Contents

Hemoglobin E

Medical condition

Hemoglobin E disease
Other names	Haemoglobin E
Crystal structure of Hemoglobin E mutant (Glu26Lys) PDB entry 1vyt. Alpha chain in pink, beta chain in red. The lysine mutation highlighted as white spheres.
Specialty	Hematology

Hemoglobin E (HbE) is an abnormal hemoglobin with a single point mutation in the β chain. At position 26 there is a change in the amino acid, from glutamic acidtolysine (E26K). Hemoglobin E is very common among people of Southeast Asian, Northeast Indian, Sri Lankan and Bangladeshi descent.^[1][2]

The βE mutation affects β-gene expression creating an alternate splicing site in the mRNA at codons 25-27 of the β-globin gene. Through this mechanism, there is a mild deficiency in normal β mRNA and production of small amounts of anomalous β mRNA. The reduced synthesis of β chain may cause β-thalassemia. Also, this hemoglobin variant has a weak union between α- and β-globin, causing instability when there is a high amount of oxidant.^[3] HbE can be detected on electrophoresis.

Hemoglobin E disease results when the offspring inherits the gene for HbE from both parents. At birth, babies homozygous for the hemoglobin E allele do not present symptoms because they still have HbF (fetal hemoglobin). In the first months of life, fetal hemoglobin disappears and the amount of hemoglobin E increases, so the subjects start to have a mild β-thalassemia. Subjects homozygous for the hemoglobin E allele (two abnormal alleles) have a mild hemolytic anemia and mild enlargement of the spleen.

Heterozygous AE occurs when the gene for hemoglobin E is inherited from one parent and the gene for hemoglobin A from the other. This is called hemoglobin E trait, and it is not a disease. People who have hemoglobin E trait (heterozygous) are asymptomatic and their state does not usually result in health problems. They may have a low mean corpuscular volume (MCV) and very abnormal red blood cells (target cells), but clinical relevance is mainly due to the potential for transmitting E or β-thalassemia.^[4]

Compound heterozygotes with sickle-hemoglobin E disease result when the gene of hemoglobin E is inherited from one parent and the gene for hemoglobin S from the other. As the amount of fetal hemoglobin decreases and hemoglobin S increases, a mild hemolytic anemia appears in the early stage of development. Patients with this disease experience some of the symptoms of sickle cell anemia, including mild-moderate anemia, increased risk of infection, and painful sickling crises.^[5]

People who have hemoglobin E/β-thalassemia have inherited one gene for hemoglobin E from one parent and one gene for β-thalassemia from the other parent. Hemoglobin E/β-thalassemia is a severe disease, and it still has no universal cure. However, the mutation is amenable to genome editing at high efficiency in preclinical studies.^[6] It affects more than a million people in the world.^[7] Symptoms of hemoglobin E/β-thalassemia vary but can include growth retardation, enlargement of the spleen (splenomegaly) and liver (hepatomegaly), jaundice, bone abnormalities, and cardiovascular problems.^[8] Recommended course of treatment depends on the nature and severity of the symptoms and may involve close monitoring of hemoglobin levels, folic acid supplements, and potentially regular blood transfusions.^[8]

There is a variety of phenotypes depending on the interaction of HbE and α-thalassemia. The presence of the α-thalassemia reduces the amount of HbE usually found in HbE heterozygotes. In other cases, in combination with certain thalassemia mutations, it provides an increased resistance to malaria (P. falciparum).^[4] This disease was first described by Virginia Minnich in 1954, who discovered a high prevalence of it in Thailand and initially referred to it as "Mediterranean Anaemia."^[8]

Hemoglobin E is most prevalent in mainland Southeast Asia (Thailand, Myanmar, Cambodia, Laos, Vietnam^[9]), Sri Lanka, Northeast India and Bangladesh. In mainland Southeast Asia, its prevalence can reach 30 or 40%, and Northeast India, in certain areas it has carrier rates that reach 60% of the population. In Thailand the mutation can reach 50 or 70%, and it is higher in the northeast of the country. In Sri Lanka, it can reach up to 40% and affects those of Sinhalese and Vedda descent.^[10][11] It is also found at high frequencies in Bangladesh and Indonesia.^[12][13] The trait can also appear in people of Turkish, Chinese and Filipino descent.^[1] The mutation is estimated to have arisen within the last 5,000 years.^[14] In Europe, there have been found cases of families with hemoglobin E, but in these cases, the mutation differs from the one found in South-East Asia. This means that there may be different origins of the βE mutation.^[15][16]

• Hemoglobin E fact sheet from the Washington State Department of Health
• American Society of Hematology Educational Program profile of Hemoglobin E disorders
• Orphanet Encyclopedia entry for Hemoglobin E
• Hemoglobin E in Europeans