Dr. Wahied Khawar Balwan
There are more than one thousand genetic abnormalities known in humans. Most are congenital, i.e. these diseases are inherited from the parents. But some may be acquired during one’s lifetime. Exposure to ionizing radiation, chemical carcinogens or different oncogenic viruses cause cancer which is of course due to mutations or genetic changes. In this article , we describe one of the most common inherited genetic diseases, thalassemia which produces insufficient or non-functional hemoglobin, the carrier protein of Oxygen in our blood. There are two different globin genes, alpha and beta, carried on chromosome 15 and 11 respectively. Beta globin mutations are more common and has been studied for the last thirty years. Blood transfusion at regular interval to the affected individual is the usual procedure but gene therapy to correct the mutational defect would be applied in future for permanent cure. Clinical diagnosis of the genetic disease is often aided by molecular detection of the mutational changes in the globin genes.
Beta-thalassemias are a group of hereditary blood disorders which are characterized by anomalous synthesis of the beta chains of hemoglobin. They result in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. The total annual incidence of symptoms is estimated at about 1 in 100,000 individuals throughout the world. There are three main forms of thalassemia: thalassemia major, thalassemia intermedia and thalassemia minor. Individuals who have thalassemia major are seen to have severe anemia and require regular red blood transfusions. Observations in patients with thalassemia who were untreated or poorly transfused, as seen in some developing countries, are growth retardation, jaundice, poor musculature, pallor, hepatosplenomegaly, leg ulcers, and development of masses from extra medullary hematopoiesis. Skeletal changes may also result due to the expansion of bone marrow. Regular transfusion therapy, although necessary for survival, can lead to iron overload-related complications including endocrine complications (growth retardation, diabetes mellitus, failure of sexual maturation, and insufficiency of the parathyroid, thyroid, pituitary, and less commonly, adrenal glands), dilated myocardiopathy, liver fibrosis and cirrhosis). Thalassemia intermedia is seen in older patients with moderate anemia and they do not require regular blood transfusions. Main clinical features are gallstones, painful leg ulcers, increased predisposition to thrombosis, hypertrophy of erythroid marrow with medullary and extramedullary hematopoiesis and its complications which include osteoporosis, masses of erythropoietic tissue that primarily affect the liver, spleen, lymph nodes, chest and spine, and bone deformities and typical facial changes. Thalassemia minor is clinically asymptomatic but moderate anemia is observed in some individuals. Beta-thalassemias are caused by point mutations or, more rarely, deletions in the beta globin gene on chromosome 11, leading to reduced (beta+) or absent (beta0 ) synthesis of the beta chains of hemoglobin. Transmission is autosomal recessive in most cases; however, reports have also shown dominant mutations. Diagnosis is based on hematologic and molecular genetic testing.
Presently prevalence of Thalassemia carrier in India is 3.7% of its total population. Annual increment of Thalassemia carrier is 50,000. Both Alpha and Beta Thalassemia are found in West Bengal, but Beta Thalassemia is most common in West Bengal.
Among the various Hemoglobinopathies, αand β-thalassemia are common throughout the world. β-thalassemia is an autosomal recessive disorder of β-globin gene and about 7% of the global population are the carriers of this genetic trait. In Indian subcontinent, 2-3% of the general population and as high as 17% of certain high risk communities are affected by β-thalassemia. App. 20,000 children are born each year in India with β-thalassemia major. Prenatal diagnosis holds the key role in prevention of this disease. Diagnosis of β-thalassemia in the 1st trimester by DNA analysis is a popular test because of the safety of termination of pregnancy if needed. The identification of the mutations in the parents and the foetus is carried out using various techniques. Altogether 785 mutations are already identified in β-globin gene and its flanking regions, of which 232 mutations are in β-globin gene causing phenotype of β-thalassemia. B-globin gene cluster is a segment of DNA on chromosome 11 in humans which is about 60 kilo base pairs long.
During embryonic development, these genes are switched on and off by selective methylation and demethylation of the genes (Epigenetics). The chronological order of expression of these genes from the conception to child birth is ε to δ to γ to β-globin sequence. Though fetal hemoglobin may persist after child birth, this genetic abnormality is known as Hereditary Persistence of Fetal Hemoglobin (HPFH). Both point mutations and insertion/deletion of DNA sequences are known in β-globin gene. The correlation between genotype and phenotype are known in some cases of β-thalassemia but a lot remains to be understood. The most common mutation found in βthalassemia both in western and eastern India is the point mutation G>C at position 5 in the first intervening sequence (IVS I, 5). The next most prevalent mutation is the deletion of 619 basepairs in the 3rd exon of β-globin gene in Sindhi population.
Of all the genetic diseases encountered in India, hemoglobinopathies are the most common. Alpha and beta thalassemia and sickle cell anemia are more common in Mediterranean countries as well as in American black population. Indian subcontinent also faces this dreaded disease, for which blood transfusion is the only remedy. However, gene therapy to correct the mutational defects is a distinct possibility and in future, it should be the alternative and permanent solution for the affected people.
“Any Error in this manuscript is silent testimony of the fact that it was a human effort”
Dr. Wahied Khawar Balwan
Senior Assistant Professor
Department of Zoology
Govt. Postgraduate College Bhaderwah
Jammu and Kashmir
E-mail: [email protected]