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Hemoglobinopathy
Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of
one of the globin chains of the hemoglobin molecule. Hemoglobinopathies are
inherited single-gene disorders; in most cases, they are inherited as autosomal co-
dominant traits. Common hemoglobinopathies include sickle-cell disease. It is
estimated that 7% of world's population (420 million) are carriers, with 60% of total
and 70% pathological being in Africa. Hemoglobinopathies are most common in
populations from Africa, the Mediterranean basin and Southeast Asia.
Hemoglobinopathies imply structural abnormalities in the globin proteins
themselves. Thalassemias, in contrast, usually result in underproduction of normal
globin proteins, often through mutations in regulatory genes. The two conditions
may overlap, however, since some conditions which cause abnormalities in globin
proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some
hemoglobinopathies are also thalassemias, but most are not.
Either hemoglobinopathy or thalassemia, or both, may cause anemia. Some well-
known hemoglobin variants such as sickle-cell anemia and congenital
dyserythropoietic anemia are responsible for diseases, and are considered
hemoglobinopathies. However, many hemoglobin variants do not cause pathology
or anemia, and thus are often not classed as hemoglobinopathies, because they are
not considered pathologies. Hemoglobin variants are a part of the
normal embryonic and fetal development, but may also be pathologic mutant forms
of hemoglobin in a population, caused by variations in genetics. Other variants cause
no detectable pathology, and are thus considered non-pathological variants.
Sickle cell disease
Definition
Sickle cell disease describes a group of inherited blood disorders characterized by
chronic anemia, painful events, and various complications due to associated tissue
and organ damage.
Description
The most common and well-known type of sickle cell disease is sickle cell anemia,
also called SS disease. All types of sickle cell disease are caused by a genetic change
in hemoglobin, the oxygen-carrying protein inside the red blood cells. The red blood
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cells of affected individuals contain a predominance of a structural variant of the
usual adult hemoglobin. This variant hemoglobin, called sickle hemoglobin, has a
tendency to develop into rod-like structures that alter the shape of the usually flexible
red blood cells. The cells take on a shape that resembles the curved blade of the
sickle, an agricultural tool. Sickle cells have a shorter life span than normally-shaped
red blood cells. This results in chronic anemia characterized by low levels of
hemoglobin and decreased numbers of red blood cells. Sickle cells are also less
flexible and more sticky than normal red blood cells, and can become trapped in
small blood vessels preventing blood flow. This compromises the delivery of
oxygen, which can result in pain and damage to associated tissues and organs. Sickle
cell disease presents with marked variability, even within families.
Genetic profile
Humans normally make several types of the oxygen- carrying protein hemoglobin.
An individual’s stage in development determines whether he or she makes primarily
embryonic, fetal, or adult hemoglobins. All types of hemoglobin are made of three
components: heme, alpha (or alpha-like) globin, and beta (or beta-like) globin.
Sickle hemoglobin is the result of a genetic change in the beta globin component of
normal adult hemoglobin. The beta globin gene is located on chromosome 11. The
sickle cell form of the beta globin gene results from the substitution of a single DNA
nucleotide, or genetic building-block. The change from adenine to thymine at
codon (position) 6 of the beta globin gene leads to insertion of the amino acid
valine—instead of glutamic acid—at this same position in the beta globin
protein. As a result of this change, sickle hemoglobin has unique properties in
comparison to the usual type of adult hemoglobin. Most individuals have two normal
copies of the beta globin gene, which make normal beta globin that is incorporated
into adult hemoglobin. Individuals who have sickle cell trait (called sickle cell
carriers) have one normal beta globin gene and one sickle cell gene. These
individuals make both the usual adult hemoglobin and sickle hemoglobin in roughly
equal proportions, so they do not experience any health problems as a result of
having the trait. Although traces of blood in the urine and difficulty in concentrating
the urine can occur, neither represents a significant health problem as a result of
sickle cell trait. Of the millions of people with sickle cell trait worldwide, a small
handful of individuals have experienced acute symptoms. In these very rare cases,
individuals were subject to very severe physical strain.
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When both members of a couple are carriers of sickle cell trait, there is a 25% chance
in each pregnancy for the baby to inherit two sickle cell genes and have sickle cell
anemia, or SS disease. Correspondingly, there is a 50% chance the baby will have
sickle cell trait and a 25% chance that the baby will have the usual type of
hemoglobin.
Other types of sickle cell disease include SC disease, SD disease, and S/beta
thalassemia. These conditions are caused by the co-inheritance of the sickle cell gene
and another altered beta globin gene. For example, one parent may have sickle cell
trait and the other parent may have hemoglobin C trait (another hemoglobin trait that
does not cause health problems). For this couple, there would be a 25% chance of
SC disease in each pregnancy.
Signs and symptoms
Normal adult hemoglobin transports oxygen from the lungs to tissues throughout the
body. Sickle hemoglobin can also transport oxygen. However, once the oxygen
is released, sickle hemoglobin tends to polymerize (line-up) into rigid rods that
alter the shape of the red blood cell. Sickling of the red blood cell can be
triggered by low oxygen, such as occurs in organs with slow blood flow. It can
also be triggered by cold temperatures and dehydration. Sickle cells have a
decreased life span in comparison to normal red blood cells. Normal red blood
cells survive for approximately 120 days in the bloodstream; sickle cells last
only 10-12 days. As a result, the bloodstream is chronically short of red blood cells
and hemoglobin, and the affected individual develops anemia.
Sickle cells can create other complications. Due to their shape, they do not fit well
through small blood vessels. As an aggravating factor, the outside surfaces of sickle
cells may have altered chemical properties that increase the cells’ ‘stickiness’. These
sticky sickle cells are more likely to adhere to the inside surfaces of small blood
vessels, as well as to other blood cells. As a result of the sickle cells’ shape and
stickiness, blockages form in small blood vessels. Such blockages prevent
oxygenated blood from reaching areas where it is needed, causing pain as well as
organ and tissue damage.
The severity of symptoms cannot be predicted based solely on the genetic
inheritance. Some individuals with sickle cell disease develop health- or life-
threatening problems in infancy, but others may have only mild symptoms
throughout their lives. Individuals may experience varying degrees of health at
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different stages in the lifecycle. For the most part, this clinical variability is
unpredictable, and the reasons for the observed variability cannot usually be
determined. However, certain types of sickle cell disease (i.e. SC disease) tend to
result in fewer and less severe symptoms on average than other types of sickle cell
disease (i.e. SS disease). Some additional modifying factors are known. For
example, elevated levels of fetal hemoglobin in a child or adult can decrease the
quantity and severity of some symptoms and complications. Fetal hemoglobin is a
normally occurring hemoglobin that usually decreases from over 90% of the total
hemoglobin to under 1% during the first year of life. This change is genetically
determined, although some individuals may experience elevated levels of fetal
hemoglobin due to variation in the genes that control fetal hemoglobin production.
Such individuals often experience a reduction in their symptoms and complications
due to the ability of fetal hemoglobin to prevent the polymerization of sickle
hemoglobin, which leads to sickling of the red blood cell.
There are several symptoms that warrant immediate medical attention, including the
following:
_ Signs of infection (fever 101_F or 38.3_C, coughs frequently or breathing trouble,
unusual crankiness, feeding difficulties)
_ Signs of severe anemia (pale skin or lips, yellowing of the skin or eyes, very tired,
very weak)
_ Signs indicating possible dehydration (vomiting, diarrhea, fewer wet diapers)
_ Other signs (pain or swelling in the abdomen, swollen hands or feet, screams when
touched). These can be signs of various complications that occur in sickle cell
disease.
Diagnosis
Inheritance of sickle cell disease or trait cannot be prevented, but it may be predicted.
Screening is recommended for individuals in high-risk populations. In the United
States, African Americans and Latino Americans have the highest risk of having the
disease or trait. Sickle cell is also common among individuals of Mediterranean,
Middle Eastern, and Eastern Indian descent.
A complete blood count (CBC) will describe several aspects of an individual’s blood
cells. A person with sickle cell disease will have a lower than normal hemoglobin
level, together with other characteristic red blood cell abnormalities.
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A hemoglobin electrophoresis is a test that can help identify the types and quantities
of hemoglobin made by an individual. This test uses an electric field applied across
a slab of gel-like material. Hemoglobins migrate through this gel at various rates and
to specific locations, depending on their size, shape, and electrical charge. Although
sickle hemoglobin (Hb S) and regular adult hemoglobin (called Hb A) differ by only
one amino acid, they can be clearly separated using hemoglobin electrophoresis.
Isoelectric focusing and high-performance liquid chromatography (HPLC) use
similar principles to separate hemoglobins and can be used instead of or in various
combinations with hemoglobin electrophoresis to determine the types of hemoglobin
present.
Thalassemia
Definition
Thalassemia describes a group of genetic blood disorders characterized by absent or
reduced production of hemoglobin, the oxygen–carrying protein inside the red blood
cells. There are two basic groups of thalassemia disorders: alpha thalassemias and
beta thalassemias. These conditions cause varying degrees of anemia, which can
range from mild to life–threatening.
Description
Normal adult hemoglobin consists of four protein chains: two alpha and two beta
globins. Each chain carries a group called a heme, a ring– like molecule that contains
the iron that binds the oxygen. Thalassemias are classified according to the globin
that is affected, hence the names alpha and beta thalassemia. Although both classes
of thalassemia affect the same protein, the alpha and beta thalassemias are distinct
diseases that affect the body in different ways.
Alpha thalassemias
People whose hemoglobin does not produce enough alpha globin have alpha
thalassemia. The condition is the result of changes in the genes that code for making
alpha chains in hemoglobin. There are four types of alpha thalassemias:
_ Hemoglobin H disease (HHD): This thalassemia causes severe anemia and serious
health problems such as an enlarged spleen, and bone deformities.
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_ Alpha thalassemia major: this is the most severe type of alpha thalassemia. It is
also called hydrops fetalis and most individuals affected by this condition die before
or shortly after birth.
_ Alpha thalassemia minor: individuals affected by this thalassemia have smaller red
blood cells and display mild anemia. It is often misdiagnosed as iron deficiency
anemia.
_ Alpha thalassemia silent carrier: this thalassemia is difficult to detect because it
usually does not cause symptoms, hence its name.
Beta thalassemias
People whose hemoglobin does not produce enough beta protein have beta
thalassemia. The condition is the result of changes in the genes that code for making
beta complete lack of beta chains in the hemoglobin. Also called Cooley’s anemia,
it causes a life–threatening anemia that requires regular blood transfusions.
_ Beta thalassemia minor: individuals affected by this thalassemia simply carry the
genetic trait for thalassemia and commonly experience no health problems other than
a possible mild anemia.
_ Beta thalassemia intermedia: with this condition, the lack of beta chains in the
hemoglobin is significant enough to cause a moderately severe anemia and
significant health problems, including bone deformities and spleen enlargement.
However, the condition has a wide range of severity, from mild to moderately severe.
Beta thalassemias can be classified based on clinical symptoms.
Beta thalassemia major usually causes severe anemia that can occur within months
after birth. If left untreated, severe anemia can result in insufficient growth and
development, as well as other characteristic physical complications that can lead to
a dramatically decreased life expectancy. Fortunately, in developed countries, beta
thalassemia is usually identified by screening in the newborn period, before
symptoms have developed. Children who are identified early can be started on
ongoing blood transfusion therapy as needed. Although transfusion therapy prevents
many of the complications of severe anemia, the body is unable to eliminate the
excess iron contained in the transfused blood. Over time, this excess iron deposits in
tissues and organs, resulting in damage and organ failure. Another medication must
be administered to help the body eliminate the excess iron and prevent iron–overload
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complications. Individuals with beta thalassemia intermedia usually have moderate
anemia that only requires blood transfusions intermittently, if at all.
Genetic profile
Humans normally make several types of hemoglobin. An individual’s stage in
development determines whether he or she makes primarily embryonic, fetal, or
adult hemoglobins. Normal adult hemoglobin (HbA) is a tetrameric protein
consisting of four chains: two alpha globins, and two beta globins, each chain also
containing a heme. It is the major hemoglobin component of red blood cells (95%).
Additionally, red blood cells contain other minor hemoglobin forms: hemoglobin
A2 (HbA2) consisting of two alpha chains and two delta chains (3%) and
hemoglobin F (HbF), consisting of two alpha chains and two gamma chains (2%). If
a person can’t produce enough of either alpha or beta globins, the red blood cells do
not form normally and cannot carry oxygen properly, resulting in anemia. All
thalassemias are caused by deletions or modifications in the genes that control
globin production. These genes are located on chromosome 16 (alpha globin
genes) and chromosome 11 (beta, gamma, and delta genes). Mutations modify
the amount of alpha globin relative to that of the other globins being produced,
leading to an abnormal hemoglobin ratio and decreased hemoglobin production.
The globin that is produced in normal amounts over the other globin
accumulates and forms aggregates that damage the red blood cell membrane.
The thalassemias are recessively inherited, meaning that a genetic change must be
inherited from both the mother and the father. The severity of the disease is
influenced by the exact thalassemia mutations inherited, as well as other genetic and
environmental factors.
There are rare exceptions, notably with beta thalassemia, where globin gene
mutations exhibit a dominant pattern of inheritance in which only one gene needs to
be altered in order to see disease expression.
Beta thalassemia
In beta thalassemia, alpha globins are produced in excess over the beta globins,
which leads to the formation of alpha globin tetramers that accumulate and
interfere with red blood cell production (erythropoiesis).
These mutations occur in the HBB gene that provides instructions for making beta
hemoglobin. As of 2009, approximately 200 genetic mutations have been described
that cause beta thalassemia, designated as either beta0 or beta+ mutations. No beta
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globin is produced with a beta0 mutation, and only a small fraction of the normal
amount of beta globin is produced with a beta+ mutation. An individual having one
normal HBB gene and one with a beta thalassemia mutation is said to carry the beta
thalassemia trait. Beta thalassemia trait, like other hemoglobin traits, is
protective against malaria infection. Trait status is generally thought not to cause
health problems, although some women with beta thalassemia trait may have an
increased tendency toward anemia during pregnancy.
When two members of a couple carry the beta thalassemia trait, there is a 25%
chance that each of their children will inherit beta thalassemia disease by inheriting
two beta thalassemia mutations, one from each parent. The clinical severity of the
beta thalassemia disease—whether an individual has beta thalassemia intermedia or
beta thalassemia major—will depend largely on whether the mutations inherited are
beta0 or beta+ thalassemia mutations. Two beta0 mutations generally lead to beta
thalassemia major, and two beta+ thalassemia mutations generally lead to beta
thalassemia intermedia. Inheritance of one beta0 and one beta+ thalassemia
mutation tends to be less predictable. Although relatively uncommon, there are
other thalassemia-like mutations that can affect the beta globin gene. Hemoglobin
E is the result of a substitution of a single nucleotide. This change results in a
structurally altered hemoglobin that is produced in decreased amounts. Therefore,
hemoglobin E is unique in that it is both a quantitative (i.e. thalassemia- like) and
qualitative trait. When co-inherited with a beta thalassemia trait, it causes a disease
that is almost indistinguishable from beta thalassemia disease.
Large deletions around and including the beta globin gene can lead to delta/beta
thalassemia or hereditary persistence of fetal hemoglobin (HPFH). Interestingly,
delta/beta thalassemia trait behaves very similarly to beta thalassemia trait clinically.
However, HPFH trait does not tend to cause hemoglobin disease when co-inherited
with a second thalassemia or other beta globin mutation.
Alpha thalassemia
In alpha thalassemia, beta globins are produced in excess over the alpha globins,
which leads to the formation of beta globin tetramers that also accumulate and
interfere with erythropoiesis. Most individuals have four normal copies of the alpha
globin gene, two copies on each chromosome 16. These genes make the alpha globin
component of HbA. Alpha globin is also a component of HbF and HbA2. Mutations
of the alpha globin genes are usually deletions of the gene, resulting in absent
production of alpha globin. Since there are four genes (instead of the usual two) to
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consider when looking at alpha globin gene inheritance, there are several alpha
globin types that are possible. Absence of one alpha globin gene leads to a condition
known as silent alpha thalassemia trait. This condition causes no health problems
and can be detected only by special genetic testing. Alpha thalassemia trait occurs
when two alpha globin genes are missing. This can occur in two ways. The genes
may be deleted from the same chromosome, causing the ‘cis’ type of alpha
thalassemia trait. Alternately, they may be deleted from different
chromosomes, causing the ‘trans’ type of alpha thalassemia trait. In both
instances, there are no associated health problems, although the trait status may be
detected by more routine blood screening.
Hemoglobin H disease results from the deletion of three alpha globin genes,
such that there is only one functioning gene. Typically, this can occur when one
parent carries the silent alpha thalassemia trait, and the other parent carries the ‘cis’
type of the alpha thalassemia trait. In this situation, there is a 25% chance for
hemoglobin H disease in each of such a couple’s children.
Hemoglobin H disease–like symptoms can also be a part of a unique condition called
alpha thalassemia mental retardation syndrome. Alpha thalassemia mental
retardation syndrome can be caused by a deletion of a significant amount of
chromosome 16, affecting the alpha globin genes. This is usually not inherited, but
rather occurs sporadically in the affected individual. Affected individuals have mild
hemoglobin H disease, mild–to– moderate mental retardation, and characteristic
facial features. This syndrome can also occur as a sex–linked form in which a
mutation is inherited in a particular gene on the X chromosome. This gene influences
alpha globin production, as well as various other developmental processes.
Individuals affected with this form of the syndrome tend to have more severe mental
retardation, delayed development, nearly absent speech, characteristic facial
features, and genital–urinary abnormalities.
Alpha thalassemia major results from the deletion of all four alpha globin
genes, such that there are no functioning alpha globin genes. This can occur
when both parents carry the ‘cis’ type of the alpha thalassemia trait. In this situation,
there is a 25% chance for alpha thalassemia major in each of such a couple’s
children.
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Diagnosis
Thalassemia may be suspected if an individual shows signs that are suggestive of
the disease. In all cases, however, laboratory diagnosis is essential to confirm the
exact diagnosis and to allow for the provision of accurate genetic counseling about
recurrence risks and testing options for parents and affected individuals. Screening
is likewise recommended to determine trait status for individuals of high–risk ethnic
groups.
The following tests are used to screen for thalassemia disease and/or trait:
_ Complete blood count
_ Hemoglobin electrophoresis with quantitative hemoglobin A2 and hemoglobin F
_ Free erythrocyte–protoporphyrin (or ferritin or other studies of serum iron levels)
A complete blood count will identify low levels of hemoglobin, small red blood
cells, and other red blood cell abnormalities that are characteristic of a thalassemia
diagnosis. Since thalassemia trait can sometimes be difficult to distinguish from iron
deficiency, tests to evaluate iron levels are important.
A hemoglobin electrophoresis is a test that can help identify the types and quantities
of hemoglobin made by an individual. This test uses an electric field applied across
a slab of gel– like material. Hemoglobins migrate through this gel at various rates
and to specific locations, depending on their size, shape, and electrical charge.
Isoelectric focusing and high–performance liquid chromatography (HPLC) use
similar principles to separate hemoglobins and can be used instead of or in various
combinations with hemoglobin electrophoresis to determine the types and quantities
of hemoglobin present. Hemoglobin electrophoresis results are usually within the
normal range for all types of alpha thalassemia. However, hemoglobin A2 levels and
sometimes hemoglobin F levels are elevated when beta thalassemia disease or trait
is present.
Hemoglobin electrophoresis can also detect structurally abnormal hemoglobins that
may be co–inherited with a thalassemia trait to cause thalassemia disease (i.e.,
hemoglobin E) or other types of hemoglobin disease (i.e., sickle hemoglobin).
Sometimes DNA testing is needed in addition to the above screening tests. This can
be performed to help confirm the diagnosis and establish the exact genetic type of
thalassemia.
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