PMC:101377 / 2016-7699 JSONTXT

{"project":"2_test","denotations":[{"id":"11943067-6156623-8600900","span":{"begin":503,"end":504},"obj":"6156623"},{"id":"11943067-8172199-8600901","span":{"begin":3086,"end":3087},"obj":"8172199"},{"id":"11943067-8952151-8600902","span":{"begin":3088,"end":3089},"obj":"8952151"}],"text":"Background\nThe beta-thalassemia syndromes (thalassemia major and beta-thalassemia intermedia) originate from the absence of or from a reduction in the synthesis of structurally normal beta-globin chains. The beta-globin chain deficiency contributes to the pathogenesis of anemia by impairing the formation of functional Hb A and by causing ineffective erythropoiesis. The anemia stimulates the secretion of Epo and leads to erythroid hyperplasia of the bone marrow and to an accelerated erythropoiesis [1]. As a result, erythroblasts expressing the fetal globin gene are generated and fetal hemoglobin (Hb F) is synthesized in the postnatal life [2]. Two more factors, the amplification of the cellular clones producing F-cells and the slower turnover of these cells in circulating blood favour the Hb F presence in thalassemia [3]. In these affections the persistent synthesis of Hb F is very important because it restores the alpha/non-alpha globin ratio, thus reducing the bone marrow hyperplasia and ineffective erythropoiesis and therefore the severity of disease.\nGenetically, the beta-thalassemia syndromes are heterogeneous. The severity of these disorders is determined primarily by the type of the gene defect as well as the gene dosage.\nThe molecular analysis has uncovered that different clinical variants of beta-thalassemia are associated with a wide spectrum of different mutations of the beta-globin gene; thalassemia major patients, characterized by a severe transfusion-dependent anemia and a marked increase in the synthesis of Hb F, are either homozygous carriers of mutations that abolish the beta-globin synthesis (beta° thai) or compound heterozygotes for beta° thal and severe beta+ thal defects which drastically reduce it. These mutations are referred to as severe beta-thal mutations. beta-thal int patients which have a less severe anemia and a modest increase in the synthesis of Hb F, are carriers mainly of beta+ thal mutations that reduce slightly beta-globin synthesis. These mutations are referred to as mild beta-thal mutations.\nFurthermore, deletions of the non-alpha globin gene cluster encompassing the beta- and delta-globin genes are associated with a genetic variant of beta-thalassemia (deltabeta thal), which is characterized by a marked increase in the synthesis of Hb F even in the heterozygous state. In these patients the gamma-globin genes remain intact and are expressed in the postnatal life, thus reducing the ineffective erythropoiesis and ameliorating the severity of the disease.\nIt is worth noting that also genetic factors unlinked to the beta globin cluster, favour the Hb F synthesis in the post-fetal life [4]. Particularly interesting for its frequency is the polimorphic single-base substitution C→T at Ggamma -158, recognizable for the creation of a XmnI restriction site, that appears to cause an increase of Hb F expecially during erythropoietic stress.\nRecently, it has been suggested that the increased synthesis of Hb F associated with beta-thalassemia syndromes is directly or indirectly dependent from the Epo level [5,6].\nThe aim of this study was to investigate the relationships between the genetic defects and the severity of the disease in patients affected by a thalassemic disease. In particular, the relationships between the genetic defect, the total Hb, and between the synthesis of Hb F and the Epo level have been examined in patients with beta thalassemia intermedia (beta thal int). In addition, the distribution and frequency of point mutations of the promoter region of gamma-globin genes were analysed and the relationship between these mutations and the content of Hb F was investigated. The analysis of the beta-globin gene and gamma-globin gene mutations was extended also to patients affected by Cooley's disease.\n\nSubjects\nSeventy-four patients with clinical picture of beta thal int have been examined: 33 of them were affected by a mild or sub-silent form of the disease, and 41 by an evident clinical picture (Tab. 1). In addition, 58 patients carried a beta thal defect and also a triplicated or quadruplicated alpha locus. Twenty-four patients were affected by thalassemia major, and 15 by Hb H disease. The control group included 53 healthy individuals and 42 iron-deficient, non thalassemic patients.\nTable 1 Hematologic and hemoglobinic data and Epo levels in thalassemic patients and control subjects.\nGroup of patients N. cases Hb g/dl Hb F % EPO mU/l Glob. synth. alpha/non-alpha Ret. ‰\nSub-silent beta thal int 33 10.1 ± 1.0 20.5 ± 18.2 3.0 → .70.6 41.22 ± 32.00 11.66 → 136.6 2.10 31\nEvident beta thal int 41 8.3 ± 1.16 33.40 ± 28.04 6.80 → 85.0 95.83 ± 64.33 17.84 → 218.97 2.20 60\nbeta thal int in double heterozygous beta thal + triplicated alpha 58 10.0 ± 1.38 5.15 ± 3.9 2.0 → 19.3 28.45 ± 17.11* 7.85 → 60.72 2.50 30\nHb H disease 15 9.4 ± 1.2 \u003c 1 32.88 ± 12.11** 0.52 28\nThal major 24 10.4 ± 1.0 7.7 ± 8.5*** 1.60 → 40.9 46.83 ± 40.78 9.82 → 129.59 17\nHealthy non-thal subjects 53 14.4 ± 1.1 \u003c1 11.90 ± 3.3 ~1.0 3\nIron-deficient non-thal subjects 42 8.7 ± 1.2 \u003c1 160.10 ± 312.6 2.7 → 1960.0 8\n* The measurement of Epo has been detected only in 17 patients. ** The measurement of Epo has been detected only in 10 patients. *** This value is not informative as patients were routinely transfused. Patients with an homozygotic condition for a delta beta thal deletion were excluded from this study, since only Hb F is synthesized. The patients homozygotes for severe beta-globin defects, and carriers of an alpha thal defect, were also excluded.\nAll of the individuals examined in this study were in the post-puberal age."}