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Thalassemias
Thalassemias DJ Weatherall, University of Oxford, Oxford, UK © 2013 Elsevier Inc. All rights reserved.
Glossary Abnormal hemoglobin A structural variant of hemoglobin. Bone marrow The site of production of the red blood cells in adult life.
The thalassemias are a group of inherited disorders of hemo globin (Hb). They were first reported independently from the United States and Italy in 1925. The word ‘thalassemia’, derived from Greek roots for ‘the sea’ and ‘blood’, reflects the Mediterranean origin of all the early cases that were described. Later, it was discovered that the thalassemias are widely dis tributed across the tropical regions of the world and that they are among the most common single-gene disorders. Both cur ious distribution and high frequency have arisen because symptomless carriers for these conditions have increased resis tance to malaria. Hence, they would be more likely to survive to have more children in highly malarious areas; the gene fre quency for the disease would have then increased until it was balanced by the deaths of the children who had received it from both parents and who would not survive to reproductive age (Figure 1).
Classification of the Thalassemias The thalassemias result from inherited abnormalities of the synthesis of the globin chains of hemoglobin. Humans have different hemoglobins at various stages of development. Normal adults have a major Hb called HbA, comprising about 97% of the total, and a minor component, HbA2 which accounts for 2–3%. The main Hb in fetal life is HbF, traces of which are found in normal adults. There are three embryonic Hbs. All these different Hbs are tetramers of two pairs of unlike globin chains. Adult and fetal Hbs have α chains associated with β (HbA and α2β2), δ (HbA2 and α2δ2), or γ chains (HbF and α2γ2), whereas in the embryo there are different α-like chains called ζ chains and distinct β-like chains called ε chains. Each globin chain has a heme moiety attached to it, to which oxygen is bound. There are two common types of thalassemia, α- and β-thalassemia, which result from defective synthesis of α or β chains. There are rarer forms in which both δ and β chain, or ε, γ, δ, and γ chain production, are defective, called δβ- or εγδβ-thalassemia, respectively. The thalassemias are inherited in a Mendelian recessive fashion. The severe, homozygous form of the disease is called thalassemia major, while the carrier state, in which only one defective globin gene is inherited, is called the trait. The disease is very heterogeneous from the clinical viewpoint and patients are encountered who fall in between these extremes; these disorders are called ‘thalassemia intermedia’.
60
Edema Accumulation of fluid in body tissues. Homotetramer A hemoglobin variant consisting of four identical peptide chains. Oxygen affinity of hemoglobin Relative efficiency by which hemoglobin is delivered to the tissues.
Molecular Basis α-Thalassemia Normal humans receive two α genes from each parent, a geno type which is written αα/αα. There are two main classes of α-thalassemia. First, there are the αo-thalassemias, in which both α genes are deleted, that is, all or part of the gene is missing; the homozygous state is written - -/- -, and the hetero zygous state - -/αα. In the α+-thalassemias only one of the α genes is lost; the homozygous and heterozygous states are designated –α/–α, and –α/αα, respectively. Sometimes α+-thalassemia results from a mutation which inactivates the α-globin gene rather than deleting it. In this case, the hetero zygous state is written αTα/αα.
β-Thalassemia Over 200 different mutations of the β-globin genes have been found in patients with β-thalassemia. They may affect gene function at any level between transcription, processing of the primary messenger RNA transcript, translation, or stability of the β-globin chain. Rarely, β-thalassemia, like α-thalassemia, may result from a deletion of the β-globin gene. Some of these mutations result in no β-chain production and the disease is called ‘βo-thalassemia’, while others cause a reduced output of β chains, β+-thalassemia. Some of the latter forms are extremely mild and may not be identifiable in carriers; most heterozy gotes for β-thalassemia have very mild anemia and an elevated level of HbA2.
Imbalanced Globin Synthesis All the thalassemias are characterized by imbalanced globin chain production. In the β-thalassemias, this results in an excess of α chains, which precipitate in the red cell precursors, leading to their damage in the bone marrow and shortening the survi val of their progeny in the peripheral blood. In the face of defective α chain production, excess γ chains produced in fetal life form γ4 molecules, while in adults excess β chains form β4 molecules; these homotetramers are called Hb Bart’s (γ4) and H (β4), respectively. They do not give up oxygen at normal phy siological tensions and are also unstable. This leads to a shortened red cell survival and hence anemia. Because the high oxygen affinity of the homotetramers leads to reduced oxygen delivery to the tissues, patients may be more sympto matic than would be expected by their degree of anemia.
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 7
doi:10.1016/B978-0-12-374984-0.01534-5
Thalassemias
61
α- and β-thalassemia Figure 1 The world distribution of the α- and β-thalassemia.
Clinical Course and Outcome
Clinical Diversity
The homozygous state for αo-thalassemia, that is, the loss of all four α globin genes, results in stillbirth, usually late in preg nancy. These infants are anemic and edematous and show all the features of severe intrauterine hypoxia. Pregnancies carrying these babies are complicated by a high frequency of toxemia and difficulties in delivery, particularly because of enormously enlarged placentas. Individuals who have lost three of their four α genes (-α/- -) have a condition called hemoglobin H disease, characterized by moderate anemia and enlargement of the spleen. Persons who have lost two or one of their α globin genes are not incapacitated. The homozygous or compound heterozygous (the inheri tance of two different alleles) states for severe forms of β-thalassemia are characterized by severe anemia which is man ifest during the first year of life when the switch from γ- to β-globin chain production occurs. Without regular transfusion, these children usually die within a few months. If they are inadequately transfused they become growth retarded, develop a mongoloid facial appearance, have gross skeletal deformities due to overgrowth of the bone marrow, and a variety of other complications (Figure 2). Children who are well transfused grow and develop normally but if they do not receive drugs to remove the excess iron gained by transfusion, they die of the effects of iron overload, which damages the liver, endocrine glands, and heart. Some of the milder forms of β-thalassemia are compatible with relatively normal development without regular blood transfusions.
All the thalassemias show remarkable clinical diversity. In the case of the β-thalassemias, this may occasionally reflect the
Figure 2 An X-ray photograph of the hands of a child with severe β-thalassemia showing the marked thinning of the bones of the hands due to expansion of bone marrow.
62
Thalassemias
inheritance of one or more mild β-thalassemia alleles but in many cases a milder course may be associated with the inheri tance of two severe alleles. At least two of the genetic modifiers that are responsible for a milder phenotype have been identi fied. It is clear that children with β-thalassemia, who are able to produce more fetal Hb than usual, tend to have milder disease. Several different gene loci have been identified as being respon sible for this increased facility for producing fetal Hb after birth but the precise mechanisms whereby they produce this effect are not yet understood. There is now strong evidence that the co-inheritance of α-thalassemia with β-thalassemia may reduce the severity of the latter, presumably by reducing the overall degree of globin chain imbalance with the production of a small excess of α chains. There is growing evidence that the severity of some of the complications of β-thalassemia, for example, iron loading and jaundice, may be modified by varia tion at particular gene loci. There also appears to be variation in the degree of adaptation to anemia and a number of environ mental factors that may modify the disease, or the patient’s response to it, have also been identified. In the case of the α-thalassemias, hemoglobin H disease exhibits particular clinical diversity. In this case, the major factor appears to be a particular molecular form of the disease. Those with the deletional variety (- -/-α) tend to run a milder course than those who have inherited one of the nondeletional forms of the disease (- -/αTα). While the former genotype is usually associated with a relatively mild disease, the latter is associated with more severe anemia which may, at least in some cases, require regular transfusion.
Coinheritance of Thalassemia with Hb Variants Although there are many structural Hb variants, most of them are rare and only three, hemoglobins S, C, and E, each high frequencies. Hence, it is not uncommon for a person with β-thalassemia to co-inherit a gene for one of these variants. The compound heterozygous state for β-thalassemia and the sickle cell gene, sickle cell β-thalassemia, results in a clinical picture similar to sickle cell anemia. Hemoglobin C β-thalassemia is restricted to certain parts of Africa and is a relatively mild disorder. Hemoglobin E, a variant which is produced at a reduced rate and hence causes a mild form of β-thalassemia, occurs at extremely high frequencies in South and Southeast Asia. Hemoglobin E β-thalassemia is the com mon form of severe thalassemia in this region and, in global terms, accounts for approximately half of the global cases of this condition. It has a remarkably diverse clinical picture ran ging from a transfusion-dependent disorder to a condition that is compatible with normal growth and development without transfusion. Although some of the mechanisms involved in this diversity are similar to those for β-thalassemia described in the previous section, much remains to be learned about the rea sons for the remarkable clinical diversity of this condition.
selective process. There is good evidence that the milder forms of α+-thalassemia, β-thalassemia, and hemoglobin E are pro tective against Plasmodium falciparum malaria. Another important factor in producing the high frequency of the tha lassemias is the high proportion of consanguineous marriages in many of the populations in which thalassemia is common; marriage to close relatives is a risk factor for all recessively inherited forms of genetic disease.
Avoidance and Treatment All the thalassemias can be identified in the carrier state, and most forms can be diagnosed in the fetus; thus, it is possible to offer counseling and prenatal diagnosis for parents who wish to terminate pregnancies carrying babies with severe forms of the disease. This approach has resulted in a major reduction in the births of new cases in many countries. The only definitive form of treatment is bone marrow trans plantation, which is only possible when there is a matching donor relative. Symptomatic treatment involves regular blood transfusion and the use of iron-chelating drugs to remove the excess iron which results from transfused blood. Children with β-thalassemia who are adequately transfused and chelated grow and develop normally and in some cases are now able to have children of their own. They require continuous expert supervi sion because they are prone to a variety of complications, including blood-borne infections, cardiac and endocrine damage due to iron loading, and the complexities of the administration of chelating agents, and their complications. Unfortunately, treatment of this type is not available to thousands of children in the developing countries, where the thalassemias and related disorders of Hb such as sickle cell anemia are presenting an increasingly serious global health problem. Future therapeutic efforts are being directed at trying to sti mulate the production of fetal Hb production, or at somatic gene therapy, directed at replacing defective α- or β-globin genes.
See also: Genetic Counseling; Sickle Cell Anemia.
Further Reading Higgs DR and Weatherall DJ (2009) The alpha thalassaemias. Cellular and Molecular Life Sciences 66(7): 1154–1162. Olivieri NF, Nathan DG, MacMillan JH, , et al. (1994) Survival of medically treated patients with homozygous β thalassemia. New England Journal of Medicine 331: 574–578. Steinberg MH, Forget BG, Higgs DR, and Weatherall DJ (eds.) (2009) Disorders of Hemoglobin, 2nd edn. New York: Cambridge University Press. Weatherall DJ and Clegg JB (2001) The Thalassaemia Syndromes, 4th edn. Oxford: Blackwell Scientific Publications Weatherall DJ (2008) Genetic variation and susceptibility to infection: The red cell and malaria. British Journal of Haematology 141(3): 276–286. Weatherall DJ (2010) The inherited diseases of hemoglobin are an emerging global health burden. Blood 115(22): 4331–4336.
Population Genetics Each population has its own particular mutations that cause α or β-thalassemia, which suggests that they have arisen by muta tion and that the gene frequency has been increased by a local
Relevant Websites http://www.ncbi.nlm.nih.gov – GeneReviews. www.thalassaemia.org.cy – Thalassaemia International Federation.
Glossary Abnormal hemoglobin A structural variant of hemoglobin. Bone marrow The site of production of the red blood cells in adult life.
The thalassemias are a group of inherited disorders of hemo globin (Hb). They were first reported independently from the United States and Italy in 1925. The word ‘thalassemia’, derived from Greek roots for ‘the sea’ and ‘blood’, reflects the Mediterranean origin of all the early cases that were described. Later, it was discovered that the thalassemias are widely dis tributed across the tropical regions of the world and that they are among the most common single-gene disorders. Both cur ious distribution and high frequency have arisen because symptomless carriers for these conditions have increased resis tance to malaria. Hence, they would be more likely to survive to have more children in highly malarious areas; the gene fre quency for the disease would have then increased until it was balanced by the deaths of the children who had received it from both parents and who would not survive to reproductive age (Figure 1).
Classification of the Thalassemias The thalassemias result from inherited abnormalities of the synthesis of the globin chains of hemoglobin. Humans have different hemoglobins at various stages of development. Normal adults have a major Hb called HbA, comprising about 97% of the total, and a minor component, HbA2 which accounts for 2–3%. The main Hb in fetal life is HbF, traces of which are found in normal adults. There are three embryonic Hbs. All these different Hbs are tetramers of two pairs of unlike globin chains. Adult and fetal Hbs have α chains associated with β (HbA and α2β2), δ (HbA2 and α2δ2), or γ chains (HbF and α2γ2), whereas in the embryo there are different α-like chains called ζ chains and distinct β-like chains called ε chains. Each globin chain has a heme moiety attached to it, to which oxygen is bound. There are two common types of thalassemia, α- and β-thalassemia, which result from defective synthesis of α or β chains. There are rarer forms in which both δ and β chain, or ε, γ, δ, and γ chain production, are defective, called δβ- or εγδβ-thalassemia, respectively. The thalassemias are inherited in a Mendelian recessive fashion. The severe, homozygous form of the disease is called thalassemia major, while the carrier state, in which only one defective globin gene is inherited, is called the trait. The disease is very heterogeneous from the clinical viewpoint and patients are encountered who fall in between these extremes; these disorders are called ‘thalassemia intermedia’.
60
Edema Accumulation of fluid in body tissues. Homotetramer A hemoglobin variant consisting of four identical peptide chains. Oxygen affinity of hemoglobin Relative efficiency by which hemoglobin is delivered to the tissues.
Molecular Basis α-Thalassemia Normal humans receive two α genes from each parent, a geno type which is written αα/αα. There are two main classes of α-thalassemia. First, there are the αo-thalassemias, in which both α genes are deleted, that is, all or part of the gene is missing; the homozygous state is written - -/- -, and the hetero zygous state - -/αα. In the α+-thalassemias only one of the α genes is lost; the homozygous and heterozygous states are designated –α/–α, and –α/αα, respectively. Sometimes α+-thalassemia results from a mutation which inactivates the α-globin gene rather than deleting it. In this case, the hetero zygous state is written αTα/αα.
β-Thalassemia Over 200 different mutations of the β-globin genes have been found in patients with β-thalassemia. They may affect gene function at any level between transcription, processing of the primary messenger RNA transcript, translation, or stability of the β-globin chain. Rarely, β-thalassemia, like α-thalassemia, may result from a deletion of the β-globin gene. Some of these mutations result in no β-chain production and the disease is called ‘βo-thalassemia’, while others cause a reduced output of β chains, β+-thalassemia. Some of the latter forms are extremely mild and may not be identifiable in carriers; most heterozy gotes for β-thalassemia have very mild anemia and an elevated level of HbA2.
Imbalanced Globin Synthesis All the thalassemias are characterized by imbalanced globin chain production. In the β-thalassemias, this results in an excess of α chains, which precipitate in the red cell precursors, leading to their damage in the bone marrow and shortening the survi val of their progeny in the peripheral blood. In the face of defective α chain production, excess γ chains produced in fetal life form γ4 molecules, while in adults excess β chains form β4 molecules; these homotetramers are called Hb Bart’s (γ4) and H (β4), respectively. They do not give up oxygen at normal phy siological tensions and are also unstable. This leads to a shortened red cell survival and hence anemia. Because the high oxygen affinity of the homotetramers leads to reduced oxygen delivery to the tissues, patients may be more sympto matic than would be expected by their degree of anemia.
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 7
doi:10.1016/B978-0-12-374984-0.01534-5
Thalassemias
61
α- and β-thalassemia Figure 1 The world distribution of the α- and β-thalassemia.
Clinical Course and Outcome
Clinical Diversity
The homozygous state for αo-thalassemia, that is, the loss of all four α globin genes, results in stillbirth, usually late in preg nancy. These infants are anemic and edematous and show all the features of severe intrauterine hypoxia. Pregnancies carrying these babies are complicated by a high frequency of toxemia and difficulties in delivery, particularly because of enormously enlarged placentas. Individuals who have lost three of their four α genes (-α/- -) have a condition called hemoglobin H disease, characterized by moderate anemia and enlargement of the spleen. Persons who have lost two or one of their α globin genes are not incapacitated. The homozygous or compound heterozygous (the inheri tance of two different alleles) states for severe forms of β-thalassemia are characterized by severe anemia which is man ifest during the first year of life when the switch from γ- to β-globin chain production occurs. Without regular transfusion, these children usually die within a few months. If they are inadequately transfused they become growth retarded, develop a mongoloid facial appearance, have gross skeletal deformities due to overgrowth of the bone marrow, and a variety of other complications (Figure 2). Children who are well transfused grow and develop normally but if they do not receive drugs to remove the excess iron gained by transfusion, they die of the effects of iron overload, which damages the liver, endocrine glands, and heart. Some of the milder forms of β-thalassemia are compatible with relatively normal development without regular blood transfusions.
All the thalassemias show remarkable clinical diversity. In the case of the β-thalassemias, this may occasionally reflect the
Figure 2 An X-ray photograph of the hands of a child with severe β-thalassemia showing the marked thinning of the bones of the hands due to expansion of bone marrow.
62
Thalassemias
inheritance of one or more mild β-thalassemia alleles but in many cases a milder course may be associated with the inheri tance of two severe alleles. At least two of the genetic modifiers that are responsible for a milder phenotype have been identi fied. It is clear that children with β-thalassemia, who are able to produce more fetal Hb than usual, tend to have milder disease. Several different gene loci have been identified as being respon sible for this increased facility for producing fetal Hb after birth but the precise mechanisms whereby they produce this effect are not yet understood. There is now strong evidence that the co-inheritance of α-thalassemia with β-thalassemia may reduce the severity of the latter, presumably by reducing the overall degree of globin chain imbalance with the production of a small excess of α chains. There is growing evidence that the severity of some of the complications of β-thalassemia, for example, iron loading and jaundice, may be modified by varia tion at particular gene loci. There also appears to be variation in the degree of adaptation to anemia and a number of environ mental factors that may modify the disease, or the patient’s response to it, have also been identified. In the case of the α-thalassemias, hemoglobin H disease exhibits particular clinical diversity. In this case, the major factor appears to be a particular molecular form of the disease. Those with the deletional variety (- -/-α) tend to run a milder course than those who have inherited one of the nondeletional forms of the disease (- -/αTα). While the former genotype is usually associated with a relatively mild disease, the latter is associated with more severe anemia which may, at least in some cases, require regular transfusion.
Coinheritance of Thalassemia with Hb Variants Although there are many structural Hb variants, most of them are rare and only three, hemoglobins S, C, and E, each high frequencies. Hence, it is not uncommon for a person with β-thalassemia to co-inherit a gene for one of these variants. The compound heterozygous state for β-thalassemia and the sickle cell gene, sickle cell β-thalassemia, results in a clinical picture similar to sickle cell anemia. Hemoglobin C β-thalassemia is restricted to certain parts of Africa and is a relatively mild disorder. Hemoglobin E, a variant which is produced at a reduced rate and hence causes a mild form of β-thalassemia, occurs at extremely high frequencies in South and Southeast Asia. Hemoglobin E β-thalassemia is the com mon form of severe thalassemia in this region and, in global terms, accounts for approximately half of the global cases of this condition. It has a remarkably diverse clinical picture ran ging from a transfusion-dependent disorder to a condition that is compatible with normal growth and development without transfusion. Although some of the mechanisms involved in this diversity are similar to those for β-thalassemia described in the previous section, much remains to be learned about the rea sons for the remarkable clinical diversity of this condition.
selective process. There is good evidence that the milder forms of α+-thalassemia, β-thalassemia, and hemoglobin E are pro tective against Plasmodium falciparum malaria. Another important factor in producing the high frequency of the tha lassemias is the high proportion of consanguineous marriages in many of the populations in which thalassemia is common; marriage to close relatives is a risk factor for all recessively inherited forms of genetic disease.
Avoidance and Treatment All the thalassemias can be identified in the carrier state, and most forms can be diagnosed in the fetus; thus, it is possible to offer counseling and prenatal diagnosis for parents who wish to terminate pregnancies carrying babies with severe forms of the disease. This approach has resulted in a major reduction in the births of new cases in many countries. The only definitive form of treatment is bone marrow trans plantation, which is only possible when there is a matching donor relative. Symptomatic treatment involves regular blood transfusion and the use of iron-chelating drugs to remove the excess iron which results from transfused blood. Children with β-thalassemia who are adequately transfused and chelated grow and develop normally and in some cases are now able to have children of their own. They require continuous expert supervi sion because they are prone to a variety of complications, including blood-borne infections, cardiac and endocrine damage due to iron loading, and the complexities of the administration of chelating agents, and their complications. Unfortunately, treatment of this type is not available to thousands of children in the developing countries, where the thalassemias and related disorders of Hb such as sickle cell anemia are presenting an increasingly serious global health problem. Future therapeutic efforts are being directed at trying to sti mulate the production of fetal Hb production, or at somatic gene therapy, directed at replacing defective α- or β-globin genes.
See also: Genetic Counseling; Sickle Cell Anemia.
Further Reading Higgs DR and Weatherall DJ (2009) The alpha thalassaemias. Cellular and Molecular Life Sciences 66(7): 1154–1162. Olivieri NF, Nathan DG, MacMillan JH, , et al. (1994) Survival of medically treated patients with homozygous β thalassemia. New England Journal of Medicine 331: 574–578. Steinberg MH, Forget BG, Higgs DR, and Weatherall DJ (eds.) (2009) Disorders of Hemoglobin, 2nd edn. New York: Cambridge University Press. Weatherall DJ and Clegg JB (2001) The Thalassaemia Syndromes, 4th edn. Oxford: Blackwell Scientific Publications Weatherall DJ (2008) Genetic variation and susceptibility to infection: The red cell and malaria. British Journal of Haematology 141(3): 276–286. Weatherall DJ (2010) The inherited diseases of hemoglobin are an emerging global health burden. Blood 115(22): 4331–4336.
Population Genetics Each population has its own particular mutations that cause α or β-thalassemia, which suggests that they have arisen by muta tion and that the gene frequency has been increased by a local
Relevant Websites http://www.ncbi.nlm.nih.gov – GeneReviews. www.thalassaemia.org.cy – Thalassaemia International Federation.