclusions of precipitated HbH can be induced and visu-
alized by staining for
1
hour with brilliant cresyl blue.
Although other unstable hemoglobins also produce inclu-
sion bodies, staining for
1
hour is usually not sufficient for
their visualization. Patients with iron deficiency together
with HbH disease may not show the presence of HbH.
Hemoglobin H has been described in several other dis-
orders. In erythroleukemia
(Di Guglielmo’s syndrome
),
unbalanced globin chain synthesis may result from chro-
mosomal aberrations associated with the leukemia. In a
patient with acute myeloblastic leukemia, 50-65% of the
hemoglobin was HbH. All four «-globin genes were in-
tact, but
a
-chain synthesis was very low. Specific «-globin
gene repressors may have been synthesized by the tumor
cells.
Several nondeletion
a
+-thalassemias have been de-
scribed. Four mutations in the normal stop codon for the
«-globin gene have been identified (Table 28-3). In these
cells, the mutated codon specifies an amino acid, and trans-
lation continues beyond the normal point, extending the
a
chains by 31 additional amino acids. Synthesis is ter-
minated by a stop codon downstream from the normal
stop codon. Hb Constant Spring is relatively common in
Southeast Asian populations. In heterozygotes, about 1%
of the «-globin is Hb Constant Spring (25% is expected
T A B L E 2 8 -3
Hemoglobins Having an Extended a-Globin Chain Due
to Mutation of the Chain Termination Codon
Hemoglobin
Codon Change at a-142
Hb Constant Spring
UAA—>CAA (Gin)
Hb Icaria
UAA—> AAA (Lys)
Hb Koya Dora
UAA—>UCA (Ser)
Hb Seal Rock
UAA—>GAA (Glu)
