α- thalassemia, H hemoglobinopathy and unstable α globin chains

Haema 2011; 2(2): 254-261

by Emmanuel Kanavakis1, Joanne Traeger-Synodinos1, Varvara Douna2

1Department of Medical Genetics, Athens University, St. Sophia’s Children’s Hospital, Athens, 2Hematology Laboratory “P. & A. Kyriakou”, Athens

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Abstract

The synthesis of α-globin chains is directed by the duplicated α-globin genes (HBA1 και ΗΒΑ2 ή a1 και a2) located at the tip of the short arm of chromosome 16 (16p13.3). Mutations that reduce the synthesis of α-globin chains cause α-thalassemia (α-thal), and over than 120 have been described worldwide (Ηb Var http://globin.cse.psu.edu/hbvar/). The majority of the most common α-thal determinants are deletions that remove some, or all of, the α-globin gene cluster. Less common are single nucleotide (nt) substitutions or micro deletions within either the α1- or α2-globin genes, also known as nondeletional mutations. An apparent reduction in α-globin chain synthesis can also be caused by substitutions that give rise to hyperunstable α-globin chains. In most cases, these variants are so unstable that they cannot be detected at the protein level, and can only be deduced from the DNA sequence. In Greece, α-thal has an estimated carrier frequency of 8.0%, with over 20 different mutations observed to date. According to the number of a genes with impaired function, four major hematological and clinical phenotypes can be characterized. Coinheritance of a thalassemia mutations may lead to the expression of clinically relevant conditions, most noteably Hb Bart’s hydrops fetalis and Hb H disease. HbH disease is the severest form of a thalassemia compatible with postnatal life, and it occurs when a thalassemia mutations interact to reduce a globin synthesis to levels approximately equivalent to the output of a single a globin gene. The clinical severity of Hb H disease may vary considerably, but strongly correlates with the underlying a thalassemia genotype. Patients with genotypes involving hyperunstable α-globin chain variants (either in the homozygous or compound heterozygous state with typical haploinsufficient a thalassemia mutations) may have classical Hb H disease, but also may have a condition with clinical and hematological findings similar to β-thal intermedia and very rarely HbH-hydrops.