Hemoglobin D

Last updated
Hemoglobin D
Specialty Hematology
Symptoms HbD/HbA asymptomatic; HbD/HbD mild hemolytic anemia; HbD/HbS sickle cell anemia; HbD/Hb-thalassemia thalassemia
CausesPoint mutation in HBB gene
TreatmentNot required

Hemoglobin D (HbD) is a variant of hemoglobin, a protein complex that makes up red blood cells. Based on the locations of the original identification, it has been known by several names such as hemoglobin D-Los Angeles, hemoglobin D-Punjab , [1] D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago. [2] Hemoglobin D-Los Angeles was the first type identified by Harvey Itano in 1951, and was subsequently discovered that hemoglobin D-Punjab is the most abundant type that is common in the Sikhs of Punjab (of both Pakistan and India) and of Gujarat. [3]

Contents

Unlike normal adult human hemoglobin (HbA) which has glutamic acid at its 121 amino acid position, it has glutamine instead. [4] The single amino acid substitution can cause various blood diseases, from fatal genetic anemia to mild hemolytic anemia, an abnormal destruction of red blood cells. [5] Depending on the type of genetic inheritance, it can produce four different conditions: [4] heterozygous (inherited in only one of the chromosome 11) HbD trait, HbD-thalassemia, HbS-D (sickle cell) disease, and, very rarely, homozygous (inherited in both chromosome 11) HbD disease. [6] It is the fourth hemoglobin type discovered after HbA, HbC and HbS; [1] the third hemoglobin variant identified after HbC and HbS; [2] and the fourth most common hemoglobin variant after HbC, HbS, and HbO. [5]

History

Hemoglobin was discovered as some sort of crystal formed from earthworm body fluid and animal blood by German biochemist Friedrich Ludwig Hünefeld at Leipzig University in 1840. [7] [8] When the protein nature was established another German Felix Hoppe-Seyler gave the name hemoglobin (literally "blood protein") in 1864. [9] [10] Its role as an oxygen transporter was later established. [1] While studying sickle cell disease, Linus Pauling and Harvey Itano at the California Institute of Technology discovered in 1949 that the disease was due to abnormal hemoglobin, later called hemoglobin S (HbS). [11] [12] In 1950, Itano and James V. Neel discovered a slightly different case in which individuals had sickled red blood cells but not anemia. [13] [14] The hemoglobin was named hemoglobin III, [15] but later known as hemoglobin C (HbC). [16] [17]

In 1934, Jean V. Cooke and J. Keller Mack, pediatricians at St. Louis, USA, reported a case of white American family which had some member suffering from sickle cell anemia. [18] [19] Of six siblings, two children had anemia, while others, including their parents, were healthy. Blood tests indicated the two children had sickled red blood cells, but with uncharacteristically slow process of sickling. The father, who had no disease, was found to have sickled re blood cells. [18] With the new techniques for identifying different hemoglobin, Itano investigated the family and found that like their father, three other children had abnormal hemoglobin but without the disease or sickled cells; their hemoglobin giving same mobility (in electrophoresis) and but different solubility as sickled cells. He recorded in 1951:

The resent report deals with the identification of still another form of human hemoglobin in five members of a family in which the genetic picture is not typical of sickle cell anemia, although two of the members have in the past been diagnosed as having sickle cell anemia. An earlier study of this family disclosed that the two anemic children and the father, who was not anemic, had sickling erythrocytes while the mother, two sisters and two brothers of the anemic children had non-sickling erythrocytes and were not anemic. [20]

In the paper published in the Proceedings of the National Academy of Sciences of the United States of America , Itano presented the need to have naming convention for the different types of hemoglobin, and introduced the alphabet-coding system such as hemoglobin a (for normal adult type), b (sickle cell type), c (sickle cell-associated type) and d (for the novel type); as he explained:

In order to facilitate the discussion in the present paper and to avoid confusion in future works, it seems desirable at this time to establish a system of symbols for identifying the various forms of adult human hemoglobin... normal hemoglobin, sickle cell hemoglobin, the abnormal hemoglobin reported by Itano and Neel, and the abnormal hemoglobin reported in the present paper will be designated adult human hemoglobins a, b, c and d, respectively, more briefly as hemoglobins a, b, c and d. [20]

It was the discovery of hemoglobin D and creation of hemoglobin naming system. [3] In 1953, Amoz Immanuel Chernoff at the Washington University School of Medicine, St. Louis, introduced the capitalised-letter designation such as A (for normal adult type), C (second abnormal type), D (third abnormal type), S (sickle cell type) and F (fetal form). [21] Although the nomeclature system became a convention, hemoglobin D, in particular, became known by various names, generally based on their origin of identification; like hemoglobin D-Los Angeles for the first discovered, [19] hemoglobin D-Punjab, [1] D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago. [2] By 1961, it was known that the structural difference of HbD from HbA was in the β-chain. [22] Around the same time, Corrado Baglioni of Massachusetts Institute of Technology identified the exact abnormality that substitution of glutamic acid with glutamine at position 121 in the β-chain was the basis of HbD, the findings which he reported in 1962. [23]

Structure

Hemoglobin D has the basic structure and composition of normal adult hemoglobin. It is a globular protein containing prosthetic (non-protein) group called heme. There are four individual peptide chains, namely two α- and two β-subunits, each made of 141 and 146 amino acid residues, respectively. One heme is associated with each chain and responsible for binding free oxygen in the blood. A single HbD is therefore a tetramer (containing four molecules), denoted as α2β2. [24] Each subunit has a molecular weight of about 16,000 Da (daltons), making the tetramer about 64,000 Da (64,458 g/mol) in size. [25] HbD is different from HbA only on the β-subunit where the amino acid glutamic acid at 121 position is replaced with glutamine (α2β2121Glu→Gln). [4] It has the same chemical characteristic as HbS (a hemoglobin of sickle cell trait), with one fewer negative charge at an alkaline pH than HbA. However, unlike HbS, it does not produce sickled RBC on its own under low level of oxygen. [4]

Genetics and diseases

Hemoglobin D is synthesised due to mutation in HBB, the gene that produces β-subunits of hemoglobin and is present on human chromosome 11. A point mutation in the first base of the 121 codon that normally has GAA sequence for normal hemoglobin is changed to CAA. [26] [27] GAA codes for glutamic acid, while CAA for glutamine. [28] This gene mutation makes HbD, which can further give rise to several genetic and disease conditions. The specific mutations can occur at different sites of the gene. According to the Globin Gene Server database, there are other types of HbD such as HbD-Agri (HBB:c.29C→A;364G→C), HbD-Bushman (HBB:c.49G→C), HbD-Ouled Rabah (HBB:c.60C→A or 60C→G), HbD-Iran (HBB:c.67G→C), HbD-Granada (HBB:c.68A→T), HbD-Ibadan (HBB:c.263C→A) and HbD-Neath (HBB:c.365A→C). [1]

Depending on the nature of inheritance of HbD mutation there are four conditions, some of which can be deadly diseases: [6]

  1. Heterozygous HbD/HbA trait, which does not affect the individuals.
  2. Heterozygous HbD-thalassemia, which causes the symptoms of thalassemia generally with mild anemia.
  3. Heterozygous HbS-D, which gives rise to sickle cell anemia, but generally milder and slower symptoms.
  4. Homozygous HbD/HbD, which is the rarest form, but is associated with HbD disease.

Effects and symptoms

Hemoglobin in combination with normal hemoglobin (heterozygous HBD/HbA) is asymptomatic, causing no effects. Individuals have normal hemoglobin level and their red blood cells are normal spherical structure. [29] Homozygous HbD/HbD causes mild hemolytic anemia and chronic non-progressive splenomegaly (enlargement of spleen). [4] Heterozygous HbD/HbS causes sickle cell anemia. However, most cases of the disease are milder than the usual HbS/HbS conditions. The most serious complication noted is stroke. HbD-thalassemia causes microcytic anemia which is generally milder that in typical thalassemia. [29]

Diagnosis

As hemoglobin can be inherited in several conditions, no single diagnostic test can confirm the specific protein completely. Electrophoresis is one of the most commonly used and requires sequential identification with other hemoglobins. All hemoglobins can be separated in cellulose acetate at pH 8.6 and in agarose gel at pH 6.2. In alkaline medium of cellulose acetate, HbD moves slower and can be identified at shorter distance than HbA, but it migrates exactly as HbS. It can be differentiated from HbS in acidic agarose gel in which it moves faster and farther than HbS, but at the same level with HbA. [30] [31] High-performance liquid chromatography (HPLC) can directly detect the protein, but its specific identification of HbD from other hemoglobins can be inconclusive. [32] HPLC coupled with mass spectrometry (HPLC-ESI-MS/MS) can accurately detect the protein but the procedure is costly and time consuming. [33] Genetic screening can be done with polymerase chain reaction that can identify HbS from other hemoglobin variants. [34]

Management

Hemoglobin D conditions such as homozygous and HbD/HbA heterozygous do not require medical intervention. HbD/HbS and HbD-thalassemia conditions are managed like the typical cases of sickle cell anemia and thalassemia. [29] In case of sickle cell anemia, daily treatment with penicillin recommended up to five years of age. [35] Dietary supplementation of folic acid is recommended by the WHO. [36] In 2019, Crizanlizumab, a monoclonal antibody was approved by the United States FDA for reducing the frequency of blood vessel blockage in 16 years and older individuals. [37] For thalassemia, regular lifelong blood transfusions is the usual treatment. Bone marrow transplants can be curative for some children. [38] Medications like deferoxamine, deferiprone and luspatercept. [39] Gene therapy, exagamglogene autotemcel is approved for medical use in the United Kingdom since November 2023. [40] [41]

Prevalence

Hemoglobin D is most abundant among Sikhs, with occurrence of 2% in Punjab and 1% in Gujarat. It is also found in small number of individuals among Africans, Americans and Europeans who usually had close ethnicity with Indians in the past. [5] It is below 2% among African-Americans. [4] Combination with β-thalassemia and HbS are known in south and east India; the first resulting in thalassemia and the latter in sickle cell anemia. [5]

There is also high occurrence in China, with prevalence rate of 12.5% in Chongqing. [42] It is sporadically recorded in some Turkish, Algerian, West African, Saudi Arabian, native American, English, and Irish population. [29] Rare conditions like HbD/HbJ, [43] HbD/ HbQ, [44] and HbD/Hb Fontainebleau [45] are also found in India. A rare case of HbS/HbD is reported from Pakistan in which individuals are diagnosed with bone infection (osteomyelitis). [31] An isolated condition of HbD/HbC is recorded in US. [46]

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 transportation of oxygen in red blood cells. Almost all vertebrates contain hemoglobin, with the sole 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 an 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">Hemoglobinopathy</span> Any of various genetic disorders of blood

Hemoglobinopathy is the medical term for a group of inherited blood disorders involving the hemoglobin, the protein of red blood cells. They are generally single-gene disorders and, in most cases, they are inherited as autosomal recessive traits.

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

Thalassemias are a group of inherited blood disorders that manifest as the production of reduced or zero quantities of hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe, including death. 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 include tiredness, pallor, bone problems, an enlarged spleen, jaundice, pulmonary hypertension, and dark urine. Children's' growth and development may be slower than normal.

<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 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">Beta thalassemia</span> Blood disorder

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 is a protein that transports oxygen in the blood. Genetic differences lead to structural variants in the hemoglobin protein structure. Some variants can cause disease while others have little to no effect.

<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.

Hereditary persistence of fetal hemoglobin (HPFH) is a benign condition in which increased fetal hemoglobin production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced.

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

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 acid to lysine (E26K). Hemoglobin E is very common among people of Southeast Asian, Northeast Indian, Sri Lankan and Bangladeshi descent.

<span class="mw-page-title-main">Sickle cell disease</span> Medical condition

Sickle cell disease (SCD), also simply called sickle cell, is a group of hemoglobin-related blood disorders that are typically inherited. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to the red blood cells adopting an abnormal sickle-like shape under certain circumstances; with this shape, they are unable to deform as they pass through capillaries, causing blockages. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain in joints, anemia, swelling in the hands and feet, bacterial infections, dizziness and stroke. The probability of severe symptoms, including long-term pain, increases with age. Without treatment, people with SCD rarely reach adulthood but with good healthcare, median life expectancy is between 58 and 66 years. All of the major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints can be damaged from the abnormal functions of the sickle cells and their inability to effectively flow through the small blood vessels.

Human genetic resistance to malaria refers to inherited changes in the DNA of humans which increase resistance to malaria and result in increased survival of individuals with those genetic changes. The existence of these genotypes is likely due to evolutionary pressure exerted by parasites of the genus Plasmodium which cause malaria. Since malaria infects red blood cells, these genetic changes are most common alterations to molecules essential for red blood cell function, such as hemoglobin or other cellular proteins or enzymes of red blood cells. These alterations generally protect red blood cells from invasion by Plasmodium parasites or replication of parasites within the red blood cell.

<span class="mw-page-title-main">Disease resistance</span> Capacity of an organism to defend itself against pathological processes

Disease resistance is the ability to prevent or reduce the presence of diseases in otherwise susceptible hosts. It can arise from genetic or environmental factors, such as incomplete penetrance. Disease tolerance is different as it is the ability of a host to limit the impact of disease on host health.

<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.

Within the medical specialty of hematology, Hemoglobin D-Punjab, also known as hemoglobin D-Los Angeles, D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago, is a hemoglobin variant. It originates from a point mutation in the human β-globin locus and is one of the most common hemoglobin variants worldwide. It is so named because of its higher prevalence in the Punjab region of India and Pakistan, along with northern China, and North America. It is also the most frequent hemoglobin variant in Xinjiang Uyghur Autonomous Region of China, with a 1997 study indicating that Hemoglobin D-Punjab accounts for 55.6% of the total hemoglobin variants.

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.

References

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  21. ↑ White, J. C.; Beaver, G. H. (1954). "A review of the varieties of human haemoglobin in health and disease". Journal of Clinical Pathology. 7 (3): 175–200. doi:10.1136/jcp.7.3.175. ISSN   0021-9746. PMC   1023791 . PMID   13192193.
  22. ↑ Bowman, B.; Ingram, V. M. (1961-11-11). "Abnormal human haemoglobins. VII. The comparison of normal human haemoglobin and haemoglobin D-Chicago". Biochimica et Biophysica Acta. 53: 569–573. doi:10.1016/0006-3002(61)90216-5. ISSN   0006-3002. PMID   13872094.
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  27. ↑ Yavarian, Majid; Karimi, Mehran; Paran, Farideh; Neven, Catherine; Harteveld, Cornelis L.; Giordano, Piero C. (2009). "Multi centric origin of Hb D-Punjab [beta121(GH4)Glu-->Gln, GAA>CAA]". Hemoglobin. 33 (6): 399–405. doi:10.3109/03630260903344598. ISSN   1532-432X. PMID   19958184. S2CID   452579.
  28. ↑ Henderson, Shirley J.; Timbs, Adele T.; McCarthy, Janice; Gallienne, Alice E.; Proven, Melanie; Rugless, Michelle J.; Lopez, Herminio; Eglinton, Jennifer; Dziedzic, Dariusz; Beardsall, Matthew; Khalil, Mohamed S. M.; Old, John M. (2016). "Ten Years of Routine α- and β-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations". Hemoglobin. 40 (2): 75–84. doi:10.3109/03630269.2015.1113990. ISSN   1532-432X. PMID   26635043. S2CID   207463855.
  29. 1 2 3 4 Mallouh, Ahmad A. (2012), Elzouki, Abdelaziz Y.; Harfi, Harb A.; Nazer, Hisham M.; Stapleton, F. Bruder (eds.), "Hemoglobinopathies-Non-Sickle Cell", Textbook of Clinical Pediatrics, Berlin, Heidelberg: Springer Berlin Heidelberg, pp. 3023–3027, doi:10.1007/978-3-642-02202-9_325, ISBN   978-3-642-02201-2 , retrieved 2024-02-29
  30. ↑ Schneider, R. G. (1974). "Differentiation of electrophoretically similar hemoglobins--such as S, D, G, and P; or A2, C, E, and O--by electrophoresis of the globin chains". Clinical Chemistry. 20 (9): 1111–1115. doi:10.1093/clinchem/20.9.1111. ISSN   0009-9147. PMID   4412820.
  31. 1 2 Tauseef, Usman; Anjum, Misbah; Ibrahim, Mohsina; Baqai, Hina Sabih; Tauseef, Abubakar; Tauseef, Marium; Asghar, Muhammad Sohaib; Zafar, Maryam; Rasheed, Uzma; Shaikh, Nimra (2021). "Occurrence of unusual haemoglobinopathies in balochistan: hb sd and hb se - presentation with osteomyelitis". Revista Paulista de Pediatria. 39: e2019365. doi:10.1590/1984-0462/2021/39/2019365. ISSN   1984-0462. PMC   7870096 . PMID   33566985.
  32. ↑ Gupta, Aastha; Saraf, Amrita; Dass, Jasmita; Mehta, Meenal; Radhakrishnan, Nita; Saxena, Renu; Bhargava, Manorama (2014). "Compound heterozygous hemoglobin d-punjab/hemoglobin d-iran: a novel hemoglobinopathy". Indian Journal of Hematology & Blood Transfusion. 30 (Suppl 1): 409–412. doi:10.1007/s12288-014-0441-x. ISSN   0971-4502. PMC   4192197 . PMID   25332633.
  33. ↑ Haynes, Christopher A.; Guerra, Stephanie L.; Fontana, Jessalyn C.; DeJesús, Víctor R. (2013-09-23). "HPLC-ESI-MS/MS analysis of hemoglobin peptides in tryptic digests of dried-blood spot extracts detects HbS, HbC, HbD, HbE, HbO-Arab, and HbG-Philadelphia mutations". Clinica Chimica Acta; International Journal of Clinical Chemistry. 424: 191–200. doi:10.1016/j.cca.2013.06.007. ISSN   1873-3492. PMID   23796846.
  34. ↑ Mahmoud, Taher; Sahli, Chaima; Hadj Fredj, Sondess; Amri, Yessine; Othmani, Rim; Mohamed, Ghaber S.; Zein, Ekhtelbenina; Messaoud, Taieb (2022). "Epidemiological and molecular study of hemoglobinopathies in Mauritanian patients". Molecular Genetics & Genomic Medicine. 10 (10): e2048. doi:10.1002/mgg3.2048. ISSN   2324-9269. PMC   9544207 . PMID   36106931.
  35. ↑ "Evidence-Based Management of Sickle Cell Disease" (PDF). 2014. Retrieved 16 November 2017. twice-daily prophylactic penicillin beginning in early infancy and continuing through at least age 5
  36. ↑ "Sickle-cell disease and other haemoglobin disorders Fact sheet N°308". January 2011. Archived from the original on 9 March 2016. Retrieved 8 March 2016.
  37. ↑ "FDA approves crizanlizumab-tmca for sickle cell disease". U.S. Food and Drug Administration. 15 November 2019. Retrieved 12 December 2023.
  38. ↑ Muncie, Herbert L.; Campbell, James S. (2009). "Alpha and Beta Thalassemia". American Family Physician. 80 (4): 339–44. PMID   19678601.
  39. ↑ Taher, Ali T.; Musallam, Khaled M.; Cappellini, M. Domenica (25 February 2021). "β-Thalassemias". New England Journal of Medicine. 384 (8): 727–743. doi:10.1056/NEJMra2021838. PMID   33626255. S2CID   232049825.
  40. ↑ "MHRA authorises world-first gene therapy that aims to cure sickle-cell disease and transfusion-dependent β-thalassemia". Medicines and Healthcare products Regulatory Agency (MHRA) (Press release). 16 November 2023. Archived from the original on 25 November 2023. Retrieved 8 December 2023.
  41. ↑ "Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, Casgevy (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia" (Press release). Vertex Pharmaceuticals. 16 November 2023. Archived from the original on 22 November 2023. Retrieved 9 December 2023– via Business Wire.
  42. ↑ Li, Chun-Li; Yang, Mei; Li, Qiu-Hong (2020). "Analysis of 34 800 cases of Abnormal Hemoglobinopathy in Couples of Child-bearing Age in Chongqing Area". Zhongguo Shi Yan Xue Ye Xue Za Zhi. 28 (4): 1316–1320. doi:10.19746/j.cnki.issn.1009-2137.2020.04.040 (inactive 1 November 2024). ISSN   1009-2137. PMID   32798419.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  43. ↑ Chandra, Dinesh; Tyagi, Seema; Deka, Roopam; Chauhan, Richa; Seth, Tulika; Saxena, Renu; Pati, H. P. (2017). "A Novel Double Heterozygous Hb D-Punjab/Hb J-Meerut Hemoglobinopathy". Indian Journal of Hematology & Blood Transfusion. 33 (4): 611–613. doi:10.1007/s12288-016-0763-y. ISSN   0971-4502. PMC   5640522 . PMID   29075078.
  44. ↑ Parab, Sushama; Sakhare, Suhas; Sengupta, Caesar; Velumani, Arokiaswamy (2014). "Diagnosis of a rare double heterozygous Hb D Punjab/Hb Q India hemoglobinopathy using Sebia capillary zone electrophoresis". Indian Journal of Pathology & Microbiology. 57 (4): 626–628. doi: 10.4103/0377-4929.142709 . ISSN   0974-5130. PMID   25308024.
  45. ↑ Rodríguez-Capote, Karina; Estey, Mathew P.; Barakauskas, Vilte; Bordeleau, Pierre; Christensen, Cathie-Lou; Zuberbuhler, Peter; Higgins, Trefor N. (2015). "A novel double heterozygous Hb Fontainebleau/HbD Punjab hemoglobinopathy". Clinical Biochemistry. 48 (13–14): 904–907. doi:10.1016/j.clinbiochem.2015.05.020. ISSN   1873-2933. PMID   26036869.
  46. ↑ Hirani, Samina; Gupta, Supriya; Veillon, Diana; Patan, Shajadi; Master, Samip; Mansour, Richard (2020-05-06). "The curious case of hemoglobin DC disease masquerading as sickle cell anemia". Hematology Reports. 12 (1): 8519. doi:10.4081/hr.2020.8519. ISSN   2038-8322. PMC   7256626 . PMID   32499906.
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