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Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of
thalassemia Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
involving the genes ''
HBA1 Hemoglobin subunit alpha, Hemoglobin, alpha 1, is a hemoglobin protein that in humans is encoded by the ''HBA1'' gene. Gene The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseu ...
'' and ''
HBA2 Hemoglobin, alpha 2 also known as HBA2 is a gene that in humans codes for the alpha globin chain of hemoglobin. Function The human alpha globin gene cluster is located on chromosome 16 and spans about 30 kb, including seven alpha like globin ...
''. Thalassemias are a group of inherited blood conditions which result in the impaired production of
hemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two
alpha chain The term alpha chain is normally used to indicate one of the subunits of a multi-subunit protein. The term "chain" is a general term given to any peptide sequence. It can often refer more specifically to mean: * a part of the T-cell receptor, * ...
s and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased
red blood cell Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
destruction. The degree of impairment is based on which clinical
phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology or physical form and structure, its developmental processes, its biochemical and physiological proper ...
is present (how many genes are affected).


Signs and symptoms

The presentation of individuals with alpha-thalassemia consists of:


Cause

Alpha-thalassemias are most commonly inherited in a
Mendelian Mendelian inheritance (also known as Mendelism) is a type of biology, biological Heredity, inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, an ...
recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
manner. They are also associated with deletions of
chromosome 16 Chromosome 16 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 16 spans about 90 million base pairs (the building material of DNA) and represents just under 3% of the total DNA in cell ...
p. Alpha thalassemia can also be acquired under rare circumstances.


Pathophysiology

The mechanism sees that α thalassemias results 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 Hemoglobin H disease is a type of alpha thalassemia caused by impaired production of three of the four alpha globins, coded by genes HBA1 and HBA2 Hemoglobin, alpha 2 also known as HBA2 is a gene that in humans codes for the alpha globin chain ...
or HbH of four
beta chain Hemoglobin subunit beta (beta globin, β-globin, haemoglobin beta, hemoglobin beta) is a globin protein, coded for by the ''HBB'' gene, which along with alpha globin ( HBA), makes up the most common form of haemoglobin in adult humans, hemogl ...
s. The excess γ chains form tetramers which are poor carriers of O2 since their affinity for O2 is too high, so it is not dissociated in the periphery.
Homozygote Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
α0 thalassaemias, where numerous γ4 but no α-globins occur at all (referred to as Hb Barts), often result in death soon after birth.


Diagnosis

Diagnosis of alpha-thalassemia is primarily by laboratory evaluation and
molecular diagnosis Molecular diagnostics is a collection of techniques used to analyze biological markers in the genome and proteome, and how their cells express their genes as proteins, applying molecular biology to medical testing. In medicine the technique is ...
. Alpha-thalassemia can be mistaken for iron-deficiency anaemia on a full blood count or blood film, as both conditions have a microcytic anaemia.
Serum iron Serum iron is a medical laboratory test that measures the amount of circulating iron that is bound to transferrin (90%) and serum ferritin (10%). Clinicians order this laboratory test when they are concerned about iron deficiency, which can cause ...
and
serum ferritin Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion. The protein is produced by almost all living organisms, including archaea, bacteria, algae, higher plants, and animals. It is the primary ' ...
can be used to exclude iron-deficiency anaemia.


Types

Two genetic loci exist for α globin, thus four alleles are in diploid cells. Two alleles are maternal and two alleles are paternal in origin. The severity of the α-thalassemias is correlated with the number of affected α-globin alleles: the greater, the more severe will be the manifestations of the disease. When noting the genotype, an "α" indicates a functional
alpha chain The term alpha chain is normally used to indicate one of the subunits of a multi-subunit protein. The term "chain" is a general term given to any peptide sequence. It can often refer more specifically to mean: * a part of the T-cell receptor, * ...
, and '-' a pathological one.


Laboratory diagnosis

The ability to measure hemoglobin Barts makes it useful in newborn screening tests. If hemoglobin Barts is detected on a newborn screen, the patient is usually referred for further evaluation since detection of hemoglobin Barts can indicate either one alpha globin gene deletion, making the baby a silent alpha thalassemia carrier, two alpha globin gene deletions (alpha thalassemia), or
hemoglobin H disease Hemoglobin H disease is a type of alpha thalassemia caused by impaired production of three of the four alpha globins, coded by genes HBA1 and HBA2. See also * Hemoglobin Barts Hemoglobin Barts, abbreviated Hb Barts, is an abnormal type of hemogl ...
(three alpha globin gene deletions). Deletion of four alpha globin genes was previously felt to be incompatible with life, but there are currently 69 patients who have survived past infancy. All such children too show high level of hemoglobin Barts on newborn screen along with other variants. Post-newborn ages, initial laboratory diagnosis should include a
complete blood count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide cytometry, information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cell ...
and
red blood cell indices Red blood cell indices are blood tests that provide information about the hemoglobin content and size of red blood cells. Abnormal values indicate the presence of anemia and which type of anemia it is. Mean corpuscular volume Mean corpuscular ...
. As well, a
peripheral blood smear A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in the ...
should be carefully reviewed. In hemoglobin H disease, red blood cells containing hemoglobin H inclusions can be visualized on the blood smear using
new methylene blue is an organic compound of the thiazine class of heterocycles. It is used as a stain and as an antimicrobial agent. It is classified as an azine dye, and the chromophore is a cation, the anion is often unspecified. Applications NMB is a staini ...
or
brilliant cresyl blue Brilliant cresyl blue is a supravital stain used for counting reticulocyte Reticulocytes are immature red blood cells (RBCs). In the process of erythropoiesis (red blood cell formation), reticulocytes develop and mature in the bone marrow a ...
stain. Hemoglobin analysis is important for the diagnosis of alpha-thalassemia as it determines the types and percentages of types of hemoglobin present. Several different methods of hemoglobin analysis exist, including
hemoglobin electrophoresis Hemoglobin electrophoresis is a blood test that can detect different types of hemoglobin. The test can detect hemoglobin S, the form associated with sickle cell disease, as well as other abnormal types of hemoglobin, such as hemoglobin C. It can a ...
,
capillary electrophoresis Capillary electrophoresis (CE) is a family of electrokinetic separation methods performed in submillimeter diameter capillaries and in micro- and nanofluidic channels. Very often, CE refers to capillary zone electrophoresis (CZE), but other electr ...
and
high-performance liquid chromatography High-performance liquid chromatography (HPLC), formerly referred to as high-pressure liquid chromatography, is a technique in analytical chemistry used to separate, identify, and quantify each component in a mixture. It relies on pumps to pa ...
. Molecular analysis of DNA sequences ( DNA analysis) can be used for the confirmation of a diagnosis of alpha-thalassemia, particularly for the detection of alpha-thalassemia carriers (deletions or mutations in only one or two alpha-globin genes).


Treatment

Treatment for alpha-thalassemia may include
blood transfusions Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
to maintain hemoglobin at a level that reduces symptoms of anemia. The decision to initiate transfusions depends on the clinical severity of the disease.
Splenectomy A splenectomy is the surgical procedure that partially or completely removes the spleen. The spleen is an important organ in regard to immunological function due to its ability to efficiently destroy encapsulated bacteria. Therefore, removal of ...
is a possible treatment option to increase total hemoglobin levels in cases of worsening anemia due to an overactive or enlarged spleen, or when transfusion therapy is not possible. However, splenectomy is avoided when other options are available due to an increased risk of serious infections and
thrombosis Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thro ...
. Additionally,
gallstones A gallstone is a stone formed within the gallbladder from precipitated bile components. The term cholelithiasis may refer to the presence of gallstones or to any disease caused by gallstones, and choledocholithiasis refers to the presence of migr ...
may be a problem that would require surgery. Secondary complications from
febrile Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...
episode should be monitored, and most individuals live without any need for treatment.update 2013 Additionally, stem cell transplantation should be considered as a treatment (and cure), which is best done in early age. Other options, such as
gene therapy Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
, are still being developed. A study by Kreger et al combining a retrospective review of three cases of alpha thalassemia major and a literature review of 17 cases found that in utero transfusion can lead to favorable outcomes. Successful hematopoietic cell transplantation was eventually carried out in four patients.


Epidemiology

Worldwide distribution of inherited alpha-thalassemia corresponds to areas of
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
exposure, suggesting a protective role. Thus, alpha-thalassemia is common in
sub-Saharan Africa Sub-Saharan Africa is, geographically, the area and regions of the continent of Africa that lies south of the Sahara. These include West Africa, East Africa, Central Africa, and Southern Africa. Geopolitically, in addition to the List of sov ...
, the
Mediterranean Basin In biogeography, the Mediterranean Basin (; also known as the Mediterranean Region or sometimes Mediterranea) is the region of lands around the Mediterranean Sea that have mostly a Mediterranean climate, with mild to cool, rainy winters and w ...
, and generally tropical (and subtropical) regions. The epidemiology of alpha-thalassemia in the US reflects this global distribution pattern. More specifically, HbH disease is seen in
Southeast Asia Southeast Asia, also spelled South East Asia and South-East Asia, and also known as Southeastern Asia, South-eastern Asia or SEA, is the geographical United Nations geoscheme for Asia#South-eastern Asia, south-eastern region of Asia, consistin ...
and the
Middle East The Middle East ( ar, الشرق الأوسط, ISO 233: ) is a geopolitical region commonly encompassing Arabian Peninsula, Arabia (including the Arabian Peninsula and Bahrain), Anatolia, Asia Minor (Asian part of Turkey except Hatay Pro ...
, while Hb Bart hydrops fetalis is acknowledged in Southeast Asia only. The data indicate that 15% of the
Greek Greek may refer to: Greece Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group. *Greek language, a branch of the Indo-European language family. **Proto-Greek language, the assumed last common ancestor ...
and
Turkish Cypriots Turkish Cypriots or Cypriot Turks ( tr, Kıbrıs Türkleri or ''Kıbrıslı Türkler''; el, Τουρκοκύπριοι, Tourkokýprioi) are ethnic Turks originating from Cyprus. Following the Ottoman conquest of the island in 1571, about 30,00 ...
are carriers of beta-thalassaemia genes, while 10% of the population carry alpha-thalassaemia genes.Haematology Made Easy. AuthorHouse. 2013-02-06. .page 246


See also

*
Beta-thalassemia Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to cl ...
*
Delta-thalassemia Delta-beta thalassemia is a rare form of thalassemia in which there is a reduced production of hemoglobin subunit delta and hemoglobin subunit beta and raised levels of hemoglobin subunit gamma. It is an autosomal recessive disorder. Signs and ...
*
Hemoglobinopathy Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits. There are tw ...


References


Further reading

* *


External links

* {{DEFAULTSORT:Alpha-Thalassemia Disorders of globin and globulin proteins Hereditary hemolytic anemias