Thalassemia is an inherited autosomal recessive blood disease. In thalassemia, the genetic defect results in reduced rate of synthesis of one of the globin chains that make up hemoglobin. Reduced synthesis of one of the globin chains causes the formation of abnormal hemoglobin molecules, and this in turn causes the anemia which is the characteristic presenting symptom of the thalassemias.

Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. The two conditions may overlap, however, since some conditions which cause abnormalities in globin proteins (hemoglobinopathy) also affect their production (thalassemia). Thus, some thalassemias are hemoglobinopathies, but most are not.Generally, thalassemias are prevalent in populations that evolved in humid climates where malaria was endemic, but affects all races. Thalassemias are particularly associated with Arab-Americans, people of Mediterranean origin, and Asians. The estimated prevalence is 16% in people from Cyprus, 3-14% in Thailand, and 3-8% in populations from India, Pakistan, Bangladesh, Malaysia and China. There are also prevalences in descendants of people from Latin America, and Mediterranean countries (e.g. Spain, Portugal, Italy, Greece and others). A very low prevalence has been reported from people in Africa (0.9%), with those in northern Africa having the highest prevalence, and northern Europe (0.1%).

The thalassemias are classified according to which chain of the hemoglobin molecule is affected (see hemoglobin for a description of the chains). In a thalassemias, production of the a globin chain is affected, while in ß thalassemia production of the ß globin chain is affected.

Thalassemia produces a deficiency of a or ß globin, unlike sickle-cell disease which produces a specific mutant form of ß globin.

Deletion of one of the a loci has a high prevalence in people of African-American or Asian descent, making them more likely to develop a thalassemias. ß thalassemias are common in African-Americans, but also in Greeks and Italians.

Alpha (a) thalassemias
The a thalassemias involve the genes HBA1 (Online 'Mendelian Inheritance in Man' (OMIM) 141800) and HBA2 (Online 'Mendelian Inheritance in Man' (OMIM) 141850), inherited in a Mendelian recessive fashion. It is also connected to the deletion of the 16p chromosome. a thalassemias result in decreased alpha-globin production, therefore fewer alpha-globin chains are produced, resulting in an excess of ß chains in adults and excess ? chains in newborns. The excess ß chains form unstable tetramers (called Hemoglobin H or HbH of 4 beta chains) which have abnormal oxygen dissociation curves.

Beta (ß) thalassemias
Beta thalassemias are due to mutations in the HBB gene on chromosome 11 (Online 'Mendelian Inheritance in Man' (OMIM) 141900), also inherited in an autosomal-recessive fashion. The severity of the disease depends on the nature of the mutation. Mutations are characterized as (?o) if they prevent any formation of ? chains; they are characterized as (?+) if they allow some ? chain formation to occur. In either case there is a relative excess of ? 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.

Delta (d) thalassemia
As well as alpha and beta chains being present in hemoglobin about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations can occur which affect the ability of this gene to produce delta chains. A mutation that prevents formation of any delta chains is termed a delta0 mutation, whereas one that decreases but does not eliminate production of delta chain is termed a delta+ mutation. When one inherits two delta0 mutations, no hemoglobin A2 (alpha2, delta2) can be formed. Hematologically, however, this is innocuous because only 2-3% of normal adult hemoglobin is hemoglobin A2. The individual will have normal hematological parameters (erythrocyte count, total hemoglobin, mean corpuscular volume, red cell distribution width). Individuals who inherit only one delta thalassemia mutation gene will have a decreased hemoglobin A2, but also no hematological consequences. The importance of recognizing the existence of delta thalassemia is seen best in cases where it may mask the diagnosis of beta thalassemia trait. In beta thalassemia, there is an increase in hemoglobin A2, typically in the range of 4-6% (normal is 2-3%). However, the co-existence of a delta thalassemia mutation will decrease the value of the hemoglobin A2 into the normal range, thereby obscurring the diagnosis of beta thalassemia trait. This can be important in genetic counseling, because a child who is the product of parents each of whom has beta0 thalassemia trait has a one in four chance of having beta thalassemia major.

Genetic prevalence
Thalassemia has an autosomal recessive pattern of inheritance.a and ß thalassemia are often inherited in an autosomal recessive fashion although this is not always the case. Reports of dominantly inherited a and ß thalassemias have been reported the first of which was in an Irish family who had a two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the ß-globin gene. For the autosomal recessive forms of the disease both parents must be carriers in order for a child to be affected. If both parents carry a hemoglobinopathy trait, there is a 25% chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families that carry a thalassemia trait.

There are an estimated 60-80 million people in the world who carry the beta thalassemia trait alone. This is a very rough estimate and the actual number of thalassemia Major patients is unknown due to the prevalence of thalassemia in less developed countries in the Middle East and Asia. Countries such as India, Pakistan and Iran are seeing a large increase of thalassemia patients due to lack of genetic counseling and screening. There is growing concern that thalassemia may become a very serious problem in the next 50 years, one that will burden the world's blood bank supplies and the health system in general. There are an estimated 1,000 people living with Thalassemia Major in the United States and an unknown number of carriers. Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult.

As with other genetically acquired disorders, genetic counseling is recommended.

Management
Genetic screening is required to identify such condition. A screening policy exists on both sides of the island of Cyprus to reduce the incidence of thalassemia, which since the program's implementation in the 1970s (which also includes pre-natal screening and abortion) has reduced the number of children born with the hereditary blood disease from 1 out of every 158 births to almost zero. Pre-marital screening with proper counseling can reduce the risk of thalassemia of the future offspring.