Main pathology of b thalassemia is reduced production of b-chain leading to excess of unpaired a -globin chain which precipitate leading to ineffective erythropoiesis or hemolysis of RBCs resulting in anemia.

• It has been noted that hypomethylation of gene increases its expression and when methylated, the gene is not expressed. A number of drugs like 5'Azacytidine and hydroxyurea have been shown to increase the production of gamma chains both in animals and human beings by causing hypomethylation of gene by decreasing the activity of the enzyme DNA methyl transferase.
• This increase in gamma chain synthesis prevents the Alpha chain precipitation by forming HbF (a 2 g 2) and thereby increasing the life span of red cells.
• 5-Azacytidine is recommended in the dose of 2 mg/kg/day intravenous infusion in ringer lactate or saline solution at the rate of 6 mg/hour for 7 days.
• This leads to an increase in Hb from 8 to 10.8 gm% in 2-3 weeks and an increase in fetal Hb from 1.06% to 20% on the 40th day.
• Side effects like nausea, vomiting, suppression of bone marrow and potential carcinogenesis have put limitations on its use in practice and unless a more effective compound with less toxicity becomes available such therapy is not recommended for thalassemia major.
  

Augmenting the production of g chain reduces imbalance of globin chain and increases synthesis of HbF and thus lessening the severity of the disease. Various drugs that stimulate HbF production are 5-azacytidine, hydroxyurea, Butyrate compounds and erythropoietin.

Butyrates :
These are found naturally increased in diabetic mothers. Their babies at birth have 100 % HbF. In vitro trials found the efficacy of these drugs in increasing the HbF production. This drug is given I.V. infusion slowly over 6-8 hours in dose of 200-400 mg/kg/day and has shown to increase HbF to 8-12% and cause a rise in Hb by 2-3 gm%. The problem with this drug is the tedious I.V. route. Oral analogue, Na Butyrate is useful in some patients to sustain the response after IV therapy. The side effects are few and include nausea, vomiting, electrolyte disturbances and occasional seizures. The actual efficacy of this drug is found to be lacking in many patients with sickle cell anemia and thalassemia intermedia. Further trials are awaited before it becomes available commercially. L-carnitine, an analogue of butyrate, has been tried in thalassemic patients but response obtained has been poor in most of the trials.

Genetic Engineering :
Insertion of normal gene in the stem cells of recipient remains a known challenging goal of future therapy. There are two main approaches to gene therapy : 1) Somatic approach in which non-germ line cells are involved. 2) Transgenic approach in which transfused gene can be expressed in subsequent generations. This therapy is still in experimental stage and likely to be therapy of future management of thalassemia.

Antenatal diagnosis and genetic counseling :
As thalassemia is inherited in an autosomal recessive manner there are 25% chances of producing thalassemia major child in each pregnancy.

Population screening, identification of carriers, genetic counseling, antenatal diagnosis in women at risk and selective termination of affected fetus can prevent the birth of thalassemia major child.
br> Prenatal diagnosis can be done by estimation of relative rate of globin biosynthesis by fetoscopy and fetal blood sampling around 16-18 weeks of intrauterine life or by analysis of foetal DNA by ultrasound guided chorionic villous biopsy at around 8-9 weeks of gestation or foetal amniocytes by amniocentesis.

Conclusion :

With the better understanding of molecular biology and pathophysiology of thalassemia, advances in the transfusion therapy, organized quality care and effective chelation therapy, thalassemics can become fully active members of the society with proper physical, mental and sexual growth (without any disfiguration). They are able to profit from their opportunities and enjoy positions that they are entitled to in the society. With the free availability of oral chelators in near future, and establishment of more and more outdoor transfusion centres and thalassemia societies, the management of thalassemia major will become easier and economically feasible. With the advent of BMT, cure is possible. Gene therapy still remains a hope for the future. In developed countries where all these facilities are already available, more and more thalassemic children are leading a normal healthy life and even achieving parenthood. Prenatal screening and diagnosis as well as modern management of thalassemia are technologically complex and expensive, and thus their benefits remain limited only to the industrialized developed world & in certain centres in India. Unfortunately, developing countries like ours still have a long way to go.

REFERENCES :


Also See Frequently Asked Questions On "Thalassemia"
Also See Expertise Views On "Thalassemia"

Last created on 06-11-2000
Last updated on 01-07-2006