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I. CHARACTERISTICS OF HEMOGLOBIN (Hb)
A.
Hb is a globular protein consisting of
four subunits.
B. Fetal Hb (HbF)
consists of two alpha-globin subunits and two gamma-globin subunits desig-
nated
Hb
2
2
.
HbF is the major form of Hb during fetal development because the O
2
affinity of
HbF is higher than the O
2
affinity of HbA and thereby “pulls” O
2
from the maternal blood into
fetal blood.
C.
Adult Hb (HbA)
consists of two alpha-globin subunits and two beta-globin subunits desig-
nated Hb
2
2.
D.
Hb contains a heme moiety, which is an iron (Fe)-containing porphyrin. Fe
2
(ferrous state) binds
O
2
, forming oxyhemoglobin. Fe
3
(ferric state) does not bind O
2
, forming deoxyhemoglobin. The
heme moiety is synthesized partially in mitochondria and partially in cytoplasm.
A.
SCD is an autosomal recessive genetic disorder caused by a missense mutation (GAG S GTG)
at the second nucleotide of the sixth codon in the
HBB gene
on
chromosome 11p15.5
which results in a normal
glutamic acid
S
S
valine
substitution (
E6V
) in the
-globin subunit of
hemoglobin.
B.
SCD is defined by the presence of
E6V HbS
and accounts for 60% to 70% of SCD cases in the
United States.
C.
E6V HbS forms highly ordered polymers that aggregate and distort the shape of red blood
cells, making them brittle and poorly deformable.
D.
SCD may also be caused by coinheritance of the E6V HBB gene mutation with another HBB
gene mutation as follows:
1.
E6V HBB gene mutation
a missense mutation, which results in a normal
glutamic
acid
S
S
lysine
substitution (
E6K
) in the HBB gene forming
HbC.
This means that both
E6V HbS and E6K HbC
will be present within red blood cells.
2.
E6V HBB gene mutation
various HBB gene mutations associated with -thalassemia.
This means that both
E6V HbS and various mutations of Hb
will be present within red blood
cells.
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Chapter 13
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3.
E6V HBB gene mutation
a missense mutation, which results in a normal
glutamic
acid
S
glutamine
substitution (
E121Q
) in the HBB gene forming
Hb D (D-Punjab).
This
means that both
E6V HbS and E121Q HbD
will be present within red blood cells.
4.
E6V HBB gene mutation
a missense mutation, which results in a normal
glutamic
acid
S
lysine
substitution (
E121K
) forming
Hb O (O-Arab).
This means that both
E6V HbS
and E121K HbO
will be present within red blood cells.
E.
Sickle cell disease has a very high carrier frequency in African, Mediterranean, Middle
Eastern, Indian, Caribbean, and portions of Central and South American populations. In
particular, sickle cell disease has a 1 in 12 carrier frequency in the African American popula-
tion and a 1 in 4 carrier frequency in the west central African population.
F. Prevalence.
The prevalence of SCD 1/200 to 650 births in the African American population.
G. Clinical features include:
infants appear healthy at birth but become symptomatic later after
fetal hemoglobin (HbF) levels decrease and HbS levels increase (note: HbF does not contain
-globin subunits); pain and/or swelling of hands and feet in infants and young children;
varying degrees of hemolysis leading to chronic anemia, cholelithiasis, and delayed growth
and sexual maturation; intermittent episodes of vascular occlusion; in patients with
osteomyelitis there is a disproportionate number of cases due to Salmonella infection; func-
tional asplenia usually results in adolescence after so-called autoinfarction of the spleen;
and acute and chronic organ dysfunction.
A.
-Thalassemia is an autosomal recessive genetic disorder most commonly caused by a dele-
tion of the
HBA1 gene
and/or the
HBA2 gene
on
chromosome 16pter-p13.3
for the
1
–globin
subunit of hemoglobin
and
2
–globin subunit of hemoglobin,
respectively. These deletions occur
during unequal crossing over between homologous chromosomes during meiosis.
B.
-Thalassemia is defined by the reduced synthesis of -globin subunits of hemoglobin. It should
be noted that the clinical amount of
-globin subunits of hemoglobin is due to
four (4) alleles.
C.
The deletions of the
HBA1 gene
and/or the
HBA2 gene
result in the
reduced amounts of HbF
(Hb
2
2
)
and
HbA (Hb
2
2
)
because there is reduced synthesis of
-globin subunits, which are
common to both HbF and HbA.
D.
There are
45 nondeletional mutations that cause -thalassemia. The most common
nondeletional mutation is a mutation in the STOP codon of the HBA2 gene resulting in an
-globin subunit elongated by 31amino acids called
Hb
Constant Spring
.
E.
-Thalassemia has two carrier states:
1.
0
-Thalassemia (or
-thalassemia trait)
a.
0
-thalassemia results from the inheritance of a deletion or dysfunction of two
-globin
alleles. This is a
carrier state
for
-thalassemia.
b. Clinical features include:
moderate thalassemialike hematologic findings.
2.
-Thalassemia
a.
-Thalassemia results from the inheritance of a deletion or dysfunction of one
-globin
allele. This is a
silent carrier state
for
-thalassemia.
b. Clinical features include:
normal hematologic findings or moderate thalassemialike
hematologic findings.
F. Prevalence.
The prevalence of
-thalassemia is very high in the African, Mediterranean,
Arabic, Indian, and Southeast Asian populations. The prevalence of Hb Bart hydrops fetalis
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1/200 births in India. The prevalence of HbH disease is 1/50 births in India. The preva-
lence of
-thalassemia (silent carriers) is 1/6 births in Sardinia.
G.
There are two clinically significant forms of
-thalassemia:
1. Hb Bart hydrops fetalis syndrome (Hb Bart).
a. Hb Bart
results from the inheritance of a deletion or dysfunction of all four
-globin
alleles and is the most severe form of
-thalassemia.
b.
An
excess of
-globin subunits
form tetramers during fetal development that have
extremely high affinity for oxygen but are unable to deliver oxygen to fetal tissues.
c. Clinical features include:
fetal onset of generalized edema, ascites, pleural and pericar-
dial effusions, severe hypochromatic anemia, and death in the neonatal period.
2. Hemoglobin H (HbH) disease.
a.
HbH results from the inheritance of a deletion or dysfunction of three
-globin alleles.
b.
A relative
excess of
-globin subunits
form insoluble inclusion bodies within mature red
blood cells.
c. Clinical features include:
mild microcytic hypochromatic hemolytic anemia and
hepatosplenomegaly.
A.
-Thalassemia is an autosomal recessive genetic disorder caused by 200 missense or
frameshift mutations in the
HBB gene
on
chromosome 11p15.5
for the
-globin subunit of
hemoglobin.
B.
-Thalassemia is defined by the absence or reduced synthesis of -globin subunits of hemo-
globin. A
0
mutation
refers to a mutation that causes the absence of
-globin subunits. A
mutation
refers to a mutation that causes the reduced synthesis of
-globin subunits. It
should be noted that the clinical amount of
-globin subunits of hemoglobin is due to
two (2)
alleles.
C.
The mutations in the
HBB gene
result in the
reduced amounts of HbA (Hb
2
2
)
because
there
is reduced synthesis of
-globin subunits, which are found only in HbA.
D.
Heterozygote carriers of
-thalassemia are often referred to as having
thalassemia minor.
1.
Thalassemia minor results from the inheritance of a
mutation of one
-globin allele
(
/normal
).
2. Clinical features include:
individuals are asymptomatic with very mild or absent anemia,
but red blood cell abnormalities may be seen.
E. Prevalence.
The prevalence of
-thalassemia is very high in the African, Mediterranean,
Arabic, Indian, and Southeast Asian populations. The prevalence of
-thalassemia is 1/7
births in Cyprus and 1/8 births in Sardinia.
F.
There are two clinically significant forms of
-thalassemia:
1. Thalassemia major.
a.
Thalassemia major results from the inheritance of a
0
mutation of both
-globin alle-
les (
0
/
0
) and is the most severe form of
-thalassemia.
b.
An
excess of
-globin subunits
form insoluble inclusion bodies within mature red blood
cell precursors.
c. Clinical features include:
microcytic hypochromatic hemolytic anemia, abnormal periph-
eral blood smear with nucleated red blood cells, reduced amounts of HbA, severe ane-
mia, hepatosplenomegaly, fail to thrive, become progressively pale, regular blood
transfusion are necessary, and usually come to medical attention between 6 months S
2 years of age.
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2. Thalassemia intermedia
.
a.
Thalassemia intermedia results from the inheritance of a
0
mutation of one
-globin
allele (
0
/normal
) and is a less severe form of -thalassemia.
b. Clinical features include:
a mild hemolytic anemia, individuals are at risk for iron over-
load, regular blood transfusions are rarely necessary, and usually come to medical
attention by
2 years of age.
V. SUMMARY TABLE OF HEMOGLOBINOPATHIES (Table 13-1)
t a b l e
13-1
Summary Table of Hemoglobinopathies
Genetic Disorder
Gene/Gene Product Chromosome
Clinical Features
Sickle cell disease
HBB gene/
-globin subunit
Infants appear healthy at birth but become symptomatic later
11p15.5
after fetal hemoglobin (HbF) levels decrease and HbS
glutamic acid
→
valine missense
levels increase; pain and/or swelling of hands and feet in
mutation very common (E6V)
infants and young children; varying degrees of hemolysis
leading to chronic anemia, cholelithiasis, and delayed
growth and sexual maturation; intermittent episodes of
vascular occlusion; and acute and chronic organ dysfunction.
-Thalassemia
HBA1 gene/
1
-globin subunit
Hb Bart
: fetal onset of generalized edema, ascites, pleural
HBA2 gene/
2
-globin subunit
and pericardial effusions, severe hypochromatic anemia,
16pter-p13.3
and death in the neonatal period.
Deletion mutation is most common
HbH:
mild microcytic hypochromatic hemolytic anemia and
Reduced amounts of HbF (Hb
2
2
) hepatosplenomegaly.
and HbA (Hb
2
2
)
0
-Thalassemia (or
-thalassemia trait; carrier state):
moderate thalassemialike hematologic findings.
-Thalassemia (silent carrier state): normal hematologic
findings or moderate thalassemialike hematologic findings.
-Thalassemia
HBB gene/
-globin subunit
Thalassemia major (
0
/
0
):
microcytic hypochromatic
11p15.5
hemolytic anemia, abnormal peripheral blood smear with
200 missense or frameshift
nucleated red blood cells, reduced amounts of HbA, severe
mutations are most common
anemia, hepatosplenomegaly, fail to thrive, become
Reduced amounts of HbA (Hb
2
2
)
progressively pale, regular blood transfusion are necessary,
and usually come to medical attention between 6 months
and 2 years of age.
Thalassemia intermedia (
0
/normal
): a mild hemolytic
anemia, individuals are at risk for iron overload, regular
blood transfusions are rarely necessary, and usually come
to medical attention by
2 years of age.
Thalassemia minor (carrier state;
/normal
): individuals
are asymptomatic with very mild or absent anemia, but red
blood cell abnormalities may be seen.
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144
BRS Genetics
A
B
Figure 13-1. Hemoglobinopathies. (A) Sickle cell disease.
Photomicrograph shows sickle RBCs (drepanocytes) due to the
rod-shaped polymers of the inherited abnormal hemoglobin S (HbS). The RBC does not become sickled until it has lost its
nucleus and has its full complement of HbS. Sickle cells are thin, elongated, and well filled with HbS. The main clinical
manifestations of sickle cell disease are chronic hemolytic anemia and occlusion of microvasculature (called vaso-
occlusive disease). Vaso-occlusive crisis may occur in the brain, liver, lung, or spleen. Factors that induce sickling are PO
2
(e.g., high altitude) or a concentration of 60% HbS or greater in RBCs. (B) Thalassemia. Photomicrograph shows micro-
cytic and hypochromic RBCs due to various mutations that result in reduced amounts of hemoglobin A (HbA). Note the tar-
get cells (arrows). In addition, RBCs show anisocytosis (excessive variation in RBC size) and poikilocytosis (abnormal
shapes of RBCs).
VI. SELECTED PHOTOMICROGRAPHS OF HEMOGLOBINOPATHIES
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