β-Thalassemia Intermedia: Interaction of α-Globin Gene Triplication With β-thalassemia Heterozygous in Spain

Abstract

ObjectivesTo verify with hematimetric data that the diagnosis and clinical grade of β-TI can be established when a triplication of alpha genes (αααanti 3.7) and heterozygous β-thalassemia coexist.Materials and MethodsRetrospective study in which 73 patients of Caucasian origin participated, who simultaneously showed a triplication or quadruplication of genes α and β-thalassemia.Screening for the most frequent α-thalassemia mutations as well as gene triplication (αααanti 3.7) was carried out by multiplex PCR followed by reverse hybridization with a commercial Alpha-Globin StripAssay kit and confirmed by MLPA (Multiplex ligation-dependent probe amplification). The molecular diagnosis of β-thalassemia was carried out by automatic sequencing according to the Sanger method.ResultsThe genotypes have been classified into three groups according to the number of α globin genes and the severity of the alteration in the β globin gene. All had a mutation in the HBB gene (β0-thalassemia, β+-thalassemia severe, and β+-thalassemia mild). Group I patients who have coherent 6 α genes and groups II and III with 5 α globin genes. In group III, the patients were carriers of mutations affecting the β and δ globin genes. The most significant hematological parameters were hemoglobin levels, MCV, RDW, and the percentage of Hb F.ConclusionsIn group I, regardless of the distribution of the 6 α globin genes, homozygous triplication (ααα/ααα) or heterozygous quadruplication (αααα/αα), the association with heterozygous β-thalassemia results in severe to moderate anemia that may or may not require transfusion therapy, is the severity of the HBB gene mutation that would determine the clinical variation. Group II patients phenotypically behaved like mild thalassemia intermedia, except for one case that presented thalassemic trait because it also presented an associated α-thalassemia (ααα/-α3.7). Finally, group III patients behaved as a thalassemic trait since all were carriers of mutations that increase the overexpression of γ genes.

Transfusion requirements and complication rate in β‐thalassemia intermedia due to heterozygous β‐globin gene mutation and triplicated α‐globin genes

“…Accordingly, transfusion requirements were significantly lower for patients with the anti‐α −3.7kb triplication. As regard to transfusions, our results are consistent with previous studies, reporting transfusion need in 30% of the whole cohort and higher needs in women, especially during pregnancy or delivery 4,10,11 …”

“…From homozygous patients and in accordance with previous studies, we showed that the level of α-chain overproduction, estimated by the number of functional α-globin gene, is the most important feature in predicting severity with 3/4 of the patients carrying the α-triplication being TD whereas none of the 41 heterozygous were. 4,10 To assess the current state of health of patients with heterozygous anti-α À3.7kb , laboratory data and complication rate were compared to those of a large cohort of patients with homozygosity or compound heterozygosity in HBB. We observed that the diagnostic of TI was made later in life and that the mean Hb level, although significantly lower than the normal range, was higher than in patients with bi-allelic mutations in HBB.…”

“…As regard to transfusions, our results are consistent with previous studies, reporting transfusion need in 30% of the whole cohort and higher needs in women, especially during pregnancy or delivery. 4,10,11 Iron can accumulate in various organs, leading to most comorbidities found in both TD and non-TD β-thalassemia patients. need.…”

“…2 This first description was followed by several case report or series of patients with homozygous or heterozygous alpha-triplication, providing genotype information and transfusion requirement with absent or limited data on iron overload or complication rate. [3][4][5][6][7][8][9][10][11] Since TI can be clinically heterogeneous, detailed descriptions of such patients is useful to better define the appropriate clinical followup. The present report describes transfusion needs, iron overload estimated by serum ferritin levels and hepatic and cardiac MRI, and complication rates in a cohort of 45 patients presenting a heterozygous β 0 or β + -thalassemia mutation associated with a triplication at HBA locus.…”

“…In the early 1980s, Galanello et al reported for the first time this particular genotype as a cause for beta‐thalassemia 2 . This first description was followed by several case report or series of patients with homozygous or heterozygous alpha‐triplication, providing genotype information and transfusion requirement with absent or limited data on iron overload or complication rate 3–11 …”