section 28.3
Inherited Disorders of Hemoglobin Structure
and
Synthesis
657
of prematurity, anemia of inflammation, and anemia of
malignancy.
Polycythemia
is characterized by an increase in the
number, and in the hemoglobin content, of circulating
red cells. In patients who have chronic anoxia from im-
paired pulmonary ventilation or congenital or acquired
heart disease, the increase in plasma erythropoietin leads
to secondary polycythemia. Some renal cell carcinomas,
hepatocarcinomas, and other tumors, which produce phys-
iologically inappropriate amounts of erythropoietin, may
also cause secondary polycythemia. Conversely, anemia
can result from renal insufficiency and from chronic dis-
orders that depress erythropoietin production. In
poly-
cythemia vera
(primary polycythemia), which is a ma-
lignancy of erythrocyte stem cells of unknown cause,
erythropoietin levels are normal or depressed.
28.3 Inherited Disorders of Hemoglobin
Structure and Synthesis
Although hemoglobin disorders are extremely diverse,
they can be generally classified into two somewhat over-
lapping groups. 1
2
1. Thalassemia syndromes are characterized by a
decreased rate of synthesis of one or more of the
globin peptides. Although there are exceptions, the
globin chains produced in thalassemic states usually
have normal amino acid sequence. In
hereditary
persistence of fetal hemoglobin (HPFH),
there is a
failure at birth to switch from synthesis of fetal
hemoglobin (HbF) to adult hemoglobin (HbA), so that
the individual continues to have high levels of HbF
throughout life. Although HPFH does not cause any
major hematological abnormalities and is compatible
with normal life, it is grouped with the thalassemias
because its molecular pathology is closely related to
that of several of the
/3-thalassemias.
2. Hemoglobinopathies are characterized by alterations
in function or stability of the hemoglobin molecule
arising from changes in the amino acid sequence of a
globin chain. They include single-amino-acid
substitutions (the largest group), insertion or deletion
of one or more amino acids, drastic changes in amino
acid sequence caused by frameshift mutations,
combination of different pieces of two normal chains
by unequal crossing over during meiosis to produce
fusion hemoglobins, and increase or decrease in chain
length from mutations that create or destroy stop
codons. Frameshift mutants, chain termination
mutants, and fusion polypeptides produce
thalassemia-like syndromes. About 750 abnormal
hemoglobins have been described, some of which
cause no physiological abnormality; consequently,
they are not true hemoglobinopathies.
Two systems of nomenclature are used for the abnor-
mal hemoglobins. Initially, each hemoglobin, normal or
abnormal, was assigned a different letter of the alphabet on
the basis of its electrophoretic mobility, e.g., hemoglobins
A (normal adult hemoglobin), C, D, E, F (normal fe-
tal hemoglobin), G, H, J, M (methemoglobin), and S
(sickle hemoglobin). It was soon realized that there were
far more mutant hemoglobins than letters of the alphabet
and that several hemoglobins might have the same elec-
trophoretic mobility. Hemoglobins were therefore named
for the geographic locations where they were discovered,
e.g., Hb Cowtown, Hb Kankakee, and Hb Dakar. If a newly
discovered hemoglobin has characteristics of a lettered
hemoglobin, the letter and the new name are used to-
gether, e.g., Hbs J, J-Capetown, J-Rovigo, and J-Altgeld
Gardens. Occasionally, abnormal hemoglobins discovered
independently in two different places and given two dif-
ferent names are shown to have the same mutation. In such
cases, both names are retained and used as synonyms. Ex-
amples include Hbs:Fort Gordon, Osier, and Nancy; and
Hbs:Perth and Abraham Lincoln. Heterozygotes for an ab-
normal hemoglobin or a thalassemia are called carriers of
the variant.
Normal Hemoglobins
Each molecule of human hemoglobin is a tetramer of two
a-like (a or £) and two /3-like (/3,
y, 8,
or
e
) chains. The
normal hemoglobins, in order of their appearance during
development, are
1. Embryonic hemoglobins
a) Gower I = £
2«2
b) Gower II = 0!2£2
c) Portland = f
2
X
2
2. Fetal hemoglobin. Hemoglobin F =
0
*
2
/
2
; the
y
may
be
Gy
or Ay, depending on whether glycine or
alanine is present at /136. HbF, the major oxygen
carrier in fetal life, accounts for less than
2
% of
normal adult hemoglobin and falls to this level by the
age of
6-12
months.
3. Adult hemoglobins
a) Hemoglobin A =
a2p2-
This is the major adult
type (HbAi), composing 95% of the total
hemoglobin.
b) Hemoglobin A
2
= a
252
. This type accounts for
less than 3.5% of the total hemoglobin. Synthesis
of
8
chains is low at all times.
