The Thalassemias

The thalassemias are a heterogeneous group of
diseases caused by decreased or absent formation
of a globin chain. The thalassemias occur
predominantly in the Mediterranean region,
parts of Africa, and Southeast Asia (the word
thalassemia is derived from thalassa, the Greek
word for sea). In these regions, they are a significant
cause of morbidity and mortality, but they
are frequent because heterozygotes are protected
from severe malarial infection

Thalassemia

Thalassemia, a chronic anemia
Depending on which globin chain is not formed
in sufficient amounts, !-thalassemia, "-thalassemia,
or #"-thalassemia results. This leads to
chronic anemia, which causes the various manifestations
of thalassemia. Oxygen deficiency in
the peripheral tissues leads to increased extramedullary
(outside the bone marrow) blood
formation. A tendency toward infection, undernourishment,
and other signs characterize the
severe clinical picture.

!-Thalassemia and "-thalassemia

The thalassemias have a wide spectrum of
different genotypes and phenotypes (disease
manifestations and course). In the "-thalassemias
(1), complete absence ("0) is distinguished
from decreased formation ("+) of the "
chain. With the !-thalassemias (2), one, two,
three, or all four loci for !-globin may be affected.
Altogether, there are 12 principal genotypes.
In individuals with two mutations at the
!-loci (!-thalassemia), the two can lie either on
the same chromosome (thal-1) or on different
chromosomes (thal-2). Thal-1 occurs mainly in
Southeast Asia; thal-2, mainly in Africa. Each !
gene is located within a 4 kb region of homology,
interrupted by small, nonhomologous
regions. The most frequent mechanism for the
origin of a chromosome with only one !-globin
gene is nonhomologous crossing-over between
two !-globin gene loci after mispairing of the
homologous chromosomes during meiosis.

!-Thalassemia due to different mutations

Many mutations in the "-globin gene region can
lead to "-thalassemia. The mutations may also
occur in noncoding sequences (5! to exon 1 and
within introns).

Haplotypes resulting from polymorphic restriction sites in the !-globin gene cluster

From the presence or absence of recognition
sites of a number of restriction enzymes (restriction
fragment length polymorphism, RFLP),
different haplotypes can be distinguished in the
"-globin-like gene region ("-globin gene
cluster). Each haplotype is characterized by the
presence or absence of several polymorphic restriction
sites. By establishing the haplotypes of
the affected and unaffected individuals within a
family, the mutation-carrying haplotype can be
identified (indirect genotype analysis). Different
mutations have occurred on the background
of different haplotypes. Frequently, a
particular mutation is linked to a distinct haplotype
(linkage disequilibrium). This reflects the
time elapsed since the mutation first occurred
in the population, where it has been maintained
by selection.

Thalassemia

Thalassemia may be associated with mental
retardation. Two different syndromes can be
distinguished: One occurs in patients with a
large (1–2 Mb) deletion on the tip of chromosome
16 including the !-globin gene cluster
(ATR-16 syndrome). The other is an X-linked
disorder with a remarkably uniform phenotype
and a mild form of HbH disease without !-globin
deletion. A trans-acting regulatory factor
appears to be encoded on the X chromosome.

Hereditary Persistence of Fetal Hemoglobin (HPFH)

Hereditary persistence of fetal hemoglobin
(HPFH) refers to a genetically heterogeneous
group of diseases in which the temporal expression
of the !-globin genes during development
has been altered. Individuals with HPFH produce
increased amounts of fetal hemoglobin
(HbF). Under some conditions, HbF may be the
only !-globin-like gene product formed. Clinically,
HPFH is relatively benign, although HbF is
not optimally adapted to postnatal conditions.
Analysis of HPFH has yielded insight into the
control of globin gene transcription and the effect
of mutations in noncoding sequences.