PREVENTION OF SICKLE-CELL CELL DISEASE BY DTN FORMULA OF GENETIC COUNSELING AND TREATMENT BY HYDROXYUREA THERAPY

Transcription

1 PREVENTION OF SICKLE-CELL CELL DISEASE BY DTN FORMULA OF GENETIC COUNSELING AND TREATMENT BY HYDROXYUREA THERAPY

2 DEFINITION Sickle Cell Anemia the Clinical Expression of Homozygosity for HbS is a Serious Disease characterised by; Unrelenting Hemolytic Anemia Recurrent Episodes of Pain and Fever Pathological involvement of many organs of the body

3 HISTORY Sickle-cell cell disease has been known to the people of Africa for hundreds of years.in west-africa various ethnic groups give the condition different names i.e. GA TRIBE, FAUTE TRIBE, EWE TRIBE etc. In 1910 a Chicago Physician James B. Herrick noted in an Anemic patient unusual red cells Sickle Shaped the patient was a West-Indies. In 1940 Sherman( a student of John Hopkin Medical School) proved that low oxygen tension altered the structure of Heamoglobin. In 1948 Janet Watson a Pediatric Haematologist in Newyork found out that the paucity of sickle cell in peripheral blood of new born was due to presence of HbF in the red cells.

4 HISTORY (Contd ) Linus Pauling and Harvey Hano showed in 1948 the technique of Protein Electrophoresis. They detected by electrophoresis that sickle cell disease is due to a fault in a Protein. In 1956 Vernom Inquam and J.A.Haunt at MRC in England showed that in a sickle-haemoglobin glutamic acid at 6 th position of beta chain was replaced by valine.this made sickle cell disease the first genetic disorder whose molecular basis was known. In may 18 th, 1995 the new England journal of medicine reported that Hydroxyurea is the first agent that can prevent episodes of Vasso-oclusive oclusive painful crisis, Hospitalisation,, ACS(acute chest syndrome), incidence of blood transfusion.

5 TYPES Sickle cell disease is a genetically transmitted Hereditary disease. If both the parents are having the disease all the offsprings born to them are likely to inherit. This disease is of two types; 1. Disease 2. Trait

6 PREVALENCE This disease is found in the following countries of the world Africa South America West-Indies India Saudi-Arabia Italy Greece Syria

7 In India a sickle cell belt prevails in which the following states are included. Jharkhand Orissa Chhatishgarh Madhya Pradesh Andhra Pradesh Karnatak Gujarat

8 In Orissa the following un-divided Districts are in the sickle cell belt; Kalahandi Balangir Koraput Sambalpur Mayurbhanj Keonjhar Boudh-Phulbani Sundargarh Dhenkanal Ganjam

9 The following races residing in the above Districts suffer from this disease ; SCHEDULE CASTE SCHEDULE TRIBE AGARIA TELI SUNDHI RAJPUT PAIKA BANKA GAUDA DUMAL KURMI CHASA KULTHA BHULIA KAMARA CHAMAR MAHARANA BADHEI KUMBHAR MALI

10 The disease cases suffer from child hood with crisis and survive with blood transfusions. The trait cases almost lead a normal life.

11 CAUSE OF SPREAD OF DISESASE The spread is due to marriage between DISEASE + DISEASE DISEASE + TRAIT TRAIT + TRAIT CASES This is happening in the above mentioned innocent races without their knowledge for the last hundreds of years.

12 SOLUTION To break this chain the DTN formula of Genetic Counseling was submitted to Govt. in If this formula will be adopted the next generation will be saved from dreaded DISEASE cases.

13 STEP-1 The above mentioned races will be made aware by extensive programmes about the seriousness of the disease how it is responsible for increased infant and maternal mortality rate among them. They will be educated about the cause of spread of the disease.

14 STEP-2 They will be informed to get their blood examined by electrophoresis machine in the pre-marital age.

15 STEP-3 The result of examination will divide the society into 3 groups; Result shortly known as DISEASE --- D TRAIT --- T NORMAL --- N

16 Marriage will be allowed or disallowed in the following manner D +D D+T T+T D+N T+N NOT ALLOWED ALLOWED N+N * DISEASE - D, TRAIT - T, NORMAL - N

17 Genetic Explanation to the Formula

18 GENETICALLY D T N SS AS AA D + D SS SS SS SS SS SS

19 D + T SS AS AS SS AS SS

20 T + T AS AS AA SS AS AS

21 This is happening in the above mentioned innocent races without their knowledge for the last hundreds of years. Hence plenty of SS or disease cases in the society.

22 If the DTN Formula will be adopted D + N S S AA AS AS AS AS

23 T + N A S A A AA AS AA AS

24 N + N A A A A AA AA AA AA

25 HYDROXYUREA THERAPY Hydroxyurea is a CHEMOTHERAPEUTIC agent with potent effects on BONE MARROW, producing HbF in the Red Blood Cells.

26 TREATMENT DETAILS Baseline measurements- at least 2 months of baseline information on the HEMATOLOGIC status of patients with sickle cell disease should be available before starting treatment. Starting dose-hydroxyurea can be started at a dose of 10 mg/kg, orally, on a daily basis. Dose escalation- the dose can be increased at a rate of 5mg/kg/week as long as the HAEMATOLOGIC values remain in an acceptable range. Maximum dose - 25mg/kg.Day Trial period - 6 to 9 months therapy to continue before any decision on the efficacy of the treatment.

27 LEAMITING EFFECTS Platelet count of less than 80,000/cu.mm Neutrophil count of less than 2,500/cu.mm. Haemoglobin of less than 6 gm/dl Hair loss, Gi Upset, rash. Foetal haemoglobin level rises in almost all patients but the response is variable. Contraindications Pregnancy Poor or erratic follow-up Allergy to hydroxyurea Use in children-many centres have advocated to use in children above 2 years of age.

28 AN OVERVIEW OF HAEMOGLOBIN What is haemoglobin? It is a protein carried by red cells. It picks up oxygen from the lungs and delivers to the peripheral tissues to maintain the viability of cells. Hb is made from 2 similar proteins that stick together.. One is Alfa the other is Beta. Before birth the Beta Protein is not expressed. The Hb protein found only during foetal development is Gamma, substitutes till birth. Abv. - Hb for Haemoglobin.

29 HOW IS Hb MADE? Like all proteins the blueprint for Hb exists in DNA (the material that makes up genes normally). An individual has 4 genes that code for Alfa Protein or Alfa Chains. 2 other genes code for Beta Chains. (2 additional genes code for Gamma Chains in the Foetus.) The Alfa and Beta Chains are in equal numbers despite the differing number of genes.the protein chains join in developing red cells and remain together for the life of the red cell.

30 HOW DO ABNORMAL Hb ARISE? The composition of Hb,, is the same in all people. The genes that code for Hb are identical through out the world. Occasionally however one of the genes is altered by any of a variety of accident that can occur in nature.these alterations in the genes (called MUTATION) are very rare. Since genes are inherited (half from mother and half from father) and they contain the information needed to make a protein. If a mutation produces an abnormal Hb.. Gene in a person, the gene will be passed on to their children. Most mutations in Hb produce no problem. Occasionally however the alteration in the protein can be problematic as it occurs in SICKLE CELL DISEASE and THALASSAEMIA.

31 WHAT HAPPENS IF A Hb.. GENE BURNS OUT? A separate gene determines the amino acid sequence of each of the globins chains. A single substitution in one type of Polypeptide Chain is accounted for replacement of one Nucleotide in a RNA Condone. The abnormality of Sickle Hemoglobin can be attributed to a change in a single purine base in the Condone which specifies the 6 th Amino acid of Beta Chain with the result that Glutamic Acid is replaced by Valine. This is called Point Mutation and accounts for several inherited HAEMOGLOBINOPATHIES like:- Hb C,Hb E, Hb D, Hb GUNHILL, Hb PUNJAB, Hb LEPORE, Hb FRIEBURG etc.

32 WHAT IS THALASSAEMIA? Genes can suffer to an extend that they no longer produce normal amount of HAEMOGLOBIN. Usually one of the sets of Hb.. Is affected:-the the Alfa Gene Set or the Beta Gene Set. if Beta Globin Gene fails to produce a normal quantity of beta chain the Alfa Gene Set will continue to produce a normal quantity of Alfa Chain protien. The result is that there is a imbalance in the amount of Alfa Chain and Beta Chain Protein. This imbalance is called THALASSAEMIA. If beta gene set fails it is BETA THALASSEAMIA and Alfa Gene Set failure is called ALFA THALASSAEMIA.

33 Why the disease is confined to a certain area? HAEMOGLOBINOPATHIES occur as a result of gene mutation. Very high frequency for harmful mutants are maintained in some areas of the world probably by strong selective pressure.

34 Red-Cell Dehydration in PATHOPHYSOLOGY and treatment of Sickle Cell Disease Abstract Cells with a markedly increased Hbs concentration are a prominent feature of sickle cell disease, as a consequence of the loss of K-Cl and water from the RBC. The extreme dependence of polymerization kinetics on Hbs concentration means that these dehydrated RBCs rapidly sickle when deoxygenated. Blockade of k loss from the RBC should therefore prevent the increase in Hbs concentration and reduce RBC sickling.

35 TWO ION TRANSPORT PATHWAYS, THE K-CL COTRANSPORT AND THE CA+ ACTIVATED K+ CHANNEL PLAY PROMINENT ROLES IN THE DEHYDRATION OF RBC. Hence the possible THERAPEUTIC strategy may be inhibition of K-CL co transport by increasing mg + in RBC,or the CA+ activated K channel by oral administration of CLOTRIMAZOLE. Deoxygenation leads to formation of Hbs polymers and cell sickling. Kinetics of Hbs Polymerization shows a LATENCY PHASE preceding the formation of polymer strands and their explosive growth inside RBC. This LATENT PHASE(DELAY TIME) is inversely proportional to the Hbs concentration in RBC.Small changes in Hbs concentration markedly affect Hb polymerization and cell sickling. The delay time plays a crucial role in the PATHOPHYSIOLOGY of sickle cell disease.

36 REHYDRATION THERAPY Contd..

37 The time required for the RBC to move from arterial end to cell-deoxygenating-then to venous end of the capillary network is called CAPPILARY TRANSIT TIME. If the delay time is shorter than the capillary transit time, sickling will occur in the capillaries hence VASSO-OCLUSIVE CRISIS. If the delay time is prolonged so that it exceeds the capillary transit time Polymerization and Sickling will occur in the venules---hence no vasso-oclusion and no crisis. One of the distinguishing characteristics of SICKLE RBC is the presence of cell dehydration. The fraction of red cells containing dense dehydrated cells with increased cell Hbs concentration, (to values of gm/dl compared with the normal 33gm/dl) has the highest percent of irreversibly Sickle Cells(ISC),which maintain their deformed shape even in the presence of normal oxygen tension.

38 NEWER THERAPIES Hydroxyurea Erythropoietin Butyrate Clotrimazole Nitric Oxide Fluocor TM Bone marrow transplantation Gene replacement therapy

39 If the DTN formula will be obeyed Not a single SS or DISEASE case will appear in the society. Let us join our hands to save the next generation from dreaded DISEASE cases.to elaborate more the DISEASE cases are very less about 0.1% and trait cases are about 7-10% 7 in the society. Hence for genetic counseling we get about 90% normal cases. One should not be panic and let us proceed for examination of blood for Hb - ELECTROPHORESIS before marriage. Our target is the pre-marital age group.take a vow that each couple is to adopt DTN formula. Special attention to be given for exclusion of THALASSAEMIA and G-6-PD deficiency also. In the next generation DISEASE cases will be nil. In subsequent generations trait cases will be also very less. It may so happen that we will have to search for trait cases.

40 THANK YOU P a d h y, - O rissa S ic k le C e ll D is e a s e s R e a s e r c h P ro je c t, B h a w a n ip a t n a S e n io r M e d ic in e S p e c ia lis t, N u a p a d a