Thalassemia is an inherited autosomal recessive
blood disease. In thalassemia, the genetic defect results
in reduced rate of synthesis of one of the globin chains
that make up hemoglobin. Reduced synthesis of one of
the globin chains causes the formation of abnormal hemoglobin
molecules, and this in turn causes the anemia which
is the characteristic presenting symptom of the thalassemias.
Hemoglobinopathies imply structural abnormalities in
the globin proteins themselves. The two conditions may
overlap, however, since some conditions which cause
abnormalities in globin proteins (hemoglobinopathy)
also affect their production (thalassemia). Thus, some
thalassemias are hemoglobinopathies, but most are not.Generally,
thalassemias are prevalent in populations that evolved
in humid climates where malaria was endemic, but affects
all races. Thalassemias are particularly associated
with Arab-Americans, people of Mediterranean origin,
and Asians. The estimated prevalence is 16% in people
from Cyprus, 3-14% in Thailand, and 3-8% in populations
from India, Pakistan, Bangladesh, Malaysia and China.
There are also prevalences in descendants of people
from Latin America, and Mediterranean countries (e.g.
Spain, Portugal, Italy, Greece and others). A very low
prevalence has been reported from people in Africa (0.9%),
with those in northern Africa having the highest prevalence,
and northern Europe (0.1%).
The thalassemias are classified according to which chain
of the hemoglobin molecule is affected (see hemoglobin
for a description of the chains). In a thalassemias,
production of the a globin chain is affected, while
in ß thalassemia production of the ß globin
chain is affected.
Thalassemia produces a deficiency of a or ß globin,
unlike sickle-cell disease which produces a specific
mutant form of ß globin.
Deletion of one of the a loci has a high prevalence
in people of African-American or Asian descent, making
them more likely to develop a thalassemias. ß
thalassemias are common in African-Americans, but also
in Greeks and Italians.
Alpha (a) thalassemias
The a thalassemias involve the genes HBA1 (Online 'Mendelian
Inheritance in Man' (OMIM) 141800) and HBA2 (Online
'Mendelian Inheritance in Man' (OMIM) 141850), inherited
in a Mendelian recessive fashion. It is also connected
to the deletion of the 16p chromosome. a thalassemias
result in decreased alpha-globin production, therefore
fewer alpha-globin chains are produced, resulting in
an excess of ß chains in adults and excess ? chains
in newborns. The excess ß chains form unstable
tetramers (called Hemoglobin H or HbH of 4 beta chains)
which have abnormal oxygen dissociation curves.
Beta (ß) thalassemias
Beta thalassemias are due to mutations in
the HBB gene on chromosome 11 (Online 'Mendelian Inheritance
in Man' (OMIM) 141900), also inherited in an autosomal-recessive
fashion. The severity of the disease depends on the
nature of the mutation. Mutations are characterized
as (?o) if they prevent any formation of ? chains; they
are characterized as (?+) if they allow some ? chain
formation to occur. In either case there is a relative
excess of ? chains, but these do not form tetramers:
rather, they bind to the red blood cell membranes, producing
membrane damage, and at high concentrations they form
toxic aggregates.
Delta (d) thalassemia
As well as alpha and beta chains being present in hemoglobin
about 3% of adult hemoglobin is made of alpha and delta
chains. Just as with beta thalassemia, mutations can
occur which affect the ability of this gene to produce
delta chains. A mutation that prevents formation of
any delta chains is termed a delta0 mutation, whereas
one that decreases but does not eliminate production
of delta chain is termed a delta+ mutation. When one
inherits two delta0 mutations, no hemoglobin A2 (alpha2,
delta2) can be formed. Hematologically, however, this
is innocuous because only 2-3% of normal adult hemoglobin
is hemoglobin A2. The individual will have normal hematological
parameters (erythrocyte count, total hemoglobin, mean
corpuscular volume, red cell distribution width). Individuals
who inherit only one delta thalassemia mutation gene
will have a decreased hemoglobin A2, but also no hematological
consequences. The importance of recognizing the existence
of delta thalassemia is seen best in cases where it
may mask the diagnosis of beta thalassemia trait. In
beta thalassemia, there is an increase in hemoglobin
A2, typically in the range of 4-6% (normal is 2-3%).
However, the co-existence of a delta thalassemia mutation
will decrease the value of the hemoglobin A2 into the
normal range, thereby obscurring the diagnosis of beta
thalassemia trait. This can be important in genetic
counseling, because a child who is the product of parents
each of whom has beta0 thalassemia trait has a one in
four chance of having beta thalassemia major.
Genetic prevalence
Thalassemia has an autosomal recessive pattern of inheritance.a
and ß thalassemia are often inherited in an autosomal
recessive fashion although this is not always the case.
Reports of dominantly inherited a and ß thalassemias
have been reported the first of which was in an Irish
family who had a two deletions of 4 and 11 bp in exon
3 interrupted by an insertion of 5 bp in the ß-globin
gene. For the autosomal recessive forms of the disease
both parents must be carriers in order for a child to
be affected. If both parents carry a hemoglobinopathy
trait, there is a 25% chance with each pregnancy for
an affected child. Genetic counseling and genetic testing
is recommended for families that carry a thalassemia
trait.
There are an estimated 60-80 million people in the world
who carry the beta thalassemia trait alone. This is
a very rough estimate and the actual number of thalassemia
Major patients is unknown due to the prevalence of thalassemia
in less developed countries in the Middle East and Asia.
Countries such as India, Pakistan and Iran are seeing
a large increase of thalassemia patients due to lack
of genetic counseling and screening. There is growing
concern that thalassemia may become a very serious problem
in the next 50 years, one that will burden the world's
blood bank supplies and the health system in general.
There are an estimated 1,000 people living with Thalassemia
Major in the United States and an unknown number of
carriers. Because of the prevalence of the disease in
countries with little knowledge of thalassemia, access
to proper treatment and diagnosis can be difficult.
As with other genetically acquired disorders, genetic
counseling is recommended.
Management
Genetic screening is required to identify such condition.
A screening policy exists on both sides of the island
of Cyprus to reduce the incidence of thalassemia, which
since the program's implementation in the 1970s (which
also includes pre-natal screening and abortion) has
reduced the number of children born with the hereditary
blood disease from 1 out of every 158 births to almost
zero. Pre-marital screening with proper counseling can
reduce the risk of thalassemia of the future offspring.
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