Hemoglobinopathy

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Hemoglobinopathy
Other namesHemoglobinopathies
Sickle cells.jpg
Red blood cells from a person with sickle cell trait
Specialty Hematology   OOjs UI icon edit-ltr-progressive.svg

Hemoglobinopathy is the medical term for a group of inherited blood disorders and diseases that primarily affect red blood cells. [1] They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits. [2]

Contents

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. [3]

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. [4] [5]

Hemoglobin structural biology

Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like (α-like) chain and one beta-like (β-like) chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the alpha-like and the beta-like (also called non-alpha-like) chains is balanced so that their ratio is relatively constant and there is no excess of either type. [6]

The specific alpha and beta-like chains that are incorporated into Hb are highly regulated during development:[ citation needed ]

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 (Hb S) and Hb C. 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.[ citation needed ]

The major functional consequences of Hb structural variants can be classified as follows:[ citation needed ]

  • Change in physical properties (solubility): Common beta globin mutations can alter the solubility of the Hb molecule: Hb S polymerizes when deoxygenated and Hb C crystallizes. [9]
  • Reduced protein stability (instability): Unstable Hb variants are mutations that cause the Hb molecule to precipitate, spontaneously or upon oxidative stress, resulting in hemolytic anemia. Precipitated, denatured Hb can attach to the inner layer of the plasma membrane of the red blood cell (RBC) and form Heinz bodies. [10]
  • Change in oxygen affinity: High or low oxygen affinity Hb molecules are more likely than normal to adopt the relaxed (R, oxy) state or the tense (T, deoxy) state, respectively. High oxygen affinity variants (R state) cause polycythemia (e.g., Hb Chesapeake, Hb Montefiore). Low oxygen affinity variants can cause cyanosis (e.g., Hb Kansas, Hb Beth Israel). [11]
  • Oxidation of heme iron: Mutations of the heme binding site, particularly those affecting the conserved proximal or distal histidine residues, can produce M-hemoglobin, in which the iron atom in heme is oxidized from the ferrous (Fe2+) state to the ferric (Fe3+) state, with resultant methemoglobinemia. [11]

Chemical abnormalities

  • Methemoglobinemia:
    • a condition caused by elevated levels of methemoglobin in the blood. Methaemoglobin is a form of Hb that contains the ferric [Fe3+] form of iron. The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methaemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric haemoglobin unit.[ citation needed ]

B) Quantitative

Production abnormalities

Red blood cells from a person with beta thalassemia B-Thal.jpg
Red blood cells from a person with beta thalassemia

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.[ citation needed ]

  • Thalassemias: Thalassemias are quantitative defects that lead to reduced levels of one type of globin chain, creating an imbalance in the ratio of alpha-like chains to beta-like chains. As noted above, this ratio is normally tightly regulated to prevent excess globin chains of one type from accumulating. The excess chains that fail to incorporate into Hb form non-functional aggregates that precipitate within the RBC. This can lead to premature RBC destruction in the bone marrow (beta thalassemia) and/or in the peripheral blood (alpha thalassemia). Types:
    • Alpha
    • Beta (Major)
    • Beta (Minor)

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. [15]

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.[ citation needed ]

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.[ citation needed ]

Acid electrophoresis

In general on acid electrophoresis in order of increasing mobility are hemoglobins F, A=D=G=E=O=Lepore, S, and C.[ citation needed ]

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[ citation needed ]

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.[ citation needed ]

Hemoglobin functions:

Pathology and organic structural abnormalities may lead to any of the following disease processes:[ citation needed ]

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. [16] [17] [18] [19] [20] [21] 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). [19] [20]

Related Research Articles

<span class="mw-page-title-main">Hemoglobin</span> Metalloprotein that binds with oxygen

Hemoglobin is a protein containing iron that facilitates the transport of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the exception of the fish family Channichthyidae. Hemoglobin in the blood carries oxygen from the respiratory organs to the other tissues of the body, where it releases the oxygen to enable aerobic respiration which powers the animal's metabolism. A healthy human has 12 to 20 grams of hemoglobin in every 100 mL of blood. Hemoglobin is a metalloprotein, a chromoprotein, and globulin.

<span class="mw-page-title-main">Globin</span> Superfamily of oxygen-transporting globular proteins

The globins are a superfamily of heme-containing globular proteins, involved in binding and/or transporting oxygen. These proteins all incorporate the globin fold, a series of eight alpha helical segments. Two prominent members include myoglobin and hemoglobin. Both of these proteins reversibly bind oxygen via a heme prosthetic group. They are widely distributed in many organisms.

<span class="mw-page-title-main">Thalassemia</span> Family of inherited blood disorders

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time.

<span class="mw-page-title-main">Fetal hemoglobin</span> Oxygen carrier protein in the human fetus

Fetal hemoglobin, or foetal haemoglobin is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.

<span class="mw-page-title-main">Hemoglobin A</span> Normal human hemoglobin in adults

Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 or α2β2, is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin. Hemoglobin is an oxygen-binding protein, found in erythrocytes, which transports oxygen from the lungs to the tissues. Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). Hemoglobin A2 (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults.

Hemoglobin A2 (HbA2) is a normal variant of hemoglobin A that consists of two alpha and two delta chains (α2δ2) and is found at low levels in normal human blood. Hemoglobin A2 may be increased in beta thalassemia or in people who are heterozygous for the beta thalassemia gene.

Hemoglobin C is an abnormal hemoglobin in which glutamic acid residue at the 6th position of the β-globin chain is replaced with a lysine residue due to a point mutation in the HBB gene. People with one copy of the gene for hemoglobin C do not experience symptoms, but can pass the abnormal gene on to their children. Those with two copies of the gene are said to have hemoglobin C disease and can experience mild anemia. It is possible for a person to have both the gene for hemoglobin S and the gene for hemoglobin C; this state is called hemoglobin SC disease, and is generally more severe than hemoglobin C disease, but milder than sickle cell anemia.

<span class="mw-page-title-main">Alpha-thalassemia</span> Thalassemia involving the genes HBA1and HBA2 hemoglobin genes

Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.

<span class="mw-page-title-main">Beta thalassemia</span> Thalassemia characterized by the reduced or absent synthesis of the beta globin chains of hemoglobin

Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.

<span class="mw-page-title-main">Hemoglobin subunit beta</span> Mammalian protein found in Homo sapiens

Hemoglobin subunit beta is a globin protein, coded for by the HBB gene, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, hemoglobin A (HbA). It is 147 amino acids long and has a molecular weight of 15,867 Da. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains.

<span class="mw-page-title-main">Hemoglobin variants</span> Forms of hemoglobin caused by variations in genetics

Hemoglobin variants are different types of hemoglobin molecules, by different combinations of its subunits and/or mutations thereof. Hemoglobin variants are a part of the normal embryonic and fetal development. They may also be pathologic mutant forms of hemoglobin in a population, caused by variations in genetics. Some well-known hemoglobin variants, such as sickle-cell anemia, are responsible for diseases and are considered hemoglobinopathies. Other variants cause no detectable pathology, and are thus considered non-pathological variants.

Hemoglobin Barts, abbreviated Hb Barts, is an abnormal type of hemoglobin that consists of four gamma globins. It is moderately insoluble, and therefore accumulates in the red blood cells. Hb Barts has an extremely high affinity for oxygen, so it cannot release oxygen to the tissue. Therefore, this makes it an inefficient oxygen carrier. As an embryo develops, it begins to produce alpha-globins at weeks 5–6 of development. When both of the HBA1 and HBA2 genes which code for alpha globins becomes dysfunctional, the affected fetuses will have difficulty in synthesizing a functional hemoglobin. As a result, gamma chains will accumulate and form four gamma globins. These gamma globins bind to form hemoglobin Barts. It is produced in the disease alpha-thalassemia and in the most severe of cases, it is the only form of hemoglobin in circulation. In this situation, a fetus will develop hydrops fetalis and normally die before or shortly after birth, unless intrauterine blood transfusion is performed.

<span class="mw-page-title-main">Hemoglobin subunit alpha</span> Human hemoglobin protein

Hemoglobin subunit alpha, Hemoglobin, alpha 1, is a hemoglobin protein that in humans is encoded by the HBA1 gene.

<span class="mw-page-title-main">HBG1</span>

Hemoglobin subunit gamma-1 is a protein that in humans is encoded by the HBG1 gene.

The human embryonic haemoglobins were discovered in 1961. These include Hb-Gower 1, consisting of 2 zeta chains and 2 epsilon chains, and Hb-Gower 2, which consists of 2 αlpha-chains and 2 epsilon-chains, the zeta and epsilon chains being the embryonic haemoglobin chains.

<span class="mw-page-title-main">Hemoglobin Lepore syndrome</span> Medical condition

Hemoglobin Lepore syndrome is typically an asymptomatic hemoglobinopathy, which is caused by an autosomal recessive genetic mutation. The Hb Lepore variant, consisting of two normal alpha globin chains (HBA) and two delta-beta globin fusion chains which occurs due to a "crossover" between the delta (HBD) and beta globin (HBB) gene loci during meiosis and was first identified in the Lepore family, an Italian-American family, in 1958. There are three varieties of Hb Lepore, Washington, Baltimore and Hollandia. All three varieties show similar electrophoretic and chromatographic properties and hematological findings bear close resemblance to those of the beta-thalassemia trait; a blood disorder that reduces the production of the iron-containing protein hemoglobin which carries oxygen to cells and which may cause anemia.

Hemoglobin H disease, also called alpha-thalassemia intermedia, is a disease affecting hemoglobin, the oxygen carrying molecule within red blood cells. It is a form of Alpha-thalassemia which most commonly occurs due to deletion of 3 out of 4 of the α-globin genes.

<span class="mw-page-title-main">Hemoglobin Hopkins-2</span>

Hemoglobin Hopkins-2 is a mutation of the protein hemoglobin, which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates. The specific mutation in Hemoglobin Hopkins-2 results in two abnormal α chains. The mutation is the result of histidine 112 being replaced with aspartic acid in the protein's polypeptide sequence. Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. This mutation can cause sickle cell anemia.

Hemoglobin O (HbO) is a rare type of hemoglobin in which there is a substitution of glutamic acid by lysine as in hemoglobin C, but at different positions. Since the amino acid substitution can occur at different positions of the β-globin chain of the protein, there are several variants. In hemoglobin O-Arab (HbO-Arab) substitution occurs at position 121, while in hemoglobin O-Padova (HbO-Padova) it is at 11 position, and in hemoglobin O Indonesia (HbOIna) it is at 116.

<span class="mw-page-title-main">Hemoglobin M disease</span> Medical condition

Hemoglobin M disease is a rare form of hemoglobinopathy, characterized by the presence of hemoglobin M (HbM) and elevated methemoglobin (metHb) level in blood. HbM is an altered form of hemoglobin (Hb) due to point mutation occurring in globin-encoding genes, mostly involving tyrosine substitution for proximal (F8) or distal (E7) histidine residues. HbM variants are inherited as autosomal dominant disorders and have altered oxygen affinity. The pathophysiology of hemoglobin M disease involves heme iron autoxidation promoted by heme pocket structural alteration.

References

  1. ↑ CDC (2019-02-08). "Hemoglobinopathies Research". Centers for Disease Control and Prevention. Retrieved 2019-05-05.
  2. ↑ Weatherall, D. J.; Clegg, J. B. (2001). "Inherited haemoglobin disorders: An increasing global health problem". Bulletin of the World Health Organization. 79 (8): 704–712. PMC   2566499 . PMID   11545326.
  3. ↑ "Hemoglobinopathies and Thalassemia". medicalassistantonlineprograms.org/. Archived from the original on 2015-01-09. Retrieved 2013-11-07.
  4. ↑ "Hemoglobin Variants". Lab Tests Online. American Association for Clinical Chemistry. 2007-11-10. Retrieved 2008-10-12.
  5. ↑ Huisman THJ (1996). "A Syllabus of Human Hemoglobin Variants". Globin Gene Server. Pennsylvania State University. Retrieved 2008-10-12.
  6. ↑ Weatherall DJ. The New Genetics and Clinical Practice, Oxford University Press, Oxford 1991.
  7. ↑ Huisman TH. The structure and function of normal and abnormal haemoglobins. In: Baillière's Clinical Haematology, Higgs DR, Weatherall DJ (Eds), W.B. Saunders, London 1993. p.1.
  8. ↑ Natarajan K, Townes TM, Kutlar A. Disorders of hemoglobin structure: sickle cell anemia and related abnormalities. In: Williams Hematology, 8th ed, Kaushansky K, Lichtman MA, Beutler E, et al. (Eds), McGraw-Hill, 2010. p.ch.48.
  9. ↑ Eaton, William A.; Hofrichter, James (1990). "Sickle Cell Hemoglobin Polymerization". Advances in Protein Chemistry. 40: 63–279. doi:10.1016/S0065-3233(08)60287-9. ISBN   9780120342402. PMID   2195851.
  10. ↑ Srivastava, P.; Kaeda, J. S.; Roper, D.; Vulliamy, T. J.; Buckley, M.; Luzzatto, L. (1995). "Severe hemolytic anemia associated with the homozygous state for an unstable hemoglobin variant (Hb Bushwick)". Blood. 86 (5): 1977–1982. doi: 10.1182/blood.V86.5.1977.bloodjournal8651977 . PMID   7655024.
  11. 1 2 Percy, M. J.; Butt, N. N.; Crotty, G. M.; Drummond, M. W.; Harrison, C.; Jones, G. L.; Turner, M.; Wallis, J.; McMullin, M. F. (2009). "Identification of high oxygen affinity hemoglobin variants in the investigation of patients with erythrocytosis". Haematologica. 94 (9): 1321–1322. doi:10.3324/haematol.2009.008037. PMC   2738729 . PMID   19734427.
  12. ↑ Wilcox I, Boettger K, Greene L, Malek A, Davis L, Steinberg MH, Luo HY, Chui DH (January 2009). "Hemoglobin Kenya composed of alpha- and ((A)gammabeta)-fusion-globin chains, associated with hereditary persistence of fetal hemoglobin". American Journal of Hematology. 84 (1): 55–8. doi: 10.1002/ajh.21308 . PMID   19006227. S2CID   29114149.
  13. ↑ Joseph Bonavetura and Austin Riggs, March 1968, "Hemoglobin Kansas, A Human Hemoglobin with a Neutral Amino Acid Substitution and an Abnormal Oxygen Equilibrium", The Journal of Biological Chemistry, Vol. 243, No. 5, Issue of March 10, pages 980–991.
  14. ↑ "rs33948057". dbSNP. National Center for Biotechnology Information. Retrieved 7 February 2014.
  15. ↑ Greene DN, Vaughn CP, Crews BO, Agarwal AM (January 2015). "Advances in detection of hemoglobinopathies". Clinica Chimica Acta; International Journal of Clinical Chemistry. 439: 50–7. doi:10.1016/j.cca.2014.10.006. PMID   25314938.
  16. ↑ Monga I, Kaur K, Dhanda S (March 2022). "Revisiting hematopoiesis: applications of the bulk and single-cell transcriptomics dissecting transcriptional heterogeneity in hematopoietic stem cells". Briefings in Functional Genomics. 21 (3): 159–176. doi:10.1093/bfgp/elac002. PMID   35265979.
  17. ↑ Nabarrete, J. M.; Pereira, A. Z.; Garófolo, A.; Seber, A.; Venancio, A. M.; Grecco, C. E.; Bonfim, C. M.; Nakamura, C. H.; Fernandes, D.; Campos, D. J.; Oliveira, F. L.; Cousseiro, F. K.; Rossi, F. F.; Gurmini, J.; Viani, K. H.; Guterres, L. F.; Mantovani, L. F.; Darrigo Lg, Junior; Albuquerque, M. I.; Brumatti, M.; Neves, M. A.; Duran, N.; Villela, N. C.; Zecchin, V. G.; Fernandes, J. F. (2021). "Brazilian Nutritional Consensus in Hematopoietic Stem Cell Transplantation: Children and adolescents". Einstein. 19: eAE5254. doi:10.31744/einstein_journal/2021AE5254. PMC   8664291 . PMID   34909973.
  18. ↑ Forman SJ, Negrin RS, Antin JH, Appelbaum FR. Thomas' hematopoietic cell transplantation: stem cell transplantation. 5th ed. Vol. 2. New Jersey: Wiley-Blackwell; 2016. p.1416.
  19. 1 2 Felfly H, Haddad GG (2014). "Hematopoietic stem cells: potential new applications for translational medicine". Journal of Stem Cells. 9 (3): 163–197. PMID   25157450.
  20. 1 2 Park B, Yoo KH, Kim C (December 2015). "Hematopoietic stem cell expansion and generation: the ways to make a breakthrough". Blood Research. 50 (4): 194–203. doi:10.5045/br.2015.50.4.194. PMC   4705045 . PMID   26770947.
  21. ↑ Mahla RS (2016). "Stem Cells Applications in Regenerative Medicine and Disease Therapeutics". International Journal of Cell Biology. 2016 (7): 6940283. doi: 10.1155/2016/6940283 . PMC   4969512 . PMID   27516776.

Category:Hereditary hemolytic anemias Category:Disorders of globin and globulin proteins

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