Thalassemia (from θάλασσα, thalassa, sea + αἷμα, haima, blood; British spelling, "thalassaemia") is an inherited autosomal co-dominant blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up
hemoglobinHemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of vertebrates, and the tissues of some invertebrates....
. Reduced synthesis of one of the globin chains can cause the formation of abnormal hemoglobin molecules, thus causing
anemiaAnemia is a decrease in normal number of red blood cells or less than the normal quantity of hemoglobin in the blood...
, the characteristic presenting symptom of the thalassemias.
Thalassemia is a quantitative problem of too few globins synthesized, whereas sickle-cell anemia (a
hemoglobinopathyHemoglobinopathy 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...
) is a qualitative problem of synthesis of an incorrectly functioning globin. Thalassemias usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. 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. Either or both of these conditions may cause anemia.
The disease is particularly prevalent among Mediterranean people, and this geographical association was responsible for its naming:
ThalassaIn Greek mythology, Thalassa was a primordial sea goddess, daughter of Aether and Hemera. With Pontus, she was the mother of the nine Telchines and Halia. Sometimes, she was thought of as the mother of Aphrodite with Uranus. She was the personification of the Mediterranean Sea.Alternative names...
(θάλασσα) is Greek for the sea,
Haema (αἷμα) is Greek for blood. In Europe, the highest concentrations of the disease are found in
GreeceGreece , officially the Hellenic Republic , is a country in southeastern Europe, situated on the southern end of the Balkan Peninsula....
and in parts of
ItalyItaly , officially the Italian Republic , is a country located on the Italian Peninsula in Southern Europe and on the two largest islands in the Mediterranean Sea, Sicily and Sardinia. Italy shares its northern, Alpine boundary with France, Switzerland, Austria and Slovenia...
, in particular, Southern Italy and the lower Po valley. The major Mediterranean islands (except the Balearics) such as
SicilySicily is the largest island in the Mediterranean Sea. It is an autonomous region of Italy. Several much smaller islands surrounding it are considered to be part of Sicily....
,
SardiniaSardinia is the second-largest island in the Mediterranean Sea . The area of Sardinia is . The nearest land masses to the island are the French island of Corsica, the Italian Peninsula, Tunisia, and the Spanish Balearic Islands...
,
MaltaMalta , officially the Republic of Malta , is a densely populated developed European country in the European Union. The Southern European island nation is an archipelago that includes the inhabited islands of Malta, Gozo and Comino, along with a number of smaller, uninhabited islands...
,
CorsicaCorsica is the fourth largest island in the Mediterranean Sea . It is located west of Italy, southeast of the French mainland, and north of the island of Sardinia....
,
CyprusCyprus , officially the Republic of Cyprus , is a Eurasian island country situated in the eastern Mediterranean, south of Turkey and west of Syria and Lebanon....
and
CreteCrete is the largest of the Greek islands and the fifth largest island in the Mediterranean Sea at 8,336 km²...
are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including Middle Easterners and North Africans. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (18% of the population) being in the
MaldivesThe Maldives , or Maldive Islands, officially Republic of Maldives, is an island country in the Indian Ocean formed by a double chain of twenty-six atolls stretching along north-south direction off India's Lakshadweep islands, between Minicoy Island and Chagos Archipelago...
.
Prevalence
Generally, thalassemias are prevalent in populations that evolved in humid climates where
malariaMalaria is a vector-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 350–500 million cases of malaria, killing between one and...
was endemic. It affects all races, as thalassemias protected these people from malaria due to the blood cells' easy degradation. Thalassemias are particularly associated with people of Mediterranean origin, Arabs, and Asians. The Maldives has the highest incidence of Thalassemia in the world with a
carrier rate of 18% of the population. The estimated prevalence is 16% in people from
CyprusCyprus , officially the Republic of Cyprus , is a Eurasian island country situated in the eastern Mediterranean, south of Turkey and west of Syria and Lebanon....
, 1% in
ThailandThe Kingdom of Thailand is an independent country that lies in the heart of Southeast Asia.It is bordered to the north by Laos and Burma, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the west by the Andaman Sea and Burma...
, and 3-8% in populations from
Bangladesh, officially the People's Republic of Bangladesh is a country in South Asia. It is bordered by India on all sides except for a small border with Burma to the far southeast and by the Bay of Bengal to the south...
,
ChinaChina is a cultural region, an ancient civilization, and, depending on perspective, a national or multinational entity extending over a large area in East Asia....
,
IndiaIndia, officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the south, the Arabian Sea on the west, and the Bay of Bengal...
,
MalaysiaMalaysia is a country in Southeast Asia that consists of thirteen states and three Federal Territories, with a total landmass of . The capital city is Kuala Lumpur, while Putrajaya is the seat of the federal government. The population stands at over 28 million inhabitants...
and
PakistanPakistan , officially the Islamic Republic of Pakistan, is a country located at the crossroads of South Asia, the Middle East, and Central Asia...
. There are also prevalences in descendants of people from
Latin AmericaLatin America is a region of the Americas where Romance languages – particularly Spanish, Portuguese, and variably French – are primarily spoken. Latin America has an area of approximately 21,069,501 km² , almost 3.9% of the Earth's surface or 14.1% of its land surface area...
and Mediterranean countries (e.g.
GreeceGreece , officially the Hellenic Republic , is a country in southeastern Europe, situated on the southern end of the Balkan Peninsula....
,
ItalyItaly , officially the Italian Republic , is a country located on the Italian Peninsula in Southern Europe and on the two largest islands in the Mediterranean Sea, Sicily and Sardinia. Italy shares its northern, Alpine boundary with France, Switzerland, Austria and Slovenia...
,
PortugalPortugal , officially the Portuguese Republic , is a country located in southwestern Europe on the Iberian Peninsula. Portugal is the westernmost country of mainland Europe and is bordered by the Atlantic Ocean to the west and south and by Spain to the north and east...
,
SpainSpain , officially the Kingdom of Spain , is a country located in southwestern Europe on the Iberian Peninsula.
[The Spanish constitution does not establish any official denomination of the country, even though España , Estado español and Nación española are used interchangeably...]
, and others). A very low prevalence has been reported from people in Northern Europe (0.1%) and Africa (0.9%), with those in
North AfricaNorth Africa or Northern Africa is the northernmost region of the African continent, linked by the Sahara to Sub-Saharan Africa.Geopolitically, the UN definition of Northern Africa includes the following seven countries or territories; Algeria, Egypt, Libya, Morocco, Sudan, Tunisia,Mauritania, and...
having the highest prevalence. Ancient Egyptians suffered from Thalassemia with as many as 40% of studied predynastic and dynastic mummies with the genetic defect. Today, it is particularly common in populations of indigenous ethnic minorities of Upper Egypt such as the Beja, Hadendoa, Saiddi and also peoples of the Delta, Red Sea Hill Region and especially amongst the Siwans.
Pathophysiology
The
thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α thalassemias, production of the α globin chain is affected, while in β thalassemia production of the β globin chain is affected.
Thalassemia produces a
deficiency of α or β globin, unlike
sickle-cell diseaseSickle-cell disease, or sickle-cell anaemia , is a life-long blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a mutation in the...
which produces a specific mutant form of β globin.
β globin chains are encoded by a single gene on chromosome 11; α globin chains are encoded by two closely linked genes on chromosome 16. Thus in a normal person with two copies of each chromosome, there are two loci encoding the β chain, and four loci encoding the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α thalassemias. β thalassemias are common in Africans, but also in Greeks and Italians.
Alpha (α) thalassemias
The α thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. α thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.
Beta (β) thalassemias
Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (β
o) if they prevent any formation of β chains (which is the most severe form of beta Thalassemia); they are characterized as (β
+) if they allow some β chain formation to occur. In either case there is a relative excess of α chains, but these do not form tetramers: rather, they bind to the
red blood cellRed blood cells are the most common type of blood cell and the vertebrate body's principal means of delivering oxygen to the body tissues via the blood. They take up oxygen in the lungs or gills and release it while squeezing through the body's capillaries. The cells are filled with hemoglobin, a...
membranes, producing membrane damage, and at high concentrations they form toxic aggregates.
Delta (δ) 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.
In combination with other hemoglobinopathies
Thalassemia can co-exist with other hemoglobinopathies. The most common of these are:
- hemoglobin E/thalassemia: common in Cambodia
The Kingdom of Cambodia , formerly known as Kampuchea , is a country in South East Asia with a population of over 14 million people. The kingdom's capital and largest city is Phnom Penh...
, ThailandThe Kingdom of Thailand is an independent country that lies in the heart of Southeast Asia.It is bordered to the north by Laos and Burma, to the east by Laos and Cambodia, to the south by the Gulf of Thailand and Malaysia, and to the west by the Andaman Sea and Burma...
, and parts of IndiaIndia, officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the south, the Arabian Sea on the west, and the Bay of Bengal...
; clinically similar to β thalassemia major or thalassemia intermedia.
- hemoglobin S/thalassemia, common in African and Mediterranean populations; clinically similar to sickle cell anemia, with the additional feature of splenomegaly
Splenomegaly is an enlargement of the spleen, which usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, the other three being cytopenia, normal or hyperplastic bone marrow, and a response to splenectomy...
- hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.
Genetic prevalence
α and β thalassemia are often inherited in an
autosomalAn autosome is a chromosome that is not a sex chromosome – that is to say there are an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes, but the X and Y chromosomes are sex chromosomes....
recessive fashion although this is not always the case. Cases of dominantly inherited α and β 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 β-globin gene. For the
autosomalAn autosome is a chromosome that is not a sex chromosome – that is to say there are an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes, but the X and Y chromosomes are sex chromosomes....
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 counselingGenetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid...
and
genetic testingGenetic testing allows the genetic diagnosis of vulnerabilities to inherit diseases, and can also be used to determine a child's paternity or a person's ancestry. Normally, every person carries two copies of every gene, one inherited from their mother, one inherited from their father. The human...
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 where genetic screening resources are limited. 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.
Treatment
Patients with thalassemia minor usually do not require any specific treatment. Treatment for patients with thalassemia major includes chronic
blood transfusionBlood transfusion is the process of transferring blood or blood-based products from one person into the circulatory system of another. Blood transfusions can be life-saving in some situations, such as massive blood loss due to trauma, or can be used to replace blood lost during surgery...
therapy, iron chelation, splenectomy, and allogeneic hematopoietic transplantation.
Medication
Medical therapy for beta thalassemia primarily involves iron chelation.
DeferoxamineDeferoxamine is a bacterial siderophore produced by the actinobacter Streptomyces pilosus. It has medical applications as a chelating agent used to remove excess iron from the body...
is the intravenously administered chelation agent currently approved for use in the United States. Deferasirox (Exjade) is an oral iron chelation drug also approved in the US in 2005.
The antioxidant
indicaxanthinIndicaxanthin is a type of betaxanthin, a plant pigment present in beets, prickly pear cactus, and a powerful antioxidant. It is also found in red dragonfruit.-Medical uses:...
, found in beets, in a spectrophotometric study showed that indicaxanthin can reduce perferryl-Hb generated in solution from met-Hb and hydrogen peroxide, more effectively than either
TroloxTrolox is a Hoffman-LaRoche's trade name for 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, a water-soluble derivative of vitamin E. It is an antioxidant, like vitamin E, and is used in biological or biochemical applications to reduce oxidative stress or damage.Trolox equivalent...
or
Vitamin CVitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate is required for a range of essential metabolic reactions in all animals and plants...
. Collectively, results demonstrate that indicaxanthin can be incorporated into the redox machinery of β-thalassemic RBC and defend the cell from oxidation, possibly interfering with perferryl-Hb, a reactive intermediate in the hydroperoxide-dependent Hb degradation.
Carrier detection
- A screening policy exists in Cyprus
Cyprus , officially the Republic of Cyprus , is a Eurasian island country situated in the eastern Mediterranean, south of Turkey and west of Syria and Lebanon....
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.
- In Iran
Iran , officially the Islamic Republic of Iran is a country in Western Asia. The name Iran has been in use natively since the Sassanid period and came into international use from 1935, before which the country was known internationally as Persia...
as a premarital screening, the man's red cell indices are checked first, if he has microcytosis (mean cell haemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic their haemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassaemia trait) they are referred to the local designated health post for genetic counselingGenetic counseling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning in order to prevent, avoid...
.
In 2008, in
SpainSpain , officially the Kingdom of Spain , is a country located in southwestern Europe on the Iberian Peninsula.
[The Spanish constitution does not establish any official denomination of the country, even though España , Estado español and Nación española are used interchangeably...]
, a baby was selectively implanted in order to be a cure for his brother's thalassemia. The child was born from an embryo screened to be free of the disease before implantation with In vitro fertilization. The baby's supply of immunocompatible cord blood was saved for transplantation to his brother. The transplantation was considered successful.
Benefits
Being a carrier of the disease may confer a degree of protection against
malariaMalaria is a vector-borne infectious disease caused by a eukaryotic protist of the genus Plasmodium. It is widespread in tropical and subtropical regions, including parts of the Americas, Asia, and Africa. Each year, there are approximately 350–500 million cases of malaria, killing between one and...
, and is quite common among people from
ItalianItaly , officially the Italian Republic , is a country located on the Italian Peninsula in Southern Europe and on the two largest islands in the Mediterranean Sea, Sicily and Sardinia. Italy shares its northern, Alpine boundary with France, Switzerland, Austria and Slovenia...
or
GreekGreece , officially the Hellenic Republic , is a country in southeastern Europe, situated on the southern end of the Balkan Peninsula....
origin, and also in some African and Indian regions. This is probably by making the red blood cells
more susceptible to the less lethal species
Plasmodium vivaxPlasmodium vivax is a protozoal parasite and a human pathogen. The most frequent and widely distributed cause of recurring malaria, P. vivax is one of four species of malarial parasite that commonly infect humans. It is less virulent than Plasmodium falciparum, which is the deadliest of the four,...
, simultaneously making the host RBC environment unsuitable for the merozoites of the lethal strain
Plasmodium falciparumPlasmodium falciparum is a protozoan parasite, one of the species of Plasmodium that cause malaria in humans. It is transmitted by the female...
. This is believed to be a selective survival advantage for patients with the various thalassemia traits. In that respect it resembles another genetic disorder,
sickle-cell diseaseSickle-cell disease, or sickle-cell anaemia , is a life-long blood disorder characterized by red blood cells that assume an abnormal, rigid, sickle shape. Sickling decreases the cells' flexibility and results in a risk of various complications. The sickling occurs because of a mutation in the...
.