thalasemia-alpha

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production of beta globin chains manifests with a more severe disease known as betathalassemia.

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Pathophysiology

The absence of normal production of a-chains results in a relative excess of -globin chains inthe fetus and newborn, and -globin chains in children and adults. Further, the -globin chainsare capable of forming soluble tetramers (beta-4, or HbH); yet this form of hemoglobin is

unstable and tends to precipitate within the cell forming insoluble inclusions (Heinz bodies) thatdamage the red cell membrane. Furthermore, diminished hemoglobinization of individual red

blood cells results in damage to erythrocyte precursors and ineffective erythropoiesis in the bonemarrow, as well as hypochromia and microcytosis of circulating red blood cells.

Genes that regulate both synthesis and structure of different globins are organized into 2 separate

clusters. The a-globin genes are encoded on chromosome 16 and the , , and -globin genes areencoded on chromosome 11. Each individual normally carries a linked pair of a-globin genes, 2

from the paternal chromosome, and 2 from the maternal chromosome. Alpha thalassemia resultswhen there is disturbance in production of -globin from any or all four of the -globin genes.

Normal hemoglobin biosynthesis requires an intact gene, silencers, enhancers, promoters, and

locus control region (LCR) sequences. Several hundred mutations causing thalassemia have beendescribed. These may affect any step in globin gene expression, transcription, pre-mRNA

splicing, mRNA translation and stability, and post-translational assembly and stability of globinpolypeptides.

The most common mechanism of aberrant a-globin production is due to deletions of either

portions of the a-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).

Production of functional hemoglobin is also impaired in alpha thalassemia when point mutations,

frame shift mutations, nonsense mutations, and chain termination mutations occur within oraround the coding sequences of the a-globin gene cluster. These gene level mutations may in turn

affect RNA splicing, initiation of mRNA translation, or result in the generation of unstable a-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 interferingwith the normal folding of otherwise normal globin peptide.

From a genetic standpoint, alpha thalassemias are extremely heterogeneous; however,phenotypic expression of alpha thalassemias may be described in simplified clinical terms related

to the number of alpha globin genes affected:


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y Alpha (0) thalassemia More than 20 different genetic mutations that result in thefunctional deletion of both pair of a-globin genes have been identified. Individuals with

this disorder are not able to produce any functional a-globin and thus are unable to makeany functional hemoglobin A, F, or A2. This leads to the development of hydrops fetalis,

also known as hemoglobin Bart, a condition that is incompatible with extra uterine life.y

Alpha (+) thalassemia There are more than 15 different genetic mutations that result indecreased production of a-globin usually due to the functional deletion of 1 of the 4 alphaglobin genes. Based on the number of inherited alpha genes, alpha (+) thalassemia is

subclassified into 3 general forms:o A- Thalassemia (-/ ) is characterized by inheritance of 3 normal -genes.

These patients are referred to clinically as silent carrier of alpha thalassemia.Other names for this condition are alpha thalassemia minima, alpha thalassemia-2

trait, and heterozygosity for alpha (+) thalassemia minor. The affected individualsexhibit no abnormality clinically and may be hematologically normal or have

mild reductions in red cell mean corpuscular volume (MCV) and meancorpuscular hemoglobin (MCH).

oB- Inheritance of 2 normal alpha genes due to either heterozygosity for alpha (0)thalassemia ( /--) or homozygosity for alpha (+) thalassemia (-/-) results in

the development of alpha thalassemia minor or alpha thalassemia-1 trait. Theaffected individuals are clinically normal but frequently have minimal anemia and

reduced mean corpuscular volume (MCV) and mean corpuscular hemoglobin(MCH). The red blood cell count is usually increased to over 5.5 x 1012/L.

o C- Inheritance of one normal alpha gene (-/--) results in abundant formation ofhemoglobin H composed of tetramers of excess beta chains. This condition is

known as HbH disease. The affected individuals have moderate to severe lifelonghemolytic anemia, modest degrees of ineffective erythropoiesis, splenomegaly,

and variable bony changes.

Frequency

United States

Recent reports suggest an increasing incidence of all subtypes of alpha thalassemia in the UnitedStates secondary to immigration of individuals from endemic areas. It is estimated that about

15% of American blacks are silent carriers for -thalassemia. In addition, -thalassemia trait(minor) occurs in 3% of American blacks and in 1-15% of persons of Mediterranean origin.

According to the National Institutes of Health sponsored North American Thalassemia Clinical

Research Network (TCRN) study of the epidemiology of thalassemia in North America, 59% ofpatients with alpha thalassemia have the (-/--) genotype, 8% have 4 alpha gene deletion (--/--),and 33% have gene deletions with structural mutations.

International


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It is estimated that there are 270 million carriers of mutant globin genes that can potentiallycause severe forms of thalassemia. In addition, 300,000-400,000 severely affected infants are

born every year, more than 95% of which occur in Asia, India, and the Middle East.

Before the introduction of DNA analysis, population surveys for alpha thalassemia were based

entirely on the measurement of hemoglobin Bart levels in cord blood. However, single genedeletion heterozygotes do not always have detectable hemoglobin Bart in the neonatal period. Asa 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. Multiplestudies have suggested that the presence of both single and double -globin gene deletions

confer a protective effect from malaria. Listed below are the approximate percentages of variouspopulations with some forms of alpha thalassemia:

y Europe 4-12%y

Middle East and western Asia - 12-55%y Southeast Asia 6-75%y Africa 11-50%y South America and the Caribbean - 7%

Mortality/Morbidity

The morbidity and mortality of alpha thalassemia are related to the degree of imbalanced globinproduction and, therefore, correlate well with the number of affected -globin genes. Individuals

with milder alpha thalassemia phenotypes, including those with single and double gene deletions(-/, --/ , -/-) have mild anemia as the only major morbidity associated with their disease

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. Patients with hemoglobin H (HbH) disease may develop hypersplenism, gallstones, leg ulcers,frequent infections, and various forms of venous thrombosis. The most severe form of alpha

thalassemia, hemoglobin Bart is characteristic of individuals with no functional -globin genes (--/--). Following a gestation of about 33 weeks, these infants develop hydrops fetalis syndrome

and usually die in utero, during delivery, or within an hour or two of birth.

Race

Abnormalities affecting the -globin genes have been documented in almost all ethnic groups yetare much more common in people of Asian, African, and Mediterranean heritage. The North

American Thalassemia Clinical Research Network (TCRN) study showed that 85% of patients

with alpha thalassemia are Asian, 4% are white, and 11% are of other ethnicities, includingAfrican, black, mixed ethnicity, and unknown.

Sex

Abnormalities of -globin genes are equally distributed between males and females. A notable

exception is the unusual alpha thalassemia associated with mental retardation, known as alphathalassemia mental retardation-X syndrome (ATR-X), which affects exclusively males.

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However, a recent report by Haas et al identified 2 females in a single center with alpha

thalassaemia myelodysplastic syndrome (ATMDS) and mutations in the ATR-X gene (ATRX).4

The investigators observed that although it was possible females may be less likely to develop

ATMDS if the inactivated copy ofATRX is reactivated throughout life, this hypothesis was ruled

out in their study by the use of a cross-sectional analysis of healthy females aged newborn to 90years to examine the pattern ofATRX inactivation.4

Age

Alpha thalassemia is a genetic disorder, thus patients are born with the disorder, with theexception of patients with ATMDS, in which case patients are usually elderly with a mean age at

diagnosis of 68 years.

Clinical

History

Clinical courses and physical findings are different for each of the 4 genotypes. Concomitant

beta chain hemoglobinopathies and beta thalassemia alter the clinical course.

y Silent carrier/alpha thalassemia-2 trait: Patients are essentially asymptomatic and theCBC, hemoglobin electrophoresis, and peripheral smear are usually normal. Slight

hypochromia and microcytosis may be evident by microscopic evaluation. The silentcarrier state becomes apparent in families when related carriers of this allele mate and

have children with HbH disease.y Homozygous alpha (+) thalassemia: The peripheral blood smear typically shows

hypochromia, microcytosis, and target cells. The MCV is frequently less than 80 fL, andthe MCH is always below 27 pg. RBC counts are usually higher than normal.

Hemoglobin electrophoresis is normal. Although elevation of hemoglobin A2 does notoccur, elevations of hemoglobin F have been reported. Individuals of African originusually carry a homozygous state of the alpha-2 allele, and deletion usually involves the

less active of 2 normal alleles. Alpha thalassemia-2 and alpha thalassemia-1 tend to bemilder in this population.

In Asia, the cis deletion is common, and subpopulations exhibit more dramatic features of

thalassemia trait. If patients have the hemoglobin CS mutation, a slowly migrating abnormalhemoglobin band is present on hemoglobin electrophoresis. Clinical symptoms do not exist. The

condition is diagnosed as a result of incidental laboratory abnormalities and family studies tocharacterize a relative.

y Hemoglobin H disease: Marked impairment of -globin production results inaccumulation of excess beta globin chains that are soluble enough to form thehomotetrameric HbH. This form of hemoglobin has a dramatically left-shifted oxygen

dissociation curve that renders it of no value in oxygen transportation. In addition, it isstructurally unstable during the later stages of erythropoiesis and during the circulating


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lifespan of the red blood cell. As HbH precipitates, it forms inclusion bodies within thered blood cell, thereby causing chronic hemolytic anemia.

o Patients are often symptomatic at birth; many others present with neonataljaundice or anemia, and some others have hydrops fetalis. Indirect

hyperbilirubinemia, elevated lactate dehydrogenase levels, and reduced

haptoglobin are all consistently seen with hemolytic anemia. Exacerbations ofhemolysis may occur when patients are exposed to oxidant stressors such asinfections or oxidizing drugs.

o Other complications occur in varying degrees and include the following: Hepatosplenomegaly Leg ulcers Gallstones Aplastic or hypoplastic crises Skeletal, developmental, and metabolic changes due to ineffective

erythropoiesis (These resemble beta thalassemia intermedia or betathalassemia major.)

Prominent frontal bossing (due to bone marrow expansion)

Delayed pneumatization of sinuses Marked overgrowth of the maxillae Ribs and long bones become box-like and convex Premature closure of epiphyses resulting in shortened limbs Compression fracture of the spine (which may result in cord compression

or other neurological deficits) Osteopenia and fractures

o Splenectomy or transfusional support is often necessary in the second or thirddecade of life. Iron overload may also occur due to increased iron absorption and

frequent transfusions.o Acquired cases are observed in myeloproliferative diseases (eg, acute

myelogenous leukemia, erythroleukemia, refractory sideroblastic anemia, acutelymphocytic leukemia).

y Hemoglobin Bart or hydrops fetalis (--/--): This disease affects individuals with nofunctional -globin genes (--/--). Infants with hemoglobin Bart/hydrops fetalis syndrome

usually die in utero.o They have massive total body edema due to high output heart failure, pallor,

massive hepatomegaly secondary to extramedullary hematopoiesis, andedematous friable placenta.

o There have now been several case reports of individuals with Hb Barts that havesurvived for variable amounts of time, but many have developmental

abnormalities, and all have required regular blood transfusion and chelationtherapy.

y Alpha thalassemia with mental retardation syndromes: There are 2 clinical entitiesdescribed in which patients are noted to have both mild forms of alpha thalassemia and

mental retardation. ATR-16 is characterized by large chromosomal rearrangements thatcause deletions of many genes from the short arm of chromosome 16. The second form,

ATR-X, results from mutations in an X-chromosome encoded gene that acts (in trans) as


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a regulator of expression of the -globin genes. Thus these patients have normal -globingenes; however, expression of -globin proteins is down-regulated.

y Alpha thalassemia myelodysplastic syndrome: This disease is characterized by markedhypochromic microcytic anemia and presence of HbH demonstrated by hemoglobin

electrophoresis and supravital staining. These patients are also found to have a very low

/ globin chain ratio (often


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y Hemoglobin H diseaseo Hemoglobin level is 7-10 g/dL.o Reticulocyte count is 5-10%.o MCV is 55-65 fL.o MCH is 20 pg.o

The peripheral blood smear shows small misshapen red cells, hypochromia,microcytosis, and targeting.o Brilliant cresyl blue stain demonstrates hemoglobin H inclusion bodies.

y Hydrops fetaliso Hemoglobin is 4-10 g/dL.o MCV is 110-120 fL.o The peripheral blood smear shows severe anisopoikilocytosis, severe

hypochromia, and nucleated red blood cells.y Alpha thalassemia combined with sickle cell anemia causes a higher hemoglobin

concentration and improved red blood cell survival. The alpha gene deletion is associatedwith improved red cell deformability, but the improved rheologic benefits often are

overcome by the greater viscosity of a higher hematocrit. Clinically, this is observed as agreater number of painful vasoocclusive crises. Interestingly, however, the incidence of

stroke is lower than that in sickle cell disease alone.

Imaging Studies

y Imaging studies are not useful in these disorders.Other Tests

y Hemoglobin electrophoresis separates hemoglobin into different types. Hemoglobin Bartis elevated at birth in patients with alpha thalassemia. In hemoglobin H disease, 20-40%of total hemoglobin is of hemoglobin Bart; however, in the silent carrier alphathalassemia condition, the percentage is only 1-2% with low or normal amounts of

hemoglobin A2.5

Hemoglobin electrophoresis is generally not sufficiently sensitive todiagnose silent carrier alpha thalassemia.

y The imbalance between the quantities of - and -globin chains initially was used todefine the thalassemias. to synthetic ratios are altered in both alpha and beta

thalassemias. Increasing ratios of - to -globin chains are observed in alpha-2thalassemia, alpha-1 thalassemia, and hemoglobin H disease, respectively. Tests are

performed by incubation of red blood cells with radiolabeled amino acid andsubsequently separating - and -globin chains using urea carboxymethyl cellulose

(CMC) chromatography.y Currently, genetic testing is used to establish the diagnosis in patients with a suggestive

family history and/or hematologic findings suggestive of alpha thalassemia.6,7,8

o Recombinant DNA technology can be diagnostic but is still a research tool.o Gene mappingo Polymerase chain reaction (PCR)o Restriction endonucleaseso Anti-L globin monoclonal antibodies


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Procedures

y Bone marrow aspiration and biopsy are not helpful in establishing the precise diagnosisand are not indicated unless other confounding problems exist.

Histologic Findings

Peripheral blood smear may reveal target cells, microcytosis, hypochromia, and

anisopoikilocytosis. Most individuals with alpha2 thalassemia (trait) have only mildmicrocytosis, which can be differentiated from other common causes of microcytosis based on

serum iron and ferritin concentrations within the reference range.

Peripheral smear from a patient with hemoglobin H disease showing target cells,

microcytosis, hypochromia, and anisopoikilocytosis. Morphological abnormalities are

similar to those observed in beta thalassemia. In alpha2 thalassemia (silent trait), only mildmicrocytosis is observed.

Treatment

Medical Care

y Avoid iron supplementation as it contributes to iron overload and does not affecthematologic values or cell morphology.

y Administer folate supplementation to provide adequate amounts of the vitamin forincreased utilization resulting from the hemolytic process and high bone marrow turnover

rate.y Provide prompt attention to infection, especially in children who have had splenectomy,

and administer appropriate vaccines to these individuals.

y Administer blood transfusions only if necessary.y If chronic transfusion is needed (hemoglobin H disease), iron chelation therapy should be

considered to avoid iron overloading.


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Surgical Care

y Hemoglobin H diseaseo Perform splenectomy if transfusion requirements are increasing.o Surgical or orthodontic correction may be necessary to correct skeletal

deformities of the skull and maxilla caused by erythroid hyperplasia.

Follow-up

Prognosis

y The prognosis is excellent for silent carriers.y Because hydrops fetalis is incompatible with life, hemoglobin H (--/--) is the most serious

syndrome.y The overall survival for hemoglobin H disease is variable; however, it is generally good.

Many patients survive into adulthood. However, some patients have a more complicatedcourse and may not do as well.

Patient Education

Patients with a family history or known carrier state for alpha thalassemia gene mutations should

obtain genetic counseling to determine genotype and risk to offspring. This is especially true incases of suspected concomitant hemoglobinopathy.

Miscellaneous

Medicolegal Pitfalls

Alpha thalassemia is frequently mistaken for iron deficiency anemia because both disorders havemicrocytic red blood cells. Iron therapy is not required, and prolonged therapy may produce

untoward effects from iron overload. Similarly, the procedures used to find a source of bleedingin patients with iron deficiency anemia have no value in patients with thalassemia.

Measurements of serum iron and ferritin can provide laboratory evidence to exclude irondeficiency as the etiology for microcytosis.

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