The α -thalassemias also occur widely throughout the world, including Africa, the Mediterranean countries, the Middle East, and Southeast Asia.

As in β-thalassemia, there is some heterogeneity in presentation of the more severe forms of α thalassemia, but much less so. Genotype phenotype correlation is consistent, and most of these individuals do not have a significant degree of IE, making them somewhat different than individuals with β -thalassemia. Since each individual normally has 2 α -globin genes on each chromosome 16, there are 4 genotypes of α-thalassemia, with 3, 2, 1, or no functioning α -globin genes.

The α -thalassemias are more difficult to diagnose because the characteristic elevations in HbA 2 or HbF seen in β -thalassemia do not occur, precluding the use of hemoglobin fractionation for diagnosis. However, the gene deletions responsible for the most common varieties are readily detectable by molecular biology methods.

Genetics

The four classic α -thalassemia syndromes are α +-thalassemia trait, in which one of the four α -globin genes is non-functional; α 0-thalassemia trait, with two dysfunctional genes; HbH disease, with three affected genes; and hydrops fetalis with Hb Bart, in which all four genes are defective. In general, partial deletions are more deleterious and create a more severe phenotype than complete deletions. In the older literature, α 0- and α +-thalassemia are referred to as α -thalassemia-1 and α -thalassemia-2, respectively. Non-function of α -globin genes is usually deletional ( Fig. 1). At the molecular level, α +-thalassemia has been found to be associated with two common gene deletions resulting from different nonhomologous crossing-over events between the two linked α -globin genes: a 3.7-kb rightward deletion (- α 3.7) resulting in a fused α 2α 1-globin gene and a 4.2-kb leftward deletion (- α 4.2) resulting in loss of the 5 ′ ( α 2) gene.  One or two α gene deletions occur at a high frequency throughout West Africa, the Mediterranean, the Middle East, and Southeast Asia. In the United States, about 30% of Americans of African descent carry these defects. In some parts of Papua New Guinea up to 80% of the population are carriers. When two genes are deleted, this may occur in the cis or trans configuration and has implications for offspring should both par ents have α-thalassemia trait. α +-thalassemia trait inherited in trans configuration is very common in individuals of African or Middle Eastern ancestry, and since cis α 0-thalassemia deletion is rare in these individuals, HbH disease is rarely encountered, and hydrops fetalis has not yet been reported in individuals of African ethnicity. α 0-thalassemia trait inherited in cis configuration is common in individuals of Asian ancestry, and hence HbH and hydrops are more commonly seen in these populations. α 0-thalassemia trait inherited in cis configuration is also found in Mediterranean populations, but less frequently than in Asians.

Fig1. GENETIC ORIGINS OF THE “CLASSIC” α-THALASSEMIA SYNDROMES CAUSED BY GENE DELETIONS IN THE α-GLOBIN GENE CLUSTER. Hemoglobin Constant Spring is an α -globin-chain variant synthesized in such small amounts (1% to 2% of normal) that it has the phenotypic impact of a severe nondeletion α -thalassemia allele; however, the α cs allele is always linked to a functioning α -globin gene, so it has never been associated with hydrops fetalis. CS, Constant Spring; Hb, hemoglobin.

Nondeletional forms of α -thalassemia, which account for 15% to 20% of patients, arise from mutations similar to those described for β -thalassemia.  Fig. 2 illustrates the different α -thalassemia mutations and phenotypes. Structurally abnormal hemoglobins have also been associated with α -thalassemia. The Quong Sze α -globin chain ( α ^125Leu→Pro) is exceedingly labile and is destroyed so rapidly after its synthesis that no Hb tetramers containing the mutant α chain can be formed.  α + -thalassemias also exhibit epistasis with haptoglobin variants that alters patterns in malaria protection.  How common the nondeletion forms of α +-thalassemia are in any particular populations is uncertain, but they have been reported quite frequently in some of the Mediterranean island populations and in the Middle Eastern and Southeast Asian populations. The α -chain termination mutants, such as Hb Constant Spring, seem to be particularly common in Southeast Asia. Approximately 4% of the population in Thailand are carriers.

Fig2. PATHOPHYSIOLOGY OF HEMOGLOBIN H DISEASE AND HYDROPS FETALIS WITH HB BART. Hb, Hemoglobin; mRNA, messenger ribonucleic acid. (Adapted from Benz EJ Jr. The hemoglobinopathies. In: Kelly WN, DeVita VT, eds. Textbook of Internal Medicine. Philadelphia: JB Lippincott; 1988:1423.)

Previously, the diagnosis of α -thalassemia trait was usually one of exclusion, with a microcytic anemia and normal iron studies and Hb Fractionation. However, with the ready availability of globin gene analysis in the developed world, the diagnosis of α-thalassemia is now easier to make conclusively. These tests are also used for prenatal diagnosis of HbH or α -thalassemia major.

Molecular Pathology and Pathophysiology

As there is a relative excess of non- β -globins in β -thalassemia, there is an excess of non– α -chain production in the α -thalassemias, but the consequences are quite different. Alpha globin chains are required for HbF and HbA production, therefore, defective α -chain production is manifest in both fetal and adult life. In the fetus, excess γ -chain production results in formation of γ 4 homotetramers or Hb Bart, while in the adult, excess of β chains forms β 4 homotetramers or HbH. Hb Bart and HbH do not precipitate to any significant degree in the marrow, and therefore the α -thalassemias are not characterized by severe IE despite marked globin-chain imbalance in the severe α -thalassemias.  The erythroid marrow is more effective, and marrow hyperplasia and EMH are not as significant. However, β 4 tetramers precipitate as red cells age, with the formation of inclusion bodies which leads to a shortened survival of red cells from their damage in the microvasculature of the spleen. Therefore, anemia of the more severe forms of α -thalassemia in the adult results from hemolysis more than IE. Hb Bart is more stable than HbH and does not form large inclusions. Also, both Hb Bart and HbH show no heme-heme interaction and have almost hyperbolic oxygen dissociation curves with very high oxygen affinities. They are, therefore, not able to effectively release oxygen at physiologic tissue tensions making them very poor oxygen carriers, which exacerbates hypoxia from the anemia, with potentially severe consequences. Infants with high levels of Hb Bart in α -thalassemia major have severe intrauterine hypoxia, which is probably responsible for the enormously hypertrophied placentas, the severe erythroblastosis, the gross hydropic state of the fetus as a result of increased capillary permeability and possibly for the associated developmental abnormalities that occur with the severe forms of intrauterine α -thalassemia.

The two α -globin genes on each chromosome, α 1 and α 2, do not function identically. Studies of newborns from the archipelago of Vanuatu in the Southwest Pacific and from Papua New Guinea indicate that homozygotes for the rightward - α ^3.7III deletion (where only a fused α 2α 1-globin gene, mostly of the α 2 type, remains) have lower Hb Bart levels (3.5% ± 0.8%) than those of infants homozygous for the leftward - α 4.2 deletion (in whom only the α 1-globin gene remains) (6.0% ± 1.4%). These results suggest that the 5 ′ α 2-globin gene has a higher output than the 3 ′ α 1-globin gene, a conclusion supported by direct measurement of α 2/ α 1 mRNA ratios.

Clinical Manifestations and Diagnosis

 Silent Carrier (α+-Thalassemia Trait)

Individuals with α +-thalassemia trait are typically completely asymptomatic and have no consistent hematologic manifestations. The Hb level is normal, and the RBCs are usually not microcytic. HbA 2 and HbF are normal. During the newborn period, small amounts ( ≤ 3 %) of Hb Bart ( γ 4 ) may be seen. This condition is most often recognized when an apparently normal individual becomes the parent of a child with HbH disease after mating with a person with α 0-thalassemia trait in cis form. The mild excess of β -globin chains is probably removed in erythroblasts by proteolysis.  α +-thalassemia is particularly common in Melanesia, as well as in Southeast Asia and in African Americans, reaching a prevalence of more than 80% in north coastal Papua New Guinea.

The level of α -globin gene expression differs in the two conditions, as discussed in the following section.

α0-Thalassemia Trait (α-Thalassemia Trait)

These individuals typically present with a mild microcytic anemia, similar to those with β -thalassemia trait. They are usually asymptomatic and have no other clinical manifestations of thalassemia. Levels of HbA 2 in the low to low-normal range (1.5% to 2.5%) and β / α syn thetic ratios averaging 1.4:1 characterize α 0-thalassemia trait. During the perinatal period, elevated amounts of Hb Bart are noted (3% to 8%). Microcytosis is present in cord blood erythrocytes. The degree of anemia and amount of Hb Bart may be related to whether the α 1 or α 2 genes are deleted.

HbH is not detected in hemolysates of peripheral RBCs, prob ably because of rapid proteolysis of HbH or free β -globin chains. However, approximately 1% of erythroblasts and BM reticulocytes have inclusions. When an α -thalassemia gene occurs in persons who are also heterozygous for α -globin chain variant Hbs, such as HbS, HbC, or HbE, the proportion of the abnormal Hb is lower than that seen in simple heterozygotes.  The lower level of the abnormal Hb is attributable to posttranslational control because of higher affinity of β Achains for a limited pool of α -globin chains coupled with proteolysis of the uncombined β variant chains.  In the nondeletion forms of α -thalassemia, there may be an extremely diverse series of phenotypes, with some individuals being more anemic, and having the clinical picture of HbH disease, while others may have only mild hypochromic anemia like the deletional form.

Hemoglobin H Disease

 HbH disease is associated with a moderately severe but variable anemia resembling β -thalassemia intermedia, with osseous changes and splenomegaly.  It occurs predominantly in Asians and occasionally in persons of European (Mediterranean) descent but is rare in persons of African ancestry. Deletional HbH occurs when three deletional alpha mutations occur. Non-deletional HbH occurs when two deletional alpha mutations occur with an alpha ( + ) mutation (e.g., Constant Spring). Though all patients have anemia, the degree is variable, based on the expression of the single α-globin gene, and any other potential genetic disease modifiers. The clinical phenotype varies considerably, being considerably milder in some patients and severe enough to cause hydrops fetalis in others.  While a few may have severe anemia, and require regular or intermittent transfusions, most have a much milder course.  Some symptoms of the chronic microcytic anemia may be seen, such as fatigue and exercise intolerance, but these are usually not severe. Since HbH is unstable, it precipitates within the circulating RBCs and hemolysis occurs. The higher the proportion of HbH, the more hemolytic the clinical phenotype. Nondeletional HbH genotypes are more likely to have higher percentage HbH, more hemolysis, more splenomegaly, and more advanced disease.

Since the degree of IE in α -thalassemia is mild, splenomegaly is somewhat variable, and the other clinical manifestations of the thalassemia intermedia syndrome, such as bone disease and iron overload are not frequently seen, though adults with deletional HbH may develop some of the same complications as β -thalassemia intermedia, including osteoporosis, cholelithiasis, and iron over load.  The degree of deletions in HbH is also relevant to clinical presentation.

Exacerbations of anemia during febrile illnesses are common and are usually characterized by increasing fatigue and jaundice.

HbH can be demonstrated by incubation of blood with supravital oxidizing stains such as 1% brilliant cresyl blue. Multiple small inclusions form in the RBCs. Electrophoresis of a freshly prepared hemolysate at alkaline or neutral pH demonstrates a fast-moving component amounting to 3% to 30% of the total Hb. Concomitant iron deficiency may reduce the amount of HbH in the patient’s RBCs. A syndrome of HbH disease associated with mental retardation, other congenital anomalies, and large deletions on chromosome 16 has been noted in several families of European origin.

Hydrops Fetalis With Hb Bart

Alpha-thalassemia major (homozygous α 0 thalassemia) is found most commonly in Mediterranean and East Asian (Chinese, Cambodian, Thai, and Filipino) populations because of the higher prevalence of two gene deletions in cis configuration, but is rare in African and Middle Eastern populations, where two gene deletions are usually in trans configuration. Affected fetuses are usually born prematurely and are either stillborn or die shortly after birth.  Hydropic infants have marked anasarca and massive hepatosplenomegaly. Extreme extramedullary erythropoiesis occurs in response to the profound hypoxia and hemolytic anemia characteristic of this disease. The universal edema characteristic of the hydrops fetalis syndrome is a reflection of severe congestive heart failure and hypoalbuminemia in utero. This is partly a consequence of anemia, but the strikingly abnormal oxygen affinity of the tetrameric Hb Bart is probably the most important determinant of the severe tissue hypoxia. The oxygen dissociation curve of Hb Bart lacks the normal sigmoid form because of noncooperation during oxygen loading and unloading and is markedly shifted to the left. The shift is so great that little oxygen is released under conditions of low oxygen concentration in the tissues.

Infants with this syndrome do not die in an earlier trimester of pregnancy because of the presence of Hb Portland ( ζ 2 γ 2 ). This Hb does display cooperativity in a manner similar to that of HbF and therefore has a much more favorable oxygen dissociation pattern than that of Hb Bart. A high incidence of toxemia of pregnancy has been described in women carrying severely affected infants, providing an increased rationale for prenatal diagnosis of this condition.

Severe anemia is usually present, with Hb levels of 3 to 10 g/dL. The RBCs are markedly microcytic and hypochromic and include target cells and large numbers of circulating nucleated RBCs. These morphologic abnormalities and a negative Coombs test result exclude hemolytic diseases caused by blood group incompatibility.

Hb electrophoresis reveals predominantly Hb Bart, with a smaller amount of HbH. A minor component identified as Hb Portland ( ζ 2 γ 2 ) migrating in the position of HbA is also seen. Normal HbA and HbF are totally absent.

Therapy

Fetuses with homozygous α 0-thalassemia usually die in utero because of severe hydrops fetalis and are stillborn. However, some infants have had successful blood exchange transfusion immediately after birth.  It is also possible to salvage affected fetuses by in utero blood transfusions.  Limb and urogenital defects are present in a substantial portion of infants with homozygous α 0-thalassemia who are rescued by these measures, and some infants have develop mental delay or other neurologic abnormalities. Management after the perinatal period is similar to the management of patients with β - thalassemia major and includes transfusion and chelation therapy as well as the possibility of BMT.

Most patients with HbH disease do not require RBC transfusions. For patients with more severe disease, characterized by lower Hb levels or frequent exacerbations of the anemia, splenectomy can be helpful. Oxidant drugs can accelerate precipitation of HbH and exacerbate hemolysis; they should therefore be avoided. Exchange transfusion can be used to decrease deleterious levels of HbH.

Infants with heterozygous α 0-thalassemia trait lose their Hb Bart during the first few months of life and are left with the hematologic findings of α -thalassemia trait, a mild hypochromic microcytosis that persists throughout life. These individuals do not require any therapy, and the same guidelines are followed for their care as with β - thalassemia trait. Iron supplementation is only necessary if there is true iron deficiency, and routine supplementation to raise the hemoglobin level is futile and should not be done. These individuals should seek genetic counseling when ready for childbearing.

Novel Therapies

Several newer approaches are being studied for α-thalassemia:

A. In order to ameliorate anemia in individuals with HbH disease, AG-348 (Mitapivat) will be entering a phase II/III clinical trial in NTD HbH patients. Mitapivat is an oral, small molecule allosteric activator of wild-type and a variety of mutated PKR enzymes. In non transfusion-dependent individuals with β -thalassemia intermedia and HbH disease, early short-term phase II data show an increase in Hb levels and a reduction in markers of hemolysis. This agent is in clinical trials in NTD patients.

B. A phase I clinical trial to evaluate the safety of in utero HSCT in fetuses with α-thalassemia major is also underway.  Maternal BM would be infused at the time of the in utero red cell transfusion. The goal is to take advantage of the maternal-fetal tolerance that exists during pregnancy, thus no conditioning chemotherapy would be required.

De Novo and Acquired Forms of α-Thalassemia

 Two distinct α -thalassemia syndromes have been described that are attributable to acquired or de novo mutations: (1) α -thalassemia associated with mental retardation and (2) HbH disease associated with MDS.

α-Thalassemia Associated With Mental Retardation

Alpha-thalassemia or HbH disease can occur as a de novo abnormaity in a rare disorder called the α -thalassemia with mental retardation syndrome (ATR).  In this disorder, affected patients have mental retardation and a number of other developmental abnormalities in association with α -thalassemia trait or HbH disease that is inherited in a nontraditional manner. Two distinct types of the ATR syndrome have been identified. In some cases, there is the de novo appearance of large (2000 kb or so) deletions involving the entire α -globin gene cluster and adjacent DNA at the tip of chromosome 16, the so-called ATR-16 syndrome. In some of these patients, the deletion produces detectable cytogenetic abnormalities of chromosome 16, indicating that a very large segment of the chromosome is deleted, sometimes because of unbalanced chromosomal translocations involving the telomeres of the affected chromosomes. In some cases, one parent is heterozygous for α +-thalassemia by various criteria and the other parent is completely normal; in such cases, the child has HbH disease (- -/- α ). In other cases, both parents are normal and the affected child has the hematologic phenotype of heterozygous α 0-thalassemia (- -/ α α ) without HbH disease. In this form of ATR, the clinical findings, such as the degree of mental retardation and associated congenital abnormalities, are variable.

The second type of ATR syndrome is not associated with detect able deletions of the α -globin gene complex. The molecular basis of the disorder consists of mutations of a gene on the X chromosome, and the condition has been called the alpha-thalassemia/mental retar dation, X-linked (ATR-X) syndrome.  In contrast to patients with the ATR-16 syndrome who have a varied phenotype of developmental abnormalities, patients with the ATR-X syndrome have a more uniform or consistent phenotype, particularly severe mental retardation (with IQs of 50 to 70) and a characteristic dysmorphic facial appearance.

The affected gene in this syndrome encodes a trans-acting factor, called ATR-X, that is thought to influence the expression of the α -globin genes as well as that of other genes.  The structure of this large (280 kDa) DNA-binding protein is complex and contains two major functional domains: an N-terminal cysteine-rich zinc finger–containing domain, called the ADD domain, that has structural features similar to those of DNA methyl transferases, and a C-terminal helicase/ATPase domain. The majority of the mutations associated with the ATR-X syndrome are located in the ADD domain or the helicase domain. The ATRX protein is widely expressed in many different tissues and its intracellular localization is within three different nuclear subcompartments: heterochromatin, ribosomal DNA arrays, and promyelocytic leukemia (PML) bodies. It has been shown to interact with other proteins such as the heterochromatin-associated protein HP1 and Daxx, one of the proteins localized in PML bodies. The prevailing opinion is that the ATRX protein is part of a large chromatin-remodeling complex of the SWI2/SNF2 family. It also has ATPase activity and has translocase activity, that is, it can move along DNA as a “molecular motor.” The precise mechanism(s) by which ATRX influences the expression of α -globin (and other) genes remains unknown.

Acquired HbH Disease Associated With Myelodysplastic Syndrome (ATMDS)

HbH disease has occasionally been observed to develop during the course of different types of MDS and more rarely in patients with other hematologic malignancies.  The disorder usually affects men over the age of 60 years. The degree of imbalance of globin chain syn thesis and of α -globin mRNA deficiency in erythroid cells of affected patients is greater than that observed in the hereditary type of HbH disease. It is conceivable that erythroid cells of the abnormal clone synthesize no α -globin chains at all and that the expression of all four α -globin genes is suppressed or silenced, 436 but this phenomenon is difficult to quantify as long as some normal erythroid cells are being produced.

Cytogenetic, gene mapping, gene sequencing, and gene or chromosome transfer studies failed to detect any deletion or mutation in the α -globin gene cluster or functional abnormality of α -globin gene of affected patients. The results of all of these prior studies suggested that the defect responsible for this disorder probably involved the abnormal expression or function of a trans-acting factor capable of influencing α -globin gene expression and, indeed, such a factor was recently identified. The discovery of the factor responsible for HbH disease in MDS results from cDNA microarray analysis of RNA isolated from granulocytes of an affected patient. One of the genes that was found to be markedly underexpressed, compared with results obtained with RNA of normal granulocytes, was the ATRX gene, the same gene that is mutated in the α -thalassemia with mental retar dation syndrome of the ATR-X type. Sequence analysis of the ATRX gene in the DNA of blood cells of affected individuals has identified a number of different mutations. It is noteworthy that the mutations of the ATRX gene associated with acquired HbH disease associated with MDS (ATMDS) occur in the same regions of the gene as the mutations associated with the ATR-X syndrome, that is, in the ADD or helicase domains. In fact, some of the ATRX gene mutations identified in ATMDS are identical or similar in expected functional consequences to various mutations found in the ATR-X syndrome.

The hematologic features in the syndrome are characterized by the presence of a dimorphic RBC population on blood smear, one of which is hypochromic, microcytic, and poikilocytic. Incubation of the blood with the supravital stain brilliant cresyl blue results in the detection of typical HbH inclusions. Hb electrophoresis or HPLC detects the presence of HbH, usually in greater quantities than that typically observed in inherited HbH disease. In typical MDS, the MCV of the erythrocytes is normal or elevated, frequently higher than 100 fL. However, in ATMDS, the MCV and MCH are low: MCV usually less than 80 fL and MCH usually less than 26 pg.  The amount of HbH usually remains stable but may actually decrease during the course of the disease and no longer persists after transformation of MDS to acute leukemia. This finding suggests that the HbH-producing clone does not have a selective survival or growth advantage.

The hematologic phenotype, as reflected by the amount of HbH present in blood, of ATMDS is much more severe than that of the ATR-X syndrome.  Some of this difference in severity may be because of the nature of the ATMDS mutations, some of which are null mutations that are likely to be lethal when present in germ line DNA of ATR-X embryos. However, the difference in severity is also observed in the case of mutations found in both syndromes that are identical or similar in expected functional consequences. This finding suggests that additional abnormalities in gene expression in ATMDS contribute to the severity of the deficit in α -globin gene expression observed in this syndrome. Perhaps the responsible defective cofactor(s) is one or more of the proteins that interact with the ATRX protein to produce a fully functional macromolecular complex that can act as a transcriptional cofactor or that can influence the epigenetic control of α -globin gene expression.

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