Beta thalassemia

From Wikipedia, the free encyclopedia
  (Redirected from Beta-thalassemia)
Jump to: navigation, search
Beta thalassemia
Classification and external resources
ICD-10 D56.1
ICD-9 282.44
OMIM 141900
DiseasesDB 3087 1373
eMedicine article/199534
MeSH D017086

Beta thalassemias (β thalassemias) are a group of inherited blood disorders. They are 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 1 in 100,000.[1][dubious ]

Beta thalassemia (β thalassemia) is a form of thalassemia caused by mutations in the HBB gene on chromosome 11[citation needed], inherited in an autosomal recessive fashion. The severity of the disease depends on the nature of the mutation[citation needed].

HBB blockage over time leads to decreased Beta-chain synthesis. The body’s inability to construct new Beta-chains leads to the underproduction of HBA. Reductions in HBA available overall to fill the red blood cells in turn leads to microcytic anemia. Microcytic anemia ultimately develops in respect to inadequate HBB for sufficient red blood cell functioning. Due to this factor, the patient must undergo a blood transfusion for survival to make up for the blockage in the Beta-chains. Repeated blood transfusions lead to build-up of iron overload ultimately resulting in iron toxicity. This iron toxicity produces myocardial siderosis and heart failure leading to the patient’s death.[2][3]

Signs and symptoms[edit]

Three main forms have been described: thalassemia major, thalassemia intermedia and thalassemia minor. All people with thalassemia are susceptible to health complications that involve the spleen (which is often enlarged and frequently removed) and gallstones. These complications are mostly found in thalassemia major and intermedia patients.

Individuals with beta thalassemia major usually present within the first two years of life with severe anemia, poor growth and skeletal abnormalities during infancy. Untreated thalassemia major eventually leads to death, usually by heart failure; therefore, birth screening is very important.

Excess iron causes serious complications within the liver, heart and endocrine glands. Severe symptoms include liver cirrhosis, liver fibrosis and in extreme cases, liver cancer. Heart failure, growth impairment, diabetes and osteoporosis are life-threatening contributors brought upon by TM. The main cardiac abnormalities seen to have resulted from thalassemia and iron overload include left ventricular systolic and diastolic dysfunction, pulmonary hypertension, valveulopathies, arrhythmias and pericarditis.[2][4]

Increased gastrointestinal iron absorption is seen in all grades of beta thalassemia and increased red blood cell destruction by the spleen due to ineffective erythropoiesis further releases additional iron into the bloodstream.[citation needed]


Bocchetta (2005) suggests potential interactions between microcytic anaemia and mood disorders. He concludes heterozygous β-thalassaemia might play a role as a susceptibility factor in bipolar spectrum disorders in specific populations.[5]



The genetic mutations present in β thalassemias are very diverse, and a number of different mutations can cause reduced or absent β globin synthesis. Two major groups of mutations can be distinguished:

  • Nondeletion forms: These defects, in general, involve a single base substitution or small deletion or inserts near or upstream of the β globin gene. Most often, mutations occur in the promoter regions preceding the beta-globin genes. Less often, abnormal splice variants are believed to contribute to the disease.
  • Deletion forms: Deletions of different sizes involving the β globin gene produce different syndromes such as (βo) or hereditary persistence of fetal hemoglobin syndromes.

Any given individual has two β globin alleles:

Name Description Alleles
Thalassemia minor Only one of β globin alleles bears a mutation. Individuals will suffer from microcytic anemia. Detection usually involves lower than normal MCV value (<80 fL). Plus an increase in fraction of Hemoglobin A2 (>3.5%) and a decrease in fraction of Hemoglobin A (<97.5%). β+/β or βo
Thalassemia intermedia Affected individuals can often manage a normal life but may need occasional transfusions, e.g., at times of illness or pregnancy, depending on the severity of their anemia. β++ or βo+
Thalassemia major Occurs when both alleles have thalassemia mutations. This is a severe microcytic, hypochromic anemia. Untreated, it causes anemia, splenomegaly and severe bone deformities. It progresses to death before age 20. Treatment consists of periodic blood transfusion; splenectomy for splenomegaly and chelation of transfusion-caused iron overload. Cure is possible by bone marrow transplantation. Cooley's anemia is named after Thomas Benton Cooley.[6] βoo

mRNA assembly[edit]

Beta thalassemia is a hereditary disease affecting hemoglobin. As with about half of all hereditary diseases,[7] an inherited mutation damages the assembly of the messenger-type RNA (mRNA) that is transcribed from a chromosome. DNA contains both the instructions (genes) for stringing amino acids together into proteins, as well as stretches of DNA that play important roles in regulating produced protein levels. Once DNA is transcribed into RNA, working mRNA uses protein-coding sections with non-coding sections removed. The spliceosome protein selects (the exonic sections) and excises the introns (the interruption(s) in the gene), joining the selected pieces. The resultant mRNA can make hemoglobin components, by serving as the "programming input" to ribosomes.

In thalassemia, an additional, contiguous length or a discontinuous fragment of non-coding instructions are included in the mRNA. This happens because the mutation obliterates the boundary between the intronic and exonic portions.[8] Because all the coding sections may still be present, normal hemoglobin may be produced and the added material, if it produces pathology, instead disrupts regulatory functions enough to produce anemia.

Hemoblogin's normal alpha and beta subunits each have an iron-containing central portion (heme) that allows the protein chain of a subunit to fold around it. Normal adult hemoglobin contains 2 alpha and 2 beta subunits. Thalassemias typically affect only the mRNAs for production of the beta chains (hence the name). Since the mutation may be a change in only a single base (a "Single Nucleotide Polymorphism"), on-going efforts seek gene therapies to make that single correction.[9][10][11]

HBB blockage over time leads to decreased Beta-chain synthesis. The body’s inability to construct new Beta-chains leads to the underproduction of HBA. Reductions in HBA available overall to fill the red blood cells in turn leads to microcytic anemia. Microcytic anemia ultimately develops in respect to inadequate HBB for sufficient red blood cell functioning. Due to this factor, the patient must undergo a blood transfusion for survival to make up for the blockage in the Beta-chains. Repeated blood transfusions lead to build-up of iron overload ultimately resulting in iron toxicity. This iron toxicity produces myocardial siderosis and heart failure leading to the patient’s death.[2][3]

Protein HBB PDB 1a00: this is a healthy Beta Globin Protein


Abdominal pain due to hypersplenism and splenic infarction and right-upper quadrant pain caused by gallstones are major clinical manifestations. However, diagnosing thalassemiæ from symptoms alone is inadequate. Physicians note these signs as associative due to this disease's complexity. The following associative signs can attest to the severity of the phenotype: pallor, poor growth, inadequate food intake, splenomegaly, jaundice, maxillary hyperplasia, dental malocclusion, cholelithiasis, systolic ejection murmur in the presence of severe anemia and pathologic fractures.

Based on symptoms, tests are ordered for a differential diagnosis. These tests include complete blood count; hemoglobin electrophoresis; serum transferrin, ferritin, Fe Binding Capacity; urine urobilin and urobilogen; peripheral blood smear; hematocrit; and serum bilirubin.[12]

DNA analysis[edit]

All beta thalassemias may exhibit abnormal red blood cells such as codocyte, anisocytosis, poikilocytosis, elliptocytosis, Hypochromic anemia and schistocyte. A family history is followed by DNA analysis.

This test is used to investigate deletions and mutations in the alpha- and beta-globin-producing genes. Family studies can be done to evaluate carrier status and the types of mutations present in other family members. DNA testing is not routine, but can help diagnose thalassemia and determine carrier status. In most cases the treating physician uses a clinical prediagnosis assessing anemia symptoms: fatigue, breathlessness and poor exercise tolerance. Further genetic analysis may include HPLC should routine electrophoresis prove difficult.[12]



Affected children require regular lifelong blood transfusions. Bone marrow transplants can be curative for some children.[13]

Surgically removed spleen of a Thalassemic child. It is about 15 times larger than normal.

Patients receive frequent blood transfusions that lead to or potentiate iron overload. Iron chelation treatment is necessary to prevent damage to internal organs. Advances in iron chelation treatments allow patients with thalassemia major to live long lives with access to proper treatment. Popular chelators include deferoxamine and deferiprone. Of the two, deferoxamine is preferred; it is more effective and is associated with fewer side-effects.[14]

The most common patient deferoxamine complaint is that they are painful and inconvenient. The oral chelator deferasirox was approved for use in 2005 in some countries. It offers some hope with compliance at a higher cost.

Bone marrow transplantation is the only cure and is indicated for patients with severe thalassemia major. Transplantation can eliminate a patient's dependence on transfusions. Absent a matching donor, a savior sibling can be conceived by preimplantation genetic diagnosis (PGD) to be free of the disease as well as to match the recipient's human leukocyte antigen (HLA) type.

Thalassemia patients show an increased number and higher degree activity of neutrophil elastase, which can effect other possible comorbidities such as alpha 1 antitrypsin deficiency.


Patients may require episodic blood transfusions. Transfusion-dependent patients develop iron overload and require chelation therapy to remove the excess iron. Transmission is autosomal recessive; however, dominant mutations and compound heterozygotes have been reported. Genetic counseling is recommended and prenatal diagnosis may be offered.[15]

Alleles without a mutation that reduces function are characterized as (β). Mutations are characterized as (βo) if they prevent any formation of β chains. Mutations are characterized as (β+) if they allow some β chain formation to occur. (Note that the "+" in β+ is relative to βo, not β.) Both cases express a relative excess of α chains, but these do not form tetramers: rather, they bind to the red blood cell membranes, producing membrane damage and at high concentrations they form toxic aggregates.

Beta Thalassemia Minor[edit]

Patients are often monitored without treatment.[16] While many of those with minor status do not require transfusion therapy, they still risk iron overload, particularly in the liver.[citation needed] A serum ferritin test checks iron levels and can point to further treatment.[citation needed] Although not life-threatening on its own, it can affect quality of life due to the anemia. Minor often coexists with other conditions such as asthma[17] and mood disorders identified by Bocchetta (2005),[5] and can cause iron overload of the liver and in those with non-alcoholic fatty liver disease, lead to more severe outcomes.[18][19]


The beta form of thalassemia is particularly prevalent among Mediterranean people and this geographical association is responsible for its naming: Thalassa (θάλασσα) is the Greek word for sea and Haema (αἷμα) is the Greek word for blood.

In Europe, the highest concentrations of the disease are found in Greece,[citation needed] coastal regions in Turkey[citation needed] (particularly the Aegean Region such as Izmir, Balikesir, Aydin, Mugla, and Mediterranean Region such as Antalya, Adana, Mersin), in parts of Italy, particularly Southern Italy[citation needed] and the lower Po valley.[citation needed]

The major Mediterranean islands (except the Balearics) such as Sicily, Sardinia, Malta, Corsica, Cyprus (18%),[20] and Crete are heavily affected in particular. Other Mediterranean people, as well as those in the vicinity of the Mediterranean, also have high incidence rates, including people from West Asia and North Africa.

ASHIOTIS, ZACHARIADIS, and SOFRONIADOU (1971) state "frequencies of the thalassaemias in Cyprus were examined by a survey of hospital inpatients and haematological investigations of adult and newborn population samples. The data indicate that 15% of the Greek and Turkish Cypriots are carriers of beta-thalassaemia genes, while 10% of the population carry alpha-thalassaemia genes. These are the highest frequencies of thalassaemia genes found today in any Caucasian population".

Far from the Mediterranean, South Asians are also affected,[citation needed] That region's highest concentration of carriers (16% of the population) is the Maldives.[citation needed]

"At least one of 6,038 newborns in Egypt is homozygous for β thalassaemia" stated by Habib (1981). Homozygous in that context, meaning born with both β thalassaemia genes.

Evolutionary adaptation[edit]

The thalassemia trait may confer a degree of protection against malaria, which is or was prevalent in the regions where the trait is common, thus conferring a selective survival advantage on carriers (known as heterozygous advantage), thus perpetuating the mutation. In that respect, the various thalassemias resemble another genetic disorder affecting hemoglobin, sickle-cell disease, (Williams Hematology- 8th Edition, 2010).[21][22]

According to Habib (1981), "the thalassaemia gene might have originated more than 50,000 years ago during the Paleolithic period, in an area now representing the southern part of Italy and Greece, as evidenced by skeletal remnants exhibiting bony changes similar to those of thalassaemia".


As of 2013 there is no high quality evidence on the usefulness of stem cell transplantation.[23] In February, 2015 the FDA granted “breakthrough therapy” designation to LentiGlobin BB305, an experimental treatment for beta thalassemia.[24]


  1. ^ Galanello, Renzo; Origa, Raffaella (21 May 2010). "Beta-thalassemia". Orphanet J Rare Dis (Orphanet Journal of Rare Diseases) 5: 11. doi:10.1186/1750-1172-5-11. PMC 2893117. PMID 20492708. 
  2. ^ a b c Isma'eel, Hussain , Maria D Cappellini, and Ali Taher. "Chronic transfusion, iron overload and cardiac dysfunction: a multi-dimensional perspective." The British Journal of Cardiology 15.1 (2008): n. pag. BJC. Web. 16 May 2013.
  3. ^ a b Tanner, M. A.; Galanello, R; Dessi, C; Smith, G. C.; Westwood, M. A.; Agus, A; Pibiri, M; Nair, S. V.; Walker, J. M.; Pennell, D. J. (2008). "Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction". Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance 10: 12. doi:10.1186/1532-429X-10-12. PMC 2289829. PMID 18298856.  edit
  4. ^ Tanner, Mark A, J Malcolm Walker, Sunil V Nair, Martina Pibiri, Annalisa Agus, Mark A Westwood, Gillian C Smith, Carlo Dessi, Renzo Galanello, and Dudley J Pennell. "Combined Chelation Therapy In Thalassemia Major For The Treatment Of Severe Myocardial Siderosis With Left Ventricular Dysfunction." Journal of Cardiovascular Magnetic Resonance 10.1 (2008): 12. Print.
  5. ^ a b Bocchetta, Alberto (2005). "Heterozygous beta-thalassaemia as a susceptibility factor in mood disorders: Excessive prevalence in bipolar patients". Clinical Practice and Epidemiology in Mental Health 1 (1): 6. doi:10.1186/1745-0179-1-6. PMC 1156923. PMID 15967056. 
  6. ^ "Cooley's anaemia". Whonamedit. Retrieved 2014-08-08. 
  7. ^ Ward, Amanda J; Cooper, Thomas A (2009). "The pathobiology of splicing". The Journal of Pathology 220 (2): 152–63. doi:10.1002/path.2649. PMC 2855871. PMID 19918805. 
  8. ^ "Physiology or Medicine 1993 - Press Release". 1993-10-11. Retrieved 2014-08-08. 
  9. ^ Chin, Joanna Y.; Kuan, Jean Y.; Lonkar, Pallavi S.; Krause, Diane S.; Seidman, Michael M.; Peterson, Kenneth R.; Nielsen, Peter E.; Kole, Ryszard; Glazer, Peter M. (2008). "Correction of a splice-site mutation in the beta-globin gene stimulated by triplex-forming peptide nucleic acids". Proceedings of the National Academy of Sciences of the United States of America 105 (36): 13514–9. doi:10.1073/pnas.0711793105. PMC 2533221. PMID 18757759. 
  10. ^ Cavazzana-Calvo, M.; Payen, E.; Negre, O.; Wang, G.; Hehir, K.; Fusil, F.; Down, J.; Denaro, M.; Brady, T.; Westerman, K.; Cavallesco, R.; Gillet-Legrand, B.; Caccavelli, L.; Sgarra, R.; Maouche-Chrétien, L.; Bernaudin, F. O.; Girot, R.; Dorazio, R.; Mulder, G. J.; Polack, A.; Bank, A.; Soulier, J.; Larghero, J. R. M.; Kabbara, N.; Dalle, B.; Gourmel, B.; Socie, G. R.; Chrétien, S.; Cartier, N.; Aubourg, P. (2010). "Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia". Nature 467 (7313): 318–22. doi:10.1038/nature09328. PMC 3355472. PMID 20844535.  edit
  11. ^ (11 July 2012) ß-Thalassemia Major With Autologous CD34+ Hematopoietic Progenitor Cells Transduced With TNS9.3.55 a Lentiviral Vector Encoding the Normal Human ß-Globin Gene, Clinical trial NCT01639690 at the Memorial Sloan-Kettering Cancer Center, Retrieved 12 February 2014
  12. ^ a b Orkin, Stuart H.; Nathan, David G.; Ginsburg, David; Look, A. Thomas; Fisher, David E.; Lux, Samuel (2009). Nathan and Oski's Hematology of Infancy and Childhood (7th ed.). Philadelphia: Saunders. ISBN 978-1-4160-3430-8. [page needed]
  13. ^ Muncie, Herbert L.; Campbell, James S. (2009). "Alpha and Beta Thalassemia". American Family Physician 80 (4): 339–44. PMID 19678601. 
  14. ^ Maggio, Aurelio; d'Amico, Gennaro; Morabito, Alberto; Capra, Marcello; Ciaccio, Calogero; Cianciulli, Paolo; Di Gregorio, Felicia; Garozzo, Giovanni et al. (2002). "Deferiprone versus Deferoxamine in Patients with Thalassemia Major: A Randomized Clinical Trial". Blood Cells, Molecules, and Diseases 28 (2): 196–208. doi:10.1006/bcmd.2002.0510. 
  15. ^ Galanello, Renzo; Origa, Raffaella (2010). "Beta-thalassemia". Orphanet Journal of Rare Diseases 5: 11. doi:10.1186/1750-1172-5-11. PMC 2893117. PMID 20492708. 
  16. ^ "Thalassemia: Treatments and drugs -". 
  17. ^ Palma-Carlos, AG; Palma-Carlos, ML; Costa, AC (2005). "'Minor' hemoglobinopathies: A risk factor for asthma". European annals of allergy and clinical immunology 37 (5): 177–82. PMID 15984316. 
  18. ^ Valenti, Luca; Canavesi, Elena; Galmozzi, Enrico; Dongiovanni, Paola; Rametta, Raffaela; Maggioni, Paolo; Maggioni, Marco; Fracanzani, Anna Ludovica; Fargion, Silvia (2010). "Beta-globin mutations are associated with parenchymal siderosis and fibrosis in patients with non-alcoholic fatty liver disease". Journal of Hepatology 53 (5): 927–33. doi:10.1016/j.jhep.2010.05.023. PMID 20739079. 
  19. ^ Stickel, Felix; Hampe, Jochen (2010). "Dissecting the evolutionary genetics of iron overload in non-alcoholic fatty liver disease". Journal of Hepatology 53 (5): 793–4. doi:10.1016/j.jhep.2010.06.010. PMID 20739088. 
  20. ^ Fawdry A. Report on present state of knowledge of erythroblastic anaemia in Cyprus. Cyprus Med Sanitary Report, 1946
  21. ^ Weatherall, David J. Lichtman, MA,; Kipps, TJ,; Seligsohn, U,; Kaushansky, K,; Prchal, JT, eds. The Thalassemias: Disorders of Globin Synthesis. Williams Hematology (8 ed.). 
  22. ^ "Thalassemia Complications". Mayoclinic. Retrieved 20 September 2011. 
  23. ^ Jagannath, VA; Fedorowicz, Z; Al Hajeri, A; Sharma, A (Oct 15, 2014). "Hematopoietic stem cell transplantation for people with ß-thalassaemia major.". The Cochrane database of systematic reviews 10: CD008708. doi:10.1002/14651858.CD008708.pub3. PMID 25316103. 
  24. ^ "Ten things you might have missed Monday from the world of business". The Boston Globe. 3 February 2015. Retrieved 13 February 2015. 

Further reading[edit]