Genomics & Annah

Ten year girl Annah was my most favorite patient while working in pediatric out-patient department. She was a cute girl who would walk in with her father every 3 weeks for packed cell transfusion. She suffered from a genetic disease called beta- thalassemia. Her parents are first cousins, but none of them suffered from any clinical symptoms. My heart cries for that girl because simple premarital screening, or even some pregnancy tests can prevent the birth of thalassemia kids. Many countries in the world have made premarital screening for thalassemia mandatory.

I propose that all countries must make these tests mandatory and it is the responsibility of the government and health authorities to educate all couples to get screened for this disease to prevent thalassemia offsprings. Thalassemias are a group of heterogeneous inherited disorders caused by genetic defects as a consequence of which decreased synthesis of either the alpha or beta chain of HbA occurs (Aster, 2007, pg. 632). When deficient synthesis of beta chain occurs, it is known as beta-thalassemia and when alpha synthesis is affected, it is known as alpha-thalassemia.

There are basically 2 types of thalassemias- alpha thalassemia and beta thalassemia. These are generally classified according to the affected globin chain. The two most clinically significant forms involve deficits of ? and ? chains. Thalassemias involving ? and ? globin chain synthesis have also been described but are not common. The gene for coding beta chain is on chromosome 11. In ? – thalassemia the defects in the genes are mainly point mutations. There are about 100 different point mutations known to cause beta- thalassemia.. Some of the common mutations are: 1.

Promoter region mutations: These occur within promoter sequences and prevent RNA polymerase from binding normally but some normal hemoglobin is synthesized. This is called ? + thalassemia or thalassemia minor (Aster, 2007). 2. Chain terminator mutations: There are 2 types of these mutations. One causes a new stop codon within an exon, the second consists of small insertions or deletions that shift the mRNA reading frames and introduce down stream stop codons that terminate protein synthesis. In both cases, there is premature chain termination preventing the synthesis of beta hemoglobin. This is called ?

– thalassemia or thalassemia major (Aster, 2007). 3. Splicing mutations: These are the commonest causes of beta- thalassemia. They affect introns more than exons. The thalassemia produced by this method is either ? + or ? -thalassemia (Aster, 2007). When both parents are carriers of the diseased gene, there is a 25% chance in each pregnancy resulting in a child with thalassemia major; 50% chance of a child who is a carrier; and a 25% chance of a healthy child with normal genes (Ghotbi & tsukatani, 2002). About 3% of the world population is carriers of a beta thalassemia mutation (Ghotbi & Tsukatani, 2002).

Thalassemia has a wide distribution, particularly in areas where malaria has been endemic like in the Middle East, Southeast Asia, India and China. It is most common around the Mediterranean Sea, especially in Italy and Greece (Al-Suliman, 2006). The prevalence rate of beta- thalassemia is about 1% to 20% in the world and that for alpha-thalassemia ranges from 10% to 80% globally. The clinical manifestations in patients with beta thalassemia vary significantly, depending on the severity of the condition and the age at the time of diagnosis.

Most of the children with beta thalassemia are healthy at birth, and become anemic between the ages of six months and two years. If no proper diagnosis and treatment is instituted, they can die from anemia or infections in the early years of life. Patients with thalassemia traits are usually asymptomatic. Those with more severe forms of the disease, manifest some pallor and slight icteric discoloration of the sclerae with splenomegaly, leading to slight enlargement of the abdomen. In some, the clue to the disease is taken from unexplained hypochromic and microcytic picture in a routine blood picture.

In the later stages, the patient may present with marked bone marrow erythroid hyperplasia due to impaired oxygen delivery and raised erythropoietin levels. The marrow space is expanded, causing facial and cranial bone deformities. Also, extramedullary hemopoiesis occurs which leads to hepatosplenomegaly and formation of soft tissue masses (Schwarting, 2007). Repeated blood transfusions may lead to blood-transmitted diseases such as hepatitis, AIDS, malaria and syphilis. These hemoglobinopathies are not curable. Patients with thalassemia minor usually do not require treatment.

For those with thalassemia major, hypertransfusional support with packed red blood cells is the main treatment. At the same time, iron chelation with desferrioxamine (Desferal) must be given. Though this treatment initially appears to improve the patient’s health, it is only short term. This is because, repeated transfusions lead to over loading of various organs with iron and subsequent organ failure. Hence, it mandatory to start iron chelating therapy in combination with blood transfusion. Allogeneic hematopoietic transplantation may be curative in some patients with thalassemia major (Takeshita, 2007).

Other emerging therapies are pharmacological induction of hemoglobin F synthesis and gene therapy. Rarely patients with thalassemia major may require splenectomy. Thalassemias can be prevented by premarital screening. The role of premarital screening is to identify carriers of hemoglobin disorders so that appropriate information can be provided on the risk of having children with these severe forms of disease. The screening also provides the parents with options for avoiding it. Due to improvement in the health care and management, the life expectancy and the numbers of thalassemic patients are increased and so is the case with expenditure.

Studies have shown that it will be impossible for most countries to provide optimal treatment for all affected patients due to serious financial implications. Hence, it is imperative that effective prevention is essential in order to liberate the resources needed for the adequate treatment of those already living with thalassemia. Prevention programs if instituted properly, can avoid up to 95% of affected births (WHO Secretariat report, 2006). Preventive programs include providing information on risk and means to avoid it after identifying individuals at risk through carrier screening programmes or family history.

Healthy carriers of beta-thalassemia can be identified by simple, inexpensive and accurate blood tests. When couples go through these tests, they can be informed of the genetic risk and the options available for reducing it, which usually include prenatal diagnosis (WHO Secretariat report, 2006). The main aim of the premarital tests is of course identification of carriers of the diseases. These carriers are identified on the basis of few hematological values which can be identified by simple blood tests like complete blood picture.

The common hematological values used to identify the carriers of Thalassemia are mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). If any abnormality is detected in these, then hemoglobin electrophoresis is performed. Hemoglobin electrophoresis results are usually within the normal range for all types of alpha thalassemia. In beta thalassemia trait or disease, hemoglobin A2 levels and sometimes hemoglobin F levels are elevated. Sometimes DNA testing is needed in addition to the above screening tests to help confirm the diagnosis and establish the exact genetic type of thalassemia.

Hemoglobin electrophoresis also helps detect other structurally abnormal hemoglobins like Hb E or Hb S which may be co-inherited with the thalassemias. Premarital testing should be done in such a way that no carrier eludes detection. There are two possible methodological approaches for identification of homozygous thalassemia carrier: 1. A primary screening in which the common hematological parameters are evaluated is done. In cases of reduced MCV and/or MCH values, secondary screening tests involving hemoglobin electrophoresis is carried out.

This type of testing is recommended in countries with low frequency and limited heterogeneity of Thalassemia (Galanello, 2005). MCH <27pg and MCV <80fl are sensitive measures to look for beta-thalassemia. 2. Complete screening based on measurement of red cell indices, hemoglobin pattern analysis and HbA2 determination from the outset in all subjects. This is done in areas where both homozygous and heterozygous thalassemia are common and interaction of the two could lead to missed diagnosis due to normalization of red cell indices in such cases (Galanello, 2005).

The gold standard test for diagnosis of the carrier state is hemoglobin electrophoresis, but it is costly and hence simpler but sensitive tests like red cell MCV or osmotic fragility test are performed in many countries for initial screening. Nestrcoft (Naked Eye Single Tube Red Cell Osmotic Fragility Test) has been shown to be a sensitive, cost effective, rapid and reliable screening test for detection of beta-thalassemia trait (the carrier state) in a population.

Infact, it has now emerged as the single most effective, inexpensive and easily reproducible test of population screening for beta-thalassemia trait (Ghotbi & Tsukatani, 2002). In countries like Cyprus, Greece, the Islamic Republic of Iran and Italy, premarital screening for thalassemia is standard practice due to high incidence of consanguinity.. Other countries where prevention programmes are introduced are China, India, Indonesia, Malaysia, Maldives, Singapore and Thailand. Recently, such programmes have been adopted in Bahrain and Saudi Arabia.

In the United Kingdom of Great Britain and Northern Ireland and other north-western European countries where prenatal diagnosis is available, prenatal diagnosis and abortion of the affected fetus is used as a prevention strategy (WHO Secretariat Report, 2006). References Al-Suliman, A. (2006). Beta- Thalassemia trait in Premarital Screening. Ann Saudi Med. , 26(1): 14-16 Aster, J. C. (2007). Red Blood Cell and Bleeding Disorders. Robbin and Cotran Pathologic Basis of Disease. 7th ed. Philadelphia: Saunders. Galanello, R. (2005). Screening and Diagnosis for Hemoglobin Disorders. European Genetics Foundation.

Retrieved on 28 November 2008 from: http://www. charite. de/ch/medgen/eumedis/thalassemia04/screening-diagnosis. html Ghotbi, N. , Tsukatani, T. (2002). An economic review of the national screening policy to prevent thalassemia major in Iran. Discussion Paper, 562, Kyoto University, 1-15 Schwarting, R. , Mckenzie, S. and Rubin, R. (2007). Hematopathology. Rubin’s Pathology: Clinicopathologic Foundations of Medicine, 5th edition. Lippincott Williams & Wilkins. 870- 885 Secretariat Report (2006). Thalassemia and other hemoglobinopathies. World Health Organisation. Provisional agenda item 5. 2, EB 118(5).

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