Hemoglobin E Authors: Doctor Dora Bachir1 and Professor Frédéric Galacteros Creation date: November 2004 Scientific Editor: Professor Gilbert Tchernia 1Centre de la drépanocytose, CHU Hôpital Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny 94010 CRETEIL, France. mailto:[email protected] Abstract Keywords Disease name Included diseases Definition Diagnostic criteria and clinical description Epidemiology Management References Abstract Hemoglobin E (HbE) is a variant hemoglobin with a mutation in the β globin gene causing substitution of glutamic acid for lysine at position 26 of the β globin chain. HbE is the second commonest abnormal hemoglobin after sickle cell hemoglobin (HbS). HbE is common in South-East Asia, where its prevalence can reach 30-40% in some parts of Thailand, Cambodia and in Laos. Hb E is also found in Sri Lanka, North Eastern India, Bangladesh, Pakistan, Nepal, Vietnam, Malaysia. The β chain of HbE (βE) is synthesized at a reduced rate compared with that of normal adult hemoglobin (HbA), as the mutation creates an alternate splicing site within an exon. Consequently heterozygotes AE, compound heterozygotes SE and homozygotes EE show some β thalassemic features. Subjects heterozygous for HbE (AE) have an asymptomatic condition with no clinical relevance, except for the risk of transmitting E/β thalassemia if the other parent carries β thalassemia. The severity of these E/β thalassemia forms is very variable, the clinical picture ranging from that of β thalassemia minor through thalassemia intermedia to thalassemia major. Subjects homozygous for HbE (EE) are asymptomatic. Management concerns exclusively E/β thalassemia forms. During childhood, regular follow-up of growth and facial deformities, hemoglobin level, prophylaxis of infections source of worsening of anemia with vaccines, treatment of potential infectious sites are essential. Daily oral penicillin is recommended. Transfusions are indicated in case of bad tolerance of anemia and /or facial deformities. The main complication of regular transfusions is iron overload, source of hepatopathy, cardiac failure, endocrinopathies requiring thus iron chelation. ® The most widely used chelator is deferoxamine (Desféral ). Splenectomy can diminish or suppress transfusion requirements in intermediate forms and should not be performed before 5 years. Pregnancy requires regular antenatal care by obstetricians, in collaboration with hematologist. Transfusions are often required in the 3rd trimester in women with β thalassemia intermedia, to reduce anemia and low weight births. Treatment of infections as well of thrombosis prophylaxis are requested. Bone marrow transplantation has very rare indications. Recombinant erythropoietin alone or associated with hydroxyurea may be useful in reducing transfusions requirements, in improving quality of life and in diminishing hemopoietic ectopic extra-medullary masses. Keywords Hemoglobin E, β globin gene, hemoglobin E trait, hemoglobin E disease, hemoglobin E/βthalassemia, sickle cell/hemoglobin E disease Bachir D and Galacteros F. Hemoglobin E disease. Orphanet Encyclopedia. November 2004. http://www.orpha.net/data/patho/GB/uk-HbE.pdf 1 Electrophoretic profile Disease name Hemoglobin electrophoresis at alkaline pH on Hemoglobin E cellulose acetate shows that the variant HbE has the same mobility than that of the variant HbC Included diseases (α2 β2 6glu_lys) and the adult hemoglobin HbA2 Hemoglobin E trait, hemoglobin E disease, (α2 δ2). On citrate agar or agarose gel at acid hemoglobin E/β thalassemia, sickle pH, the mobility of HbE is the same than that of cell/hemoglobin E disease HbA and HbA2. HbE has a characteristic mobility on isoelectric focusing, being well Definition 26 Glu_Lys separated from HbA and focusing like HbA2, and Hemoglobin E =HbE (α2β2 ) is a variant thus unlike HbC. On HPLC, HbE is easily hemoglobin with a mutation in the β globin gene separated from HbA and HbC, but may co elute causing substitution of glutamic acid for lysine at with HbA2. position 26 of the β globin chain. HbE may be In HbE heterozygotes, the variant usually present in the heterozygous state (genotype AE comprises 33 % or less of total HbA. Individuals or hemoglobin E trait), the homozygous state with less than 30% of HbE almost always have (EE or hemoglobin E disease) and a variety of co existing α thalassemia trait. compound heterozygous states such as HbE is slightly unstable in heat and isopropanol hemoglobin E/βthalassemia (E/βthal), sickle stability tests. cell/hemoglobin E disease (SE genotype). E The β chain of HbE (β ) is synthesized at a Hemoglobin E disease reduced rate compared with that of normal adult Hemoglobin E disease is defined by the hemoglobin (HbA). This is because the mutation coexistence of two βE alleles (homozygous creates an alternate splicing site within an exon. state EE). At birth, differential diagnosis is E This results in reduced rate of synthesis of β E/βOthalassemia, which is always symptomatic chain and therefore of HbE, and consequently after disappearance of HbF. Study of both heterozygotes, compound heterozygotes and parents (heterozygotes AE in case of homozygotes show some β thalassemic homozygous EE in the child) is mandatory. features. HbE may therefore be regarded as a + β thalassemic hemoglobinopathy. Clinical features Individuals with the genotype EE are usually Diagnostic criteria and clinical description completely asymptomatic. There is usually no Hemoglobin E trait anemia and rarely any evidence of hemolysis. HbE trait is defined by the heterozygous The spleen is not usually enlarged. Otherwise a condition associating with one normal adult coexisting HbH disease (α 3 thalassemia) must hemoglobin (HbA) β gene and one variant be considered. hemoglobin E β gene. Laboratory features Clinical features Blood count. The blood count often HbE trait is an asymptomatic condition with no ressembles that of βthalassemia trait, with a clinical relevance, except for the risk of normal hemoglobin concentration or very mild compound heterozygous states with anemia and increased red blood cell (RBC), βthalassemia in the offspring. reduced MCV and MCH. MCHC is usually normal. Laboratory features Most of individuals with HbE trait have reduced Blood film. The blood film usually shows mean corpuscular volume (MCV) and mean cell hypochromia and microcytosis with variable hemoglobin (MCH), with or without mild anemia. numbers of target cells, basophilic stippling and The red blood cell indices resemble those of irregularly contracted cells. thalassemia trait. Individuals with HbE trait may carry α thalassemia conditions of varying Electrophoretic profile severity according to the number of non- Hemoglobin electrophoresis shows the major functional α genes 1,2,3. However even those hemoglobin to be HbE, with HbE plus HbA2 with a full complement of α genes may be constituting 95-99 % of total hemoglobin. microcytic and mildly anemic. The blood film may be normal or may show Hemoglobin E/βthalassaemia hypochromia, microcytosis, target cells, Hemoglobin E trait may be co inherited with irregularly contracted cells, basophilic stippling either β0 or β+ thalassemia. The compound or any combination of these features. heterozygous state is quite common in Thailand and occurs throughout a large part of South-East Bachir D and Galacteros F. Hemoglobin E disease. Orphanet Encyclopedia. November 2004. http://www.orpha.net/data/patho/GB/uk-HbE.pdf 2 Asia, stretching form Indonesia to Sri Lanka, uncommon. HbS represents a larger proportion North-East India and Bangladesh, making this of total hemoglobin than HbE (around 65%). HbF the most common β thalassemia phenotype in may be normal or slightly elevated. the world and one of the most prevalent genetic disease in the world. Epidemiology HbE is common in South-East Asia. The highest Clinical features prevalence of carriers is in some parts of The severity of compound heterozygotes for Thailand, in Cambodia and in Laos. Thailand HbE and β thalassemia is very variable, the and Myanmar (previously Burma) have an clinical picture ranging from that of βthalassemia overall prevalence of around 14-15 %. Gene minor through thalassemia intermedia to frequency in Thailand varies from 8 to 50-70 %, thalassemia major. Most patients have a disease being highest in North-Eastern Thailand. that is at least moderately severe. Hemoglobin E is also found in Sri Lanka, North The most severely affected individuals are Eastern India, Bangladesh, Pakistan, Nepal, transfusion dependent and have liver Vietnam, Malaysia, the Philippines, Indonesia enlargement and splenomegaly, intermittent and Turkey. jaundice, growth retardation and over expansion Management of the bone marrow cavity leading to facial SE forms deformity and defective tooth implantation. Less Management is comparable to that of sickle cell severely affected individuals may have form, although vasoocclusive symptomatology is splenomegaly and facial deformity but do not reduced, except in rare situations (air travel) and require regular transfusions to maintain life. pregnancy. Hypersplenism may occur. Splenectomy is usually efficient in reducing transfusion E β thalassemia forms requirements. During pregnancy, patients may During childhood, regular follow-up of growth temporarily become transfusion dependant. and facial deformities, hemoglobin level, Extramedullary hemopoiesis can occur and has prophylaxis of infections source of worsening of sometimes led to compression of the spinal cord anemia