Hemoglobinopathy is the medical term for a group of inherited blood disorders involving the hemoglobin, the protein of red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits. There are two main groups: abnormal structural hemoglobin variants caused by mutations in the hemoglobin genes, and the thalassemias, which are caused by an underproduction of otherwise normal hemoglobin molecules. The main structural hemoglobin variants are HbS, HbE and HbC. The main types of thalassemia are alpha-thalassemia and beta thalassemia. The two conditions may overlap because some conditions which cause abnormalities in hemoglobin proteins also affect their production. Some hemoglobin variants do not cause pathology or anemia, and thus are often not classed as hemoglobinopathies.

Hemoglobin structural biology

Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one α (alpha) chain and one β (beta) chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the α and the β chains is balanced so that their ratio is relatively constant and there is no excess of either type. The specific α and β chains that are incorporated into Hb are highly regulated during development:

Classification of hemoglobinopathies

A) Qualitative

Structural abnormalities

Hb variants: Hb structural variants are qualitative defects that cause a change in the structure (primary, secondary, tertiary, and/or quaternary) of the Hb molecule. The majority of Hb variants do not cause disease and are most commonly discovered either incidentally or through newborn screening. A subset of Hb variants can cause severe disease when inherited in the homozygous or compound heterozygous state in combination with another structural variant or a thalassemia mutation. When clinical consequences occur, they may include anemia due to hemolysis or polycythemia due to alterations in the oxygen affinity of the abnormal Hb. Common examples of hemoglobin variants associated with hemolysis include sickle Hb (HbS) and HbC. Hb variants can usually be detected by protein-based assay methods; however, DNA-based methods may be required for variants with ambiguous or unusual results from protein analysis. The major functional consequences of Hb structural variants can be classified as follows:

Chemical abnormalities

B) Quantitative

Production abnormalities

Copy number variation (e.g., deletion, duplication, insertion) is also a common genetic cause of Hb disorders, and complex rearrangements and globin gene fusions can also occur.

Hemoglobin variants

Haemoglobin variant are not necessarily pathological. For example, haemoglobin Valletta and haemoglobin Marseille are two haemoglobin variants which are non-pathological

Electrophoretic migration patterns

Hemoglobin variants can be detected by gel electrophoresis.

Alkaline electrophoresis

In general on alkaline electrophoresis in order of increasing mobility are hemoglobins A2, E=O=C, G=D=S=Lepore, F, A, K, J, Bart's, N, I, and H. In general a sickling test is performed on abnormal hemoglobins migrating in the S location to see if the hemoglobin precipitates in solution of sodium bisulfite.

Acid electrophoresis

In general on acid electrophoresis in order of increasing mobility are hemoglobins F, A=D=G=E=O=Lepore, S, and C. This is how abnormal hemoglobin variants are isolated and identified using these two methods. For example, a Hgb G-Philadelphia would migrate with S on alkaline electrophoresis and would migrate with A on acid electrophoresis, respectively

Evolution

Some hemoglobinopathies (and also related diseases like glucose-6-phosphate dehydrogenase deficiency) seem to have given an evolutionary benefit, especially to heterozygotes, in areas where malaria is endemic. Malaria parasites live inside red blood cells, but subtly disturb normal cellular function. In patients predisposed for rapid clearance of red blood cells, this may lead to early destruction of cells infected with the parasite and increased chance of survival for the carrier of the trait. Hemoglobin functions: Pathology and organic structural abnormalities may lead to any of the following disease processes:

Treatments

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood to replicate inside a patient and to produce normal blood cells. It may be autologous (the patient's own stem cells are used), allogeneic (the stem cells come from a donor) or syngeneic (from an identical twin).