beta thalassemia

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Symptoms depend on the type and severity of thalassemia. Carriers of thalassemia genes may have no symptoms (thalassemia minor) or very mild symptoms with occasional crisis (thalassemia intermedia); individuals who are homozygous for the mutation have severe and life threatening symptoms (thalassemia major).{{Cite web |date=17 Nov 2021 |title=Thalassemia-Thalassemia - Symptoms & causes |url=https://www.mayoclinic.org/diseases-conditions/thalassemia/symptoms-causes/syc-20354995 |access-date=2025-01-07 |website=Mayo Clinic |language=en}}{{cite journal | vauthors = Taher AT, Musallam KM, Cappellini MD | title = β-Thalassemias | journal = The New England Journal of Medicine | volume = 384 | issue = 8 | pages = 727–743 | date = February 2021 | pmid = 33626255 | doi = 10.1056/NEJMra2021838 | s2cid = 232049825 }}

Individuals with beta-thalassemia major usually present within the first two years of life with symptomatic severe anemia, poor growth, and skeletal abnormalities. Untreated thalassemia major eventually leads to death, usually by heart failure.{{Cite book |url=https://books.google.com/books?id=RTRv18iTn8YC&q=beta+thalassemia+major+symptoms&pg=PA170 |title=Introduction to Pathology for the Physical Therapist Assistant |date=2011 |publisher=Jones & Bartlett Publishers |isbn=978-0-7637-9908-3 |access-date=2020-10-25 |archive-url=https://web.archive.org/web/20230114142639/https://books.google.com/books?id=RTRv18iTn8YC&q=beta+thalassemia+major+symptoms&pg=PA170 |archive-date=2023-01-14 |url-status=live}}

Those with beta-thalassemia intermedia (those who are compound heterozygotes for the beta thalassemia mutation) usually present later in life with mild to moderate symptoms of anemia.

Beta thalassemia trait (beta thalassemia minor) involves heterozygous inheritance of a beta-thalassemia mutation. Individuals usually have microcytosis with mild anemia; they are usually asymptomatic or have mild symptoms. Beta thalassemia minor can also present as beta-thalassemia silent carriers; those who inherit a beta thalassemic mutation but have no hematologic abnormalities or symptoms.

Individuals with thalassemia thalassemia major and intermedia (to a lesser extent) are susceptible to health complications that involve the spleen (hypersplenism) and gallstones (due to hyperbilirubinemia from peripheral hemolysis).{{Cite web |title=Beta thalassemia |url=http://ghr.nlm.nih.gov/condition/beta-thalassemia |url-status=live |archive-url=https://web.archive.org/web/20150513180244/http://ghr.nlm.nih.gov/condition/beta-thalassemia |archive-date=2015-05-13 |access-date=2015-05-26 |website=Genetics Home Reference}} Additional symptoms of beta-thalassemia major or intermedia include the classic symptoms of anemia including fatigue, developmental delay in childhood, leg ulcers, and organ failure. Ineffective erythropoiesis (red blood cell production) can lead to expansion of the bone marrow in compensation; this can then lead to deformity, bone pain, and craniofacial abnormalities. Organs such as the liver and spleen that can also become enrolled in red blood cell production, leading to hepatosplenomegaly (enlargement of the liver and spleen).

People with thalassemia can get too much iron in their bodies, either from the disease itself as RBCs are destroyed, or as a consequence of frequent blood transfusions. Excess iron is not excreted, but forms toxic non-transferrin-bound iron.{{cite journal | vauthors = Angoro B, Motshakeri M, Hemmaway C, Svirskis D, Sharma M | title = Non-transferrin bound iron | journal = Clinica Chimica Acta; International Journal of Clinical Chemistry | volume = 531 | pages = 157–167 | date = June 2022 | pmid = 35398023 | doi = 10.1016/j.cca.2022.04.004 }} This can lead to organ damage, potentially affecting the heart, liver, endocrine system, bones and spleen. Symptoms include an irregular heartbeat, cardiomyopathy, cirrhosis of the liver, hypothyroidism, delayed puberty and fertility problems, brittle and deformed bones, and an enlarged spleen.{{Cite web |date=January 2016 |title=Endocrine Problems in Thalassemia |url=https://www.swbh.nhs.uk/wp-content/uploads/2012/07/Endoctorine-Problems-in-Thalassemia_ML5090.pdf |website=Sandwell and West Birmingham NHS Trust}}{{Cite web |date=25 Oct 2023 |title=Thalassaemia |url=https://111.wales.nhs.uk/thalassaemia/ |access-date=8 Jan 2025 |website=Wales Ambulance Service NHS Trust}}

For clinical purposes, thalassemia is categorised as either transfusion-dependent thalassemia (TDT) or non-transfusion-dependent thalassemia (NTDT) are used. Patients are usually considered as having NTDT if they have received fewer than 6 red blood cell units in the past 6 months and none in the preceding 2 months.{{cite journal | vauthors = Saliba AN, Musallam KM, Taher AT | title = How I treat non-transfusion-dependent β-thalassemia | journal = Blood | volume = 142 | issue = 11 | pages = 949–960 | date = September 2023 | pmid = 37478396 | pmc = 10644094 | doi = 10.1182/blood.2023020683 }}

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{{Excerpt|Thalassemia|Hemoglobin structural biology}}

β-globin chains are encoded by the HBB gene on chromosome 11;{{OMIM|141900|Hemoglobin—Beta Locus; HBB}} in a healthy person with two copies on each chromosome, two loci encode the β chain.Robbins Basic Pathology, Page No:428 In beta thalassemia, a single faulty gene can be either asymptomatic or cause mild disease; if both genes are faulty this causes moderate to severe disease.{{cite journal | vauthors = Thein SL | title = The molecular basis of β-thalassemia | journal = Cold Spring Harbor Perspectives in Medicine | volume = 3 | issue = 5 | pages = a011700 | date = May 2013 | pmid = 23637309 | pmc = 3633182 | doi = 10.1101/cshperspect.a011700 }}

More than 350 mutations have been identified which can cause beta thalassemia; 20 of these account for 80% of beta-thalassemia cases.{{cite journal | vauthors = Rao E, Kumar Chandraker S, Misha Singh M, Kumar R | title = Global distribution of β-thalassemia mutations: An update | journal = Gene | volume = 896 | pages = 148022 | date = February 2024 | pmid = 38007159 | doi = 10.1016/j.gene.2023.148022 }}

Two major groups of mutations can be distinguished:

• Nondeletion forms: These defects, in general, involve a single base-pair substitution or small insertions near or upstream of the HBB gene.{{Cite book | vauthors = Leonard DG |url=https://books.google.com/books?id=Z2YNhh51SmQC&q=beta+thalassemia+nondeletion+form&pg=PA155 |title=Molecular Pathology in Clinical Practice |date=2007-11-25 |publisher=Springer |isbn=978-0-387-33227-7 |access-date=2020-10-25 |archive-url=https://web.archive.org/web/20230114142642/https://books.google.com/books?id=Z2YNhh51SmQC&q=beta+thalassemia+nondeletion+form&pg=PA155 |archive-date=2023-01-14 |url-status=live}}
• Deletion forms: base-pair deletions of different sizes involving the HBB gene produce syndromes such as hereditary persistence of fetal hemoglobin syndrome.{{Cite book | vauthors = Bowen JM, Mazzaferri EL |url=https://books.google.com/books?id=k-jiBwAAQBAJ&q=beta+thalassemia+deletion+form&pg=PA199 |title=Contemporary Internal Medicine: Clinical Case Studies |date=2012-12-06 |publisher=Springer |isbn=978-1-4615-6713-4}}

Mutations are characterized as (β^o) if they prevent any formation of β globin chains, and mutations are characterized as (β⁺) if they allow some β globin chain formation to occur.

Due to globin defects, beta thalassemia patients do not have normal levels of adult hemoglobin (HbA), and instead have elevated levels of HbA2 (α₂δ₂). Production of this form of hemoglobin may increase as a consequence of stress erythropoiesis.{{Cite journal |last=Paulson |first=Robert F. |last2=Hariharan |first2=Sneha |last3=Little |first3=Jane A. |date=2020-09-01 |title=Stress erythropoiesis: definitions and models for its study |url=https://linkinghub.elsevier.com/retrieve/pii/S0301472X20303052 |journal=Experimental Hematology |language=English |volume=89 |pages=43–54.e2 |doi=10.1016/j.exphem.2020.07.011 |issn=0301-472X |pmc=7508762 |pmid=32750404}}

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{{#section:Thalassemia|Thal_Diag}}

Family history and ancestry are factors that increase the risk of beta-thalassemia. Depending on family history, if a person's parents or grandparents had beta thalassemia major or intermedia, there is a 75% (3 out of 4) probability (see inheritance chart at top of page) of the mutated gene being inherited by an offspring. Even if a child does not have symptomatic beta thalassemia they can still be a carrier, leading to an increased risk in future generations of their offspring having beta-thalassemia.

Beta thalassemia occurs most often in people of Mediterranean, Middle Eastern, Southern Asian, and African ancestry.{{Cite web |title=Risk Factors |url=http://www.mayoclinic.org/diseases-conditions/thalassemia/symptoms-causes/dxc-20261829 |url-status=live |archive-url=https://web.archive.org/web/20161120112707/http://www.mayoclinic.org/diseases-conditions/thalassemia/symptoms-causes/dxc-20261829 |archive-date=20 November 2016 |access-date=4 April 2017 |website=Mayo Clinic}}

The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant should be offered testing to see if they have thalassemia trait.{{cite web |date=October 2022 |title=Carrier Screening for Hemoglobinopathies: Sickle Cell Disease and Thalassemia |url=https://www.acog.org/womens-health/faqs/carrier-screening-for-hemoglobinopathies |url-status= |archive-url= |archive-date= |access-date=21 February 2025 |website=American College of Obstetricians and Gynecologists}} Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait.{{cite journal | vauthors = Hussein N, Henneman L, Kai J, Qureshi N | title = Preconception risk assessment for thalassaemia, sickle cell disease, cystic fibrosis and Tay-Sachs disease | journal = The Cochrane Database of Systematic Reviews | volume = 10 | issue = 10 | pages = CD010849 | date = October 2021 | pmid = 34634131 | pmc = 8504980 | doi = 10.1002/14651858.CD010849.pub4 | collaboration = Cochrane Cystic Fibrosis and Genetic Disorders Group }} Understanding the genetic risk, ideally before a family is started, would hopefully allow families to understand more about the condition and make an informed decision that is best for their family.

A number of countries have programs aimed at reducing the incidence of beta-thalassemia:-

• Cyprus has one of the highest carrier rates in the world. A program of premarital screening and counselling has, since the program's implementation in the 1970s, reduced the number of children born with thalassemia major from one of every 158 births to almost zero.{{cite journal | vauthors = Leung TN, Lau TK, Chung TK | title = Thalassaemia screening in pregnancy | journal = Current Opinion in Obstetrics & Gynecology | volume = 17 | issue = 2 | pages = 129–134 | date = April 2005 | pmid = 15758603 | doi = 10.1097/01.gco.0000162180.22984.a3 | s2cid = 41877258 }}{{cite journal | vauthors = Cousens NE, Gaff CL, Metcalfe SA, Delatycki MB | title = Carrier screening for beta-thalassaemia: a review of international practice | journal = European Journal of Human Genetics | volume = 18 | issue = 10 | pages = 1077–1083 | date = October 2010 | pmid = 20571509 | pmc = 2987452 | doi = 10.1038/ejhg.2010.90 }} Greece also has a screening program to identify people who are carriers.{{cite journal | vauthors = Loukopoulos D | title = Haemoglobinopathies in Greece: prevention programme over the past 35 years | journal = The Indian Journal of Medical Research | volume = 134 | issue = 4 | pages = 572–576 | date = October 2011 | pmid = 22089622 | pmc = 3237258 }}
• In Iran as a premarital screening, the man's red cell indices are checked first. If he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic, their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.{{cite journal | vauthors = Samavat A, Modell B | title = Iranian national thalassaemia screening programme | journal = BMJ | volume = 329 | issue = 7475 | pages = 1134–1137 | date = November 2004 | pmid = 15539666 | pmc = 527686 | doi = 10.1136/bmj.329.7475.1134 }}
• Large-scale awareness campaigns are being organized in India both by government and non-government organizations to promote voluntary premarital screening, with marriage between carriers strongly discouraged.{{cite journal | vauthors = Petrou M | title = Screening for beta thalassaemia | journal = Indian Journal of Human Genetics | volume = 16 | issue = 1 | pages = 1–5 | date = January 2010 | pmid = 20838484 | pmc = 2927788 | doi = 10.4103/0971-6866.64934 | doi-access = free }}

Main article: Management of thalassemia

{{#section:Thalassemia|Thal_Management}}

A combination hemoglobinopathy occurs when someone inherits two different abnormal hemoglobin genes. If these are different versions of the same gene, one having been inherited from each parent it is an example of compound heterozygosity.{{cite journal | vauthors = Khatri G, Sahito AM, Ansari SA | title = Shared molecular basis, diagnosis, and co-inheritance of alpha and beta thalassemia | journal = Blood Research | volume = 56 | issue = 4 | pages = 332–333 | date = December 2021 | pmid = 34776416 | pmc = 8721464 | doi = 10.5045/br.2021.2021128 }}{{cite journal | vauthors = Wambua S, Mwacharo J, Uyoga S, Macharia A, Williams TN | title = Co-inheritance of alpha+-thalassaemia and sickle trait results in specific effects on haematological parameters | journal = British Journal of Haematology | volume = 133 | issue = 2 | pages = 206–209 | date = April 2006 | pmid = 16611313 | pmc = 4394356 | doi = 10.1111/j.1365-2141.2006.06006.x }}

Some examples of clinically significant combinations involving beta thalassemia include:

• Hemoglobin C/ beta thalassemia: common in Mediterranean and African populations generally results in a moderate form of anemia with splenomegaly.{{Cite web |date=February 2011 |title=Hemoglobin C |url=https://doh.wa.gov/sites/default/files/legacy/Documents/5220/HbCFactSheet.pdf |website=Washington State Department of Health}}
• Hemoglobin D/ beta thalassemia: common in the northwestern parts of India and Pakistan (Punjab region).{{cite journal | vauthors = Torres L, Okumura JV, Silva DG, Bonini-Domingos CR | title = Hemoglobin D-Punjab: origin, distribution and laboratory diagnosis | journal = Revista Brasileira De Hematologia E Hemoterapia | volume = 37 | issue = 2 | pages = 120–126 | date = March 2015 | pmid = 25818823 | pmc = 4382585 | doi = 10.1016/j.bjhh.2015.02.007 }}

• Hemoglobin E/ beta thalassemia: common in Cambodia, Thailand, and parts of India, it is clinically similar to β thalassemia major or β thalassemia intermedia.{{cite journal | vauthors = Olivieri NF, Muraca GM, O'Donnell A, Premawardhena A, Fisher C, Weatherall DJ | title = Studies in haemoglobin E beta-thalassaemia | journal = British Journal of Haematology | volume = 141 | issue = 3 | pages = 388–397 | date = May 2008 | pmid = 18410572 | doi = 10.1111/j.1365-2141.2008.07126.x }}
• Hemoglobin S/ beta thalassemia: common in African and Mediterranean populations, it is clinically similar to sickle-cell anemia.{{Cite web | vauthors = Gerber GF |date=April 2024 |title=Hemoglobin S–Beta-Thalassemia Disease - Hematology and Oncology |url=https://www.msdmanuals.com/professional/hematology-and-oncology/anemias-caused-by-hemolysis/hemoglobin-s-beta-thalassemia-disease |access-date=2024-12-24 |website=MSD Manual Professional Edition |language=en}}
• Delta-beta thalassemia is a rare form of thalassemia in which there is a reduced production of both the delta and beta globins. It is generally asymptomatic.{{cite book | vauthors = Pal GK |url=https://books.google.com/books?id=XpUAihQ7Ib4C&q=microcytosis+definition&pg=PA53 |title=Textbook Of Practical Physiology | edition = 2nd |date=2005 |publisher=Orient Blackswan |isbn=9788125029045 |page=53 |language=en |access-date=17 September 2016}}

Beta thalassemia is particularly prevalent among the Mediterranean peoples and this geographical association is responsible for its naming: thalassa (θάλασσα) is the Greek word for sea and haima (αἷμα) is the Greek word for blood.{{OEtymD|thalassemia}}{{LSJ|qa/lassa|θάλασσα}}, {{LSJ|ai({{=}}ma|αἷμα|ref}}. In Europe, the highest prevalence of beta-thalassemia trait is found in Greece, Turkey, and Mediterranean islands such as Sicily, Sardinia, Corsica, Cyprus, Malta and Crete.{{Cite web |title=WHO {{!}} Global epidemiology of haemoglobin disorders and derived service indicators |url=https://www.who.int/bulletin/volumes/86/6/06-036673/en/ |url-status=dead |archive-url=https://web.archive.org/web/20111030203104/http://www.who.int/bulletin/volumes/86/6/06-036673/en/ |archive-date=October 30, 2011 |access-date=2015-05-26 |website=www.who.int}}{{Cite book | vauthors = Berg S, Bittner EA |url=https://books.google.com/books?id=TftPBAAAQBAJ&q=beta+thalassemia+epidemiology+greek+turkey&pg=PA135 |title=The MGH Review of Critical Care Medicine |date=2013-10-16 |publisher=Lippincott Williams & Wilkins |isbn=978-1-4511-7368-0}}

Beta thalassemia is most prevalent in the "thalassemia belt" which includes areas in Sub-Saharan Africa, and the Mediterranean extending into the Middle East and Southeast Asia. This geographical distribution is thought to be due to the beta-thalassemia carrier state (beta-thalassemia minor) conferring resistance to malaria. In 2005, it was estimated that 1.5% of the world's population are carriers and 60,000 affected infants are born with the thalassemia major annually.

The thalassemia trait may confer a degree of protection against malaria, which is historically endemic in the regions where the trait is common.{{Cite book |url=https://books.google.com/books?id=5gMiqaiJ0VAC&q=The+thalassemia+trait+may+confer+a+degree+of+protection+against+malaria&pg=PA237 |title=Basic Genetics: A Primer Covering Molecular Composition of Genetic Material, Gene Expression and Genetic Engineering, and Mutations and Human Genetic |vauthors=Abouelmagd A, Ageely HM |date=2013 |publisher=Universal-Publishers |isbn=978-1-61233-192-8 |access-date=2020-10-25 |archive-url=https://web.archive.org/web/20230114142647/https://www.google.com/books/edition/Basic_Genetics/5gMiqaiJ0VAC?hl=en&gbpv=1&bsq=The+thalassemia+trait+may+confer+a+degree+of+protection+against+malaria&pg=PA237&printsec=frontcover |archive-date=2023-01-14 |url-status=live}} This is thought to confer a selective survival advantage on carriers (known as heterozygous advantage), thus perpetuating the mutation. In that respect, the various thalassemias resemble other genetic disorders affecting hemoglobin, such as sickle-cell disease or Hemoglobin C disease.{{Cite book | vauthors = Weatherall DJ |title=Williams Hematology |publisher=The McGraw-Hill Companies |year=2010 | veditors = Lichtman MA, Kipps TJ, Seligsohn U, Kaushansky K, Prchal JT |edition=8th |chapter=The Thalassemias: Disorders of Globin Synthesis |access-date=2012-10-02 |chapter-url=http://www.accessmedicine.com/content.aspx?aID=6123722 |archive-url=https://web.archive.org/web/20131104000352/http://www.accessmedicine.com/content.aspx?aID=6123722 |archive-date=2013-11-04 |url-status=live}}

• Alpha-thalassemia
• Anisopoikilocytosis
• Delta-thalassemia
• Hemoglobinopathy

{{Reflist}}

{{refbegin}}

• {{Cite book | vauthors = Cao A, Galanello R |title=GeneReviews |title-link=GeneReviews |publisher=University of Washington, Seattle |year=2010 | veditors = Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP |chapter=Beta-Thalassemia |pmid=20301599 |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK1426/}}
• {{cite journal | vauthors = Bahal R, Ali McNeer N, Quijano E, Liu Y, Sulkowski P, Turchick A, Lu YC, Bhunia DC, Manna A, Greiner DL, Brehm MA, Cheng CJ, López-Giráldez F, Ricciardi A, Beloor J, Krause DS, Kumar P, Gallagher PG, Braddock DT, Mark Saltzman W, Ly DH, Glazer PM | title = In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery | journal = Nature Communications | volume = 7 | pages = 13304 | date = October 2016 | pmid = 27782131 | pmc = 5095181 | doi = 10.1038/ncomms13304 | bibcode = 2016NatCo...713304B }}

{{refend}}

{{Medical resources

| DiseasesDB = 3087

| ICD10 = {{ICD10|D|56|1|d|55}}

| ICD9 = {{ICD9|282.44}}

| ICDO =

| OMIM = 141900

| MedlinePlus =

| eMedicineSubj = article

| eMedicineTopic = 199534

| MeshID = D017086

| Orphanet = 848

}}

{{Scholia|topic}}

{{Commons}}

{{Diseases of RBCs}}

{{DEFAULTSORT:Beta-Thalassemia}}

Category:Disorders of globin and globulin proteins

Category:Hereditary hemolytic anemias

Category:Rare diseases