A novel molecular basis for β thalassemia intermedia poses new questions about its pathophysiology

Premawardhena, Anuja; Fisher, Christopher A.; Olivieri, Nancy F.; Silva, Shanthimala de; Sloane-Stanley, Jackie; Wood, W. G.; Weatherall, D. J.

doi:10.1182/blood-2005-02-0593

Cited by 40 publications

(26 citation statements)

References 18 publications

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“…Contrary to the beneficial effect demonstrated by coinheritance of a-and b-thalassemia, inheritance of excess a-globin genes worsens the a-like/b-like globin chain imbalance and results in a more severe clinical phenotype. [67][68][69] This observation further emphasizes that the number of functional a-globin genes has a clear direct effect on the clinical severity of patients with b-thalassemia. …”

Section: Coinheritance Of A-and B-thalassemiamentioning

confidence: 73%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

122

120

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The thalassemias, together with sickle cell anemia and its variants, are the world’s most common form of inherited anemia, and in economically undeveloped countries, they still account for tens of thousands of premature deaths every year. In developed countries, treatment of thalassemia is also still far from ideal, requiring lifelong transfusion or allogeneic bone marrow transplantation. Clinical and molecular genetic studies over the course of the last 50 years have demonstrated how coinheritance of modifier genes, which alter the balance of α-like and β-like globin gene expression, may transform severe, transfusion-dependent thalassemia into relatively mild forms of anemia. Most attention has been paid to pathways that increase γ-globin expression, and hence the production of fetal hemoglobin. Here we review the evidence that reduction of α-globin expression may provide an equally plausible approach to ameliorating clinically severe forms of β-thalassemia, and in particular, the very common subgroup of patients with hemoglobin E β-thalassemia that makes up approximately half of all patients born each year with severe β-thalassemia.

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Section: Coinheritance Of A-and B-thalassemiamentioning

confidence: 73%

α-Globin as a molecular target in the treatment of β-thalassemia

Mettananda

Gibbons

Higgs

2015

Blood

122

120

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“…Individuals homozygous for b-thalassemia who inherit a chromosome having a single a-globin gene deletion may have a milder phenotype, whereas deletion of both a-globin genes on one chromosome is typically associated with thalassemia intermedia. Another mechanism for thalassemia intermedia is heterozygous b-thalassemia inherited along with either triplicated a-globin gene arrangement or with homozygosity for a triplicated globin gene arrangement (Premawardhena et al 2005).…”

Section: Genetic Modifiersmentioning

confidence: 99%

Pathophysiology and Clinical Manifestations of the -Thalassemias

Nienhuis

Nathan

2012

Cold Spring Harbor Perspectives in Medicine

149

111

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The b-thalassemia syndromes reflect deficient or absent b-globin synthesis usually owing to a mutation in the b-globin locus. The relative excess of a-globin results in the formation of insoluble aggregates leading to ineffective erythropoiesis and shortened red cell survival. A relatively high capacity for fetal hemoglobin synthesis is a major genetic modifier of disease severity, with polymorphisms in other genes also having a significant role. Iron overload secondary to enhanced absorption and red cell transfusions causes an increase in liver iron and in various other tissues, leading to endocrine and cardiac dysfunction. Modern chelation regimens are effective in removing iron and preserving or restoring organ function.

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“…Environmental factors, such as malaria infection, may also be of considerable importance . The phenotype of TI may also result from the increased production of a globin chains by a triplicated or quadruplicated a genotype associated with b heterozygosity (Sampietro et al, 1983;Camaschella et al, 1997;Premawardhena et al, 2005). Table I summarises the main molecular forms and interactions that result in the TI phenotype (Steinberg et al, 2009).…”

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confidence: 99%

Optimal management of β thalassaemia intermedia

et al. 2011

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SummaryOur understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with b thalassaemia intermedia (TI) has substantially increased over the past decade. The hallmark of disease process in patients with TI includes ineffective erythropoiesis, chronic haemolytic anaemia, and iron overload. There are a number of options currently available for managing patients with TI including splenectomy, transfusion therapy, iron chelation therapy, modulation of fetal haemoglobin production, and several other agents targeting specific clinical complications. Limited studies assessed the efficacy and safety of these modalities; hence, there are currently no clear guidelines for managing patients with TI. Until solid evidence-based guidelines are available, individualised treatment should be entertained.

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A novel molecular basis for β thalassemia intermedia poses new questions about its pathophysiology

Cited by 40 publications

References 18 publications

α-Globin as a molecular target in the treatment of β-thalassemia

α-Globin as a molecular target in the treatment of β-thalassemia

Pathophysiology and Clinical Manifestations of the -Thalassemias

Optimal management of β thalassaemia intermedia

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