- Author: Alexandra C Cheerva, MD, MS; Chief Editor: Hassan M Yaish, MD more...
The alpha thalassemia (α-thalassemia) syndromes are a group of hereditary anemias of varying clinical severity. They are characterized by reduced or absent production of 1 or more of the globin chains of which human hemoglobin is composed.
The oxygen carrying capability of the red blood cells (RBCs) relies on hemoglobin, a tetramer protein that comprises 4 globin chains bound to the heme molecule. There are 4 major types of globins: alpha (α), beta (β), gamma (γ), and delta (δ). The dominant hemoglobin in adults (hemoglobin A) is composed of 2 alpha and 2 beta chains. Two minor forms of hemoglobin constitute a small percentage of normal blood: hemoglobin F (fetal), composed of 2 alpha chains and 2 gamma chains, and hemoglobin A2, composed of 2 alpha chains and 2 delta chains.
A very tightly controlled globin chain production process keeps the ratio of alpha chains to non-alpha chains at 1.00 (± 0.05). Thalassemia, by altering this process, disrupts this ratio. Decreased production of alpha-globin gene products, whether alpha1 globin or alpha2 globin (alpha-globin gene is present in duplicate on chromosome 16), yields a relative excess of beta chains, which results in less stable chains; this leads to the clinical disease known as alpha thalassemia.[1, 2] Similarly, impaired production of beta-globin gene products manifests with a more severe disease known as beta thalassemia.[3, 4]
Thalassemia is one of the world’s most common single-gene disorders. Individuals with thalassemia syndrome are most often of African, Asian, Mediterranean, or Middle Eastern descent. Mutations and gene deletions causing the various thalassemia genotypes have arisen independently in different populations but have subsequently propagated by means of natural selection.[5, 6, 7]
Thalassemia is more prevalent in regions in which malaria is endemic because the RBC phenotype confers some protection against malaria. Individuals with beta thalassemia syndromes have somewhat better protection against malaria than individuals with alpha thalassemia syndromes.
Genes that regulate both the synthesis and the structure of different globins are organized into 2 separate clusters. The alpha-globin genes are encoded on chromosome 16, and the gamma-, delta-, and beta-globin genes are encoded on chromosome 11. Healthy individuals have 4 alpha-globin genes, 2 on each chromosome 16 (αα/αα; see the image below). Alpha thalassemia syndromes are caused by deficient expression of 1 or more of the 4 alpha-globin genes on chromosome 16 and are characterized by absent or reduced synthesis of alpha-globin chains.
Abnormal production of alpha-globin chains results in a relative excess of gamma-globin chains in fetuses and newborns and of beta-globin chains in children and adults. Furthermore, the beta-globin chains are capable of forming soluble tetramers (β4, or hemoglobin H [HbH]); yet this form of hemoglobin is unstable and tends to precipitate within the cell, forming insoluble inclusions (Heinz bodies) that damage the red cell membrane.
In addition, diminished hemoglobinization of individual red blood cells results in damage to erythrocyte precursors and ineffective erythropoiesis in the bone marrow, as well as hypochromia and microcytosis of circulating red blood cells.
From a genetic standpoint, alpha thalassemia syndromes are extremely heterogeneous; however, their phenotypic expression may be described in simplified clinical terms related to the number of inherited alpha-globin genes. Alpha thalassemia may be broadly classified according to whether the loss of alpha-globin genes is complete or partial—that is, alpha(0) thalassemia or alpha(+) thalassemia. Some subclasses are present within the latter category, based on the number of genes affected. In all, there are four general forms of alpha thalassemia.
More than 20 different genetic mutations resulting in the functional deletion of both pairs of alpha-globin genes (--/--) have been identified. The resulting disorder is referred to as hydrops fetalis, alpha thalassemia major, or hemoglobin Bart’s. Individuals with this disorder cannot produce any functional alpha globin and thus are unable to make any functional hemoglobin A, F, or A2. Hydrops fetalis is incompatible with extrauterine life. Fetuses with this condition die either in utero or shortly after birth because of severe anemia.
There are more than 15 different genetic mutations that result in decreased production of alpha globin, usually through functional deletion of 1 or more of the 4 alpha-globin genes. Alpha(+) thalassemia is subclassified into the following three general forms on the basis of the number of inherited alpha genes.
Persons who inherit 3 normal alpha-globin genes (-α/αα) are referred to clinically as silent carriers. Other names for this condition are alpha thalassemia minima, alpha thalassemia-2 trait, and heterozygosity for alpha(+) thalassemia minor. The affected individuals exhibit no clinical abnormalities and may be hematologically normal or have slight reductions in RBC mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH).
Alpha thalassemia trait
Inheritance of 2 normal alpha-globin genes through either heterozygosity for alpha(0) thalassemia (αα/--) or homozygosity for alpha(+) thalassemia (-α/-α) results in the development of alpha thalassemia trait, also referred to as alpha thalassemia minor or alpha thalassemia-1 trait. If both alpha2- and alpha1-globin genes are deleted on the same chromosome (--/αα), the genotype is said to have the cis form; if the 2 alpha2 -globin genes of both alleles of chromosome 16 are deleted but the alpha1 -globin genes are intact (-α/-α), it is said to have the trans form.
The affected individuals are clinically normal but frequently have minimal anemia and reduced MCV and MCH. The RBC count is usually increased, typically exceeding 5.5 × 1012/L.
Hemoglobin H disease
Inheritance of only one out of the four normal alpha-globin genes (-α/--) leads to a condition known as HbH disease, or alpha thalassemia intermedia. The loss of 3 alpha-globin genes results in abundant formation of HbH, which is characterized by a high ratio of beta globin to alpha globin and a 2-fold to 5-fold excess in beta-globin production. The excess beta chains aggregate into tetramers, which account for 5-30% of the hemoglobin level in patients with HbH disease.
HbH has a high affinity for oxygen and has no Bohr effect or heme-heme interaction; therefore, it is an ineffective supplier of oxygen to the tissues under physiologic conditions. Patients with significant amounts of HbH have a defect in oxygen-carrying capacity that is more severe than would be expected on the basis of the hemoglobin concentration alone. RBCs that contain HbH are sensitive to oxidative stress; thus, they may be more susceptible to hemolysis when oxidants such as sulfonamides are administered.
Aging erythrocytes contain more precipitated HbH than younger erythrocytes; consequently, they are removed from the circulation prematurely. Thus, HbH disease is primarily a hemolytic disorder. When bone marrow cells are examined, HbH inclusions are rare, and erythropoiesis is apparently effective. Erythroid hyperplasia can result in typical structural bone abnormalities with marrow hyperplasia, bone thinning, maxillary hyperplasia, and pathologic fractures.
An Iranian study, by Farashi et al, of 66 patients with HbH disease found that point mutations produced a more severe form of the condition than did deletional mutations. The clinical severity of HbH disease may depend on which alpha-globin gene is deleted, since one of the alpha genes may produce only 25% of the alpha-globin chains, while the other provides 75% of them.
Normal hemoglobin biosynthesis requires an intact gene, silencers, enhancers, promoters, and locus control region (LCR) sequences. Several hundred mutations causing thalassemia have been described. These may affect any step in globin gene expression, transcription, pre-mRNA splicing, mRNA translation and stability, and posttranslational assembly and stability of globin polypeptides.
The most common mechanism of aberrant alpha-globin production involves deletion of either portions of the alpha-globin genes themselves or the genetic regulatory elements that control their expression. Regulatory elements may be located on the same chromosome (cis -acting elements) or on separate chromosomes (trans -acting elements).
The (--SEA) type of alpha thalassemia deletion removes both alpha-globin genes in cis, is common in Southeast Asia, and is the most common cause of HbH disease and hydrops fetalis in that part of the world. Nondeletional forms of alpha thalassemia in which the alpha-globin genes are intact are caused by mutations similar to those causing beta thalassemia and are relatively uncommon.[11, 12]
Production of functional hemoglobin is also impaired in alpha thalassemia when point mutations, frame shift mutations, nonsense mutations, and chain termination mutations occur within or around the coding sequences of the alpha-globin gene cluster. These gene-level mutations may in turn affect RNA splicing, hinder initiation of mRNA translation, or result in the generation of unstable alpha-globin chain variants.
Mutations affecting transcription, pre-mRNA splicing, or canonical splice signals are rare causes of alpha thalassemia. Other forms of alpha thalassemia are caused by either premature or failed translation termination. More rare mutations have been found to cause thalassemia by interfering with the normal folding of otherwise normal globin peptide.
United States statistics
The frequency of alpha thalassemia is low among whites. It is estimated that about 15% of American blacks are silent carriers for alpha thalassemia and about 3% have alpha thalassemia trait; HbH disease is rare in this population. In North America, many multicultural communities are growing, and these populations have increased frequencies of thalassemia syndromes.
In some ethnic groups, such as the Southeast Asian population (in particular) and Mediterranean populations, HbH disease and hemoglobin Bart’s (γ4) are common because of the frequent coinheritance of an allele lacking both alpha-globin genes and another allele lacking 1 alpha-globin gene. The high frequency of hemoglobin Constant Spring (CS) in the Southeast Asian population can lead to the HbH (--/-αCS) phenotype, which involves an elongated form of alpha-globin chain.[13, 1]
The results of one study suggested that HbH Constant Spring (HCS) should be identified as a distinct thalassemia syndrome with a high-risk of life-threatening anemia. The study also found that HbH disease was managed without blood transfusions and was not associated with an increased rate of severe anemia. Because many patients with these disorders encompassed mixed ethnic backgrounds, the study emphasizes the need for extended newborn screening in populations that are customarily considered to be at low risk for HbH.
According to the National Institutes of Health (NIH)-sponsored North American Thalassemia Clinical Research Network (TCRN) study of the epidemiology of thalassemia in North America, 59% of patients with alpha thalassemia have a single alpha-globin gene (-α/--), 8% have no alpha-globin genes (--/--), and 33% have gene deletions with structural mutations.
Alpha thalassemia is perhaps the most common single-gene disorder in the world. It is estimated that there are 270 million carriers of mutant globin genes that can potentially cause severe forms of thalassemia. In addition, 300,000-400,000 severely affected infants are born every year, more than 95% of whom are in Asia, India, or the Middle East.
Before the introduction of DNA analysis, population surveys for alpha thalassemia were based entirely on the measurement of hemoglobin Bart’s levels in cord blood. However, single-gene-deletion heterozygotes do not always have detectable hemoglobin Bart’s in the neonatal period. As a result, reliable data on population frequencies for various types of alpha thalassemia are not always available.
Alpha thalassemia is common throughout parts of the world where malaria is endemic. Multiple studies have suggested that the presence of both single and double alpha-globin gene deletions has a protective effect against malaria.
The frequency of alpha thalassemia alleles is 5-10% in the Mediterranean basin, 20-30% in portions of West Africa, and as high as 60-80% in parts of Saudi Arabia, India, Thailand, Papua New Guinea, and Melanesia. In Thailand, which has a population of 62 million people, approximately 7000 infants are born each year with HbH disease. The frequency of heterozygote carrier status among the Chinese population has been reported to range from 5% to 15%. The frequency of alpha thalassemia is lower than 0.01% in Great Britain, Iceland, and Japan.[15, 16, 17, 18]
Abnormalities of alpha-globin chains are genetic, and individuals are born with the disorder. The exception to this rule is patients with alpha thalassemia myelodysplastic syndrome (ATMDS), who are usually elderly, with a mean age of 68 years at diagnosis.
In general, males and females are equally affected. However, there is a type of alpha thalassemia that is associated with mental retardation and affects only males. This condition is referred to as alpha thalassemia mental retardation-X syndrome (ATR-X).
However, a report by Haas et al identified 2 females in a single center with ATMDS and mutations in the ATR-X gene (ATRX). The investigators observed that although it was possible that females may be less likely to develop ATMDS if the inactivated copy of ATRX is reactivated throughout life, this hypothesis was ruled out in their study by the use of a cross-sectional analysis of healthy females ranging in age from neonate to 90 years to examine the pattern of ATRX inactivation.
Alpha thalassemia occurs in individuals of all ethnic backgrounds but particularly those of African, Asian, Central American, Mediterranean, and Middle Eastern descent. Emigration from regions in which carrier frequency is high increases the presence of thalassemia syndromes in other parts of the world. The North American TCRN study showed that 85% of patients with alpha thalassemia are Asian, 4% are white, and 11% are of other ethnicities, including African, black, mixed ethnicity, and unknown.
For silent carriers and individuals with alpha thalassemia trait, the prognosis is excellent.
For individuals with HbH disease, the overall survival rate varies but is generally good, with most patients surviving into adulthood. However, some patients have a more complicated course and may not do as well. Patients with HbH disease are at risk for severe anemia and have a lifelong requirement for transfusions. One study suggests that the subtype of hemoglobin H Constant Spring (HCS) is associated with a high risk of life-threatening anemia. Patients identified with this subtype of HbH disease require close follow-up. If anemia is well managed and iron overload is prevented with chelation therapy, individuals with HbH disease can live long and healthy lives.
Hydrops fetalis (alpha thalassemia major) is incompatible with life and requires identification in utero and in utero transfusions if the fetus is to survive and be born. To identify fetuses with this condition, family genetic studies must be done, high-risk couples identified, and the fetus tested in utero for the absence of alpha-globin chains.
Those rare fetuses that survive to be born, with the help of intrauterine transfusions, continue to require lifelong transfusions and medical care. They may be considered for hematopoietic stem cell transplantation, which is curative of their alpha thalassemia major syndrome.
A study by Joly et al supported the idea that alpha thalassemia reduces the risk of cerebral vasculopathy in children with sickle cell anemia. The report involved three groups of children with sickle cell anemia, including one group with cerebral vasculopathy (ie, stroke, silent infarct, or abnormal transcranial Doppler ultrasonography results), a second group without cerebral vasculopathy, and a third group with conditional transcranial Doppler ultrasonography results. The data indicated that alpha thalassemia has a protective effect against, and that glucose-6-phosphate dehydrogenase (G6PD) deficiency increases the risk for, cerebral vasculopathy in sickle cell anemia.
Patients with a family history or a known carrier state for alpha thalassemia gene mutations should obtain genetic counseling to determine the genotype and assess the risk to offspring. This is especially true in cases of suspected concomitant hemoglobinopathy.
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