1. Haemoglobinopathies Sickle cell disease Thallassaemia

2. MIMS : DNA Transcription Why does Sickle cell disease occur? What is the molecular basis? What happens to blood cells in sickle cell anaemia? What about the inheritance? What are the clinical features and complications?

3. What happens in Sickle cell disease? Haemoglobin S differs from haemoglobin A by the substitution of valine for glutamic acid at position 6 in the beta chain. Haemoglobin S undergoes liquid crystal formation as it becomes deoxygenated. Polymerised HbS forms rod-like structures with a diameter of about 11.6 nm. It is thought that there is a tendency for normal haemoglobin molecules to form similar arrays and that the beta 6 valine substitution stabilises these molecular stacks. When HbS accounts for less than 40%, sickling only occurs under conditions of severe hypoxia.

10. The Sickling disorders consist of: heterozygous state or the sickle cell trait (AS), homozygous state or sickle cell disease (SS) compound heterozygous state for haemoglobin S with other structural haemoglobin variants or thalassaemias

11. What happens? Haemoglobin S differs from haemoglobin A by the substitution of valine for glutamic acid at position 6 in the beta chain. Haemoglobin S undergoes liquid crystal formation as it becomes deoxygenated. Polymerised HbS forms rod-like structures with a diameter of about 11.6 nm. It is thought that there is a tendency for normal haemoglobin molecules to form similar arrays and that the beta 6 valine substitution stabilises these molecular stacks. When HbS accounts for less than 40%, sickling only occurs under conditions of severe hypoxia.

12. Sickle cell trait Sickle cell trait occurs in heterozygotes where approximately 40% of the haemoglobin is HbS, the rest being HbA, which interacts only weakly with HbS during the processes of gelation. The heterozygote has little tendency to sickle except under conditions of severe hypoxia, ie when saturation is less than 40%. A patient with sickle cell trait has no splenomegaly; growth, development and life-expectancy are normal. Patients may exhibit hyposthenuria - reduced ability to concentrate urine - due to diminished vasa recta flow, and small renal infarcts may also occur. Sickle cell trait can be detected by exposing the red cells in vitro to a very low oxygen tension - Sickledex test - to initiate sickling, and by electrophoresis to show the relative globin components

13. Inheritance

14. Epidemiology The frequency of sickle cell disease is: 1 in 4 in West Africa 1 in 10 in Afro-Caribbeans HbS is also common in Cyprus, Greece, Italy, the Middle East and in populations who originate from these areas. Sickle cell anaemia is a significant problem in the black population of the USA and the Caribbean. It is estimated that 100,000 homozygotes are born each year in Africa, 1500 in the USA, 700 in the Carribean, and 140 in the UK.

15. Where does sickle cell disease occur? Africa African Americans Arab nations Latin Americans Italians Greece Turkey

16. Diagnosis history and examination blood - shortened red cell survival results in: –low haemoglobin, usually around 8 or 9 g/dl –normochromic normocytic anaemia of moderate degree and sickle cells present –target cells and sickle cells on the blood film –the reticulocyte count is usually elevated to 10-20% the diagnosis is confirmed by identification of HbS on a haemoglobin electrophoresis gel prenatal diagnosis: –amniocentesis and chorionic villus sampling are employed –extracted DNA may be characterised by restriction fragment polymorphism analysis or Southern blotting with a mutation-specific oligonucleotide

18. Complications pigment stones, in up to 33% of 15 year olds folate deficiency functional hyposplenism, from splenic atrophy due to the recurrent sickling pneumococcal septicaemia as a result of loss of splenic function stroke occurs in up to 8% of patients by age 14 –usually the result of large vessel disease –recurrences cluster within three years of the first event –stroke may be predicted by transcranial doppler or by the presence of sleep apnoea salmonella osteomyelitis chronic leg ulceration impaired renal-concentrating ability - the osmolarity of the urine is rarely above 800 mOsm per litre - and episodic haematuria

19. Clinical features Homozygotes are not anaemic from birth. A progressive anaemia develops from about 3 months of age. The chronic haemolysis may result in exogenous erythropoeisis, with frontal bossing. Repeated splenic infarction results in hyposplenism and an increased rate of infection. Patients may lead normal lives free of complications but for the majority, their life is complicated by crises of varying frequency, severity and type: painful aplastic sequestration lung abdominal

32. Prognosis Sickle cell disease is very variable in its outlook. In rural parts of Africa children rarely survive beyond the first year. On the other hand in developed Western countries many patients with sickle cell anaemia survive well into adult life. The commonest cause of death is infection. In the USA the median life expectancy in HbSS is: 42 for men 48 for women In the USA the median life expectancy in HbSC is: 60 for men 68 for women Factors which modify the condition are elevated levels of fetal haemoglobin and the co-existence of thalassaemia. For example, in India and parts of Eastern Saudi Arabia patients are often asymptomatic with sickle cell anaemia because they produce very high levels of foetal haemoglobin. Most deaths from this condition occur in the second six months of life.

33. What about other genetically inherited Haemoglobinopathies? Thallasaemia Imbalance of alpha and beta chains of Hb, precipitates in red cells and shortens life of red cells – causes haemolysis Major – homeogenous Minor – Heterogenours – Beta Thal minor

34. What about other genetically inherited Haemoglobinopathies Haemoglobin Haemoglbin C Haemoglobin SC Other inherited causes of haemolytic anaemia G-6-P-D deficiency Pyruvate Kinase deficiency Spherocytosis