Alpha-thalassemia

Alpha-thalassemia
Specialty	Hematology

Alpha-thalassemia (α-thalassemia, α-thalassaemia) is a form of thalassemia involving the genes HBA1 and HBA2. 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).

Signs/symptoms

The presentation of individuals with alpha-thalassemia consist of the following:

2

Cause

It is most commonly inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome.It can also be acquired, under rare circumstances. Due to the low occurrence of alpha-thalassemia, the disease can be mistaken for iron deficiency anemia.

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.

Diagnosis

Diagnosis is primarily via laboratory evaluation and haemoglobin electrophoresis. 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 and serum ferritin can be used to exclude iron deficiency anaemia.

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	Haematopoiesis(production of blood cells) 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.	-/- 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. In the future, in utero stem cell transplantation may be available for this disease	-/- -/-

Epidemiology

Malaria

The worldwide distribution of inherited alpha-thalassemia corresponds to areas of malaria exposure, 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. 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. 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.

See also

• Beta thalassemia
• Delta-thalassemia
• Hemoglobinopathy

Further reading

• Origa, Raffaella; Moi, Paolo; Galanello, Renzo; Cao, Antonio (1 January 1993). "Alpha-Thalassemia". GeneReviews(®). University of Washington, Seattle. Retrieved 11 September 2016.update 2013
• "What Are Thalassemias? - NHLBI, NIH". www.nhlbi.nih.gov. Retrieved 15 September 2016.
• "Home | Thalassemia | Blood Disorders | NCBDDD | CDC". www.cdc.gov. Retrieved 15 September 2016.
• "Thalassaemia | Doctor | Patient". Patient. Retrieved 15 September 2016.
• Anie, Kofi A; Massaglia, Pia (6 March 2014). "Psychological therapies for thalassaemia". Cochrane Database of Systematic Reviews. John Wiley & Sons, Ltd. doi:10.1002/14651858.cd002890.pub2/full. Retrieved 15 September 2016.