may edition file

genetics
ADVANCES IN MANAGING
THALASSEMIA
Several promising therapy regimens are underway to deal with the
hereditary haemolytic disease
DR RAJANI KANTH VANGALA
Thalassemia comes from two Greek
words “Thalassa” and “emia”
meaning “sea” and “blood”. This
naming has a unique meaning as the
disease affects the hemoglobin and
was described almost 90 years ago
by Cooley and Lee. Two gene clusters
controlling haemoglobin synthesis are
located on chromosome 16 (α-like
globins) and chromosome 11 (β-like
globins) in such a manner that they
are differentially expressed at different
stages of development like embryonic,
foetal and adult. This is seen in
β-globin gene cluster where, ε-gene is
only expressed in early embryos and
two γ-genes, which are expressed
during gestation, are found in foetal
haemoglobin (Hb F, α2γ2). The δ-gene
used in diagnosing thalassemias is a
component of Hb A2 (α2δ2), whereas
α and β-globins combine to form
major haemoglobin component Hb
A (α2β2) carried by adult red blood
cells. The heritable mutations in α and
β gene clusters in thalassemias results
in defective haemoglobin which binds
to less oxygen and also reduces the
transport of oxygen.
There are three types of
β-thalassemia, based on the β-globin
chain imbalance and severity of
anaemia; namely minor, intermedia and
major. Several mutations have been
identified and were classified into silent
— which have no effect, mild — leading
to a reduction in β-globin production
levels, and severe — causing a complete
absence of the β-globin gene product.
The minor trait or carrier patients have
heterozygous inheritance of mutations
and are often clinically asymptomatic.
Patients with the major trait have severe
anaemia from infancy and become
life-long dependents on transfusion.
However, β –thalassemia intermedia has
variable anaemia of mild to moderate
requiring variable transfusions.
β-thalassemia major and intermedia
THE CLASSIFICATION
OF α-THALASSEMIA IS
DEPENDENT ON HOW THE
TWO α-GLOBIN GENES ARE
DELETED OR REDUCED IN
ACTIVITY DUE TO MUTATIONS
can be due to several homozygous or
compound heterozygous inheritances
of mutations in β-globin gene. Different
modifications like the extent of
α-globin to β-globin chain imbalance,
ineffective erythropoiesis and the
severity of anaemia cause β-thalessemia
intermedia, rather than β-thalessemia
major in most patients. Most frequent
are mutations in the β-globin
gene, second are co-inheritance of
α-thalassemia, higher levels of γ-chains
of globin and sustained production of
foetal haemoglobin after infancy. The
last factor — hereditary persistence of
foetal haemoglobin — can be due to
several rare mutations like deletions of
upstream promoter or regulatory region
but the presence of an intact gene,
and the complete deletion of δ-globin
and β-globin genes. These patients
have one intact γ-globin gene which
is called δβ-thalassemia. Some of the
other complications, such as dominant
inclusion body β-thalassemia, have a
triplicated or quadruplicated α-genotype
along with β-heterozygosity or E/
β-thalassemia where β-thalassemia is
co-inherited with a structural variant of
hemoglobin E.
Clinical categories
The classification of α-thalassemia
is dependent on how both the α-globin
genes are deleted or reduced in activity
due to mutations. The first group of
α+-thalassemias are of several types,
but are dominated by –α3.7 and –α4.2
that correspond to the lengths of
deletion in the α-globin gene. The other
α+-thalassemias have several point
mutations, the most common being
chain-termination mutant haemoglobin
Constant Spring called αCSα. The second
group α0-thalassemias are due to
deletion of both the α-globin genes (-/-
), which might occur in heterozygous
condition with α+-thalassemias (-α/- or
αCSα/-). The ATR-16 syndrome, which
involves α-globin gene on chromosome
16, was shown to be associated
with mental retardation, also called
α-thalassemia x-linked intellectual
disability (ATRX).
The clinical categorization of
thalassemias is being simplified based
on clinical-management criteria. As
transfusion remains the major form of
12 / FUTURE MEDICINE / May 2019