Alpha-thalassemia

Alpha-thalassemia
Classification and external resources
Specialty	hematology
ICD-10	D56.0
ICD-9-CM	282.43
OMIM	141800 141850 142310 604131 141800 141850 142310 604131
DiseasesDB	448 33334
eMedicine	article/955496
MeSH	D017085
GeneReviews	Alpha-Thalassemia

Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of thalassemia involving the genes HBA1^[1] and HBA2.^[2] Alpha-thalassemia is due to impaired production of alpha chains from 1,2,3, or all 4 of the alpha globin genes, leading to a relative excess of beta globin chains. The degree of impairment is based on which clinical phenotype is present (how many genes are affected).

Epidemiology

The worldwide distribution of inherited alpha-thalassemia corresponds to areas of malaria exposure,^[3] suggesting a protective role for alpha-thalassemia against the more severe manifestations of malaria. Thus, alpha-thalassemia is common in sub-Saharan Africa, the Mediterranean Basin, the Middle East, South Asia, and Southeast Asia, and different genetic subtypes have variable frequencies in each of these areas.^[4] The epidemiology of alpha-thalassemia in the US reflects this global distribution pattern. The most common form of alpha(+) thalassemia seen in the US is due to the -alpha(3.7) deletion, a single alpha-globin gene deletion, and is present in approximately 30% of African Americans.^[5] However, even in the homozygous state this disorder will result only in a mild microcytic anemia. The more serious clinical disorders of Hb H and Hb Bart hydrops fetalis syndrome, although found throughout the US today, are more common in the Western US and have dramatically increased in prevalence in the past 2 decades due to increased Asian immigration.^[6]

Causes

It is most commonly inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome.^[7]

It can also be acquired, under rare circumstances.^[8] Due to the low occurrence of alpha-thalassemia, the disease can be mistaken for iron deficiency anemia.^[9]

Pathophysiology

α thalassemias result 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 or HbH of 4 beta chains) which have abnormal oxygen dissociation curves. 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 α⁰ thalassaemias, where there is lots of γ₄ but no α-globins at all (referred to as Hb Barts), often result in still birth or die soon after birth.

Types

There are two genetic loci for α globin, and thus four genes in diploid cells. Two genes are maternal in origin and two genes are paternal in origin. The severity of the α thalassemias is correlated with the number of affected α globin genes: the greater, the more severe will be the manifestations of the disease.

When noting the genotype, a "-" indicates an absence of function, and a "α" indicates a functional alpha chain. (In contrast to the "β^o" and "β⁺" notation used in beta-thalassemia, in alpha-thalassemia a distinction between absent and reduced function is not usually noted.)

Alleles affected	Description	Genotype
One	This is known as alpha thalassemia minima and with this type there is minimal effect on hemoglobin synthesis. Three α-globin genes are enough to permit normal hemoglobin production, and there are no clinical symptoms. They have been called silent carriers. They may have a slightly reduced mean corpuscular volume and mean corpuscular hemoglobin.	-/α α/α
Two	The condition is called alpha thalassemia minor. Two α genes permit nearly normal production of red blood cells, but there is a mild microcytic hypochromic anemia. The disease in this form can be mistaken for iron deficiency anemia and treated inappropriately with iron. Alpha thalassemia minor can exist in two forms: alpha-thal-1 (αα/--), associated with Asians, involves cis deletion of both alpha genes on the same chromosome; alpha-thal-2 (α-/α-), associated with Africans, involves trans deletion of alpha genes on different (homologous) chromosomes.[10]	-/- α/α or -/α -/α
Three	The condition is called Hemoglobin H disease. Two unstable hemoglobins are present in the blood: Hemoglobin Barts (tetrameric γ chains) and Hemoglobin H (tetrameric β chains). Both of these unstable hemoglobins have a higher affinity for oxygen than normal hemoglobin, resulting in poor oxygen delivery to tissues. There is a microcytic hypochromic anemia with target cells and Heinz bodies (precipitated HbH) on the peripheral blood smear, as well as hepatosplenomegaly. The disease may first be noticed in childhood or in early adult life, when the anemia and hepatosplenomegaly are noted.	-/- -/α
Four	This is known as alpha thalassemia major. These fetuses are edematous and have little circulating hemoglobin, and the hemoglobin that is present is all tetrameric γ chains (also called hemoglobin Barts). When all four alleles are affected, the fetus likely will not survive gestation without in utero intervention: most infants with alpha thalassemia major are stillborn with hydrops fetalis, and those who do not receive in utero treatment and are born alive die shortly after birth. Fetuses treated with intrauterine transfusions throughout pregnancy starting at an early gestational age (18-25 weeks) can survive to birth with acceptable morbidity. After birth, the treatment options include bone marrow transplantation or continued chronic transfusions.[11] In the future, in utero stem cell transplantation may be available for this disease.	-/- -/-

Other Resources

• Northern California Comprehensive Thalassemia Center.
• UCSF Fetal Treatment Center information about alpha thalassemia major.
• Cooley's Anemia Foundation.

See also

• Beta thalassemia
• Delta-thalassemia
• Hemoglobinopathy

References

1. Online 'Mendelian Inheritance in Man' (OMIM) Hemoglobin—Alpha locus 1; HBA1 -141800
2. Online 'Mendelian Inheritance in Man' (OMIM) Hemoglobin—Alpha locus 2; HBA2 -141850
3. Flint J, Hill AV, Bowden DK; et al. (1986). "High frequencies of alpha-thalassaemia are the result of natural selection by malaria". Nature 321 (6072): 744–50. doi:10.1038/321744a0. PMID 3713863.
4. Bernini LF. Geographic distribution of alpha thalassemia. In: Steinberg M, Forget B, Higgs D, et al., eds. Disorders of hemoglobin. New York, NY: Cambridge University Press; 2001:878-894.
5. Beutler E, West C (July 2005). "Hematologic differences between African-Americans and whites: the roles of iron deficiency and alpha-thalassemia on hemoglobin levels and mean corpuscular volume". Blood 106 (2): 740–5. doi:10.1182/blood-2005-02-0713. PMC 1895180. PMID 15790781.
6. Vichinsky EP, MacKlin EA, Waye JS, Lorey F, Olivieri NF (December 2005). "Changes in the epidemiology of thalassemia in North America: a new minority disease". Pediatrics 116 (6): e818–25. doi:10.1542/peds.2005-0843. PMID 16291734.
7. BRS Pathology (4th ed.). Lippincott Williams & Wilkins medical. December 2009. p. 162. ISBN 978-1451115871.
8. Steensma DP, Gibbons RJ, Higgs DR (January 2005). "Acquired alpha-thalassemia in association with myelodysplastic syndrome and other hematologic malignancies". Blood 105 (2): 443–52. doi:10.1182/blood-2004-07-2792. PMID 15358626.
9. http://www.cooleysanemia.org/updates/pdf/Alpha_Thalassemia.pdf
10. "Alpha Thalassemia Trait". St. Jude Children's Research Hospital. Retrieved 15 January 2014.
11. Vichinsky, Elliott P. (2009-01-01). "Alpha thalassemia major—new mutations, intrauterine management, and outcomes". ASH Education Program Book 2009 (1): 35–41. doi:10.1182/asheducation-2009.1.35. ISSN 1520-4391. PMID 20008180.