1. Haemoglobin disorders

2. There are approximately 1200 different types of Haemoglobin Normal Haemoglobin: consists of Four Globin chains each holding a molecule that contains iron Globin A complex protein containing a precise number of amino acids

3. Adult Haemoglobin (Hb AA) = 4 Globin Chains 2 Alpha 2 Beta Globin Chains Fetus and New Born Infant Mainly fetal haemoglobin (Hb F) 2 Alpha 2 Gamma Globin Chains

4. Production of the three types of Globin Chains Controlled by three different pairs of genes Alpha Genes are active in fetal and adult life Gamma Genes active in fetal life then replaced by Beta Genes about the time of birth

5. Abnormalities or Variations within the Globin Chains In Thalassaemia leads to an Absence of production or Diminished production of Haemoglobin

6. Thalassaemia Reduced production of Beta Globin chains The blood cells are small Microcytic Do not contain as much iron Hypochromic

7. Haemoglobinopathies Thalassaemia is an inherited blood disorder affecting the production of normal adult Haemoglobin The frequency of many Haemoglobinopathies including Thalassaemia relates to the geographic distribution of MALARIA. Estimated that over 6% of the population of England and 11% of births are in groups at risk of Haemoglobin disorders.

8. Thalassaemia Trait Carrier state for the Disorder often confused with Iron deficiency due to reduced MCV and MCH Check serum Ferritin Normal Hb A2 1.5-3.5 Hb A2 above 3.3-Diagnostic

9. Most Common Haemoglobinopathy Traits Beta Thalassaemia Trait Haemoglobin E Trait Haemoglobin D Haemoglobin C Haemoglobin S Alpha-Zero Thalassaemia Trait Alpha-Plus Thalassaemia Trait

10. Known as Autosomal Recessive disorders Mode of Inheritence

11. When one parent carries the trait In each Pregnancy There is a 1 in 2 chance that the child will be a carrier There is a 1 in 2 chance that the child will be normal

12. Where both parents are carriers of the disorder In each Pregnancy There is a 1 in 4 chance the child will have the disorder There is a 1 in 4 chance that the child will be normal There is a 1 in 2 chance that the child will be a carrier of the trait

13. Major Haemoglobin Disorders Beta Thalassaemia Major Haemoglobin E/Beta Thalassaemia Alpha Zero Thalassaemia (Hydrops Fatalis) Haemoglobin H Disease Sickle Cell disorders

14. Major Haemoglobin Disorders The major Haemoglobin disorders are life long illnesses. Most are forms of anaemia and some more severe than others, they fall in to two groups: Thalassaemias Sickle Cell Disorders

15. Thalassaemia Most common single gene disorder First recognised in 1925 by Thomas Cooley Also known as Cooley’s Anaemia Later it was noticed that many patients with the disorder came from the mediterranean region hence the Greek word “Thalassa” meaning from the sea.

16. Prevalence Mainly found in people with origins from Pakistan, India, Bangladesh, Sri-Lanka and countries from around the mediterranean. In the UK 78% of babies with the disorder are Asian

17. Beta Thalassaemia Most Common type of Thalassaemia A disorder of the Beta Globin genes, affecting adult Haemoglobin. Beta Thalassaemia trait in the carrier form has no affect upon the individuals general health

18. Beta Thalassaemia Major Symptoms arise from about 3-6 months of age Children with Thalassaemia Major are healthy at birth due to the presence of fetal haemoglobin They become severely anaemic (Typical Haemoglobin level below 7gm/dl) before they reach 2 years of age

19. Untreated children with Thalassaemia Major are severely anaemic failure to thrive Irritable Stunted growth Enlarged liver and spleen

20. 17 year old girl with Beta Thalassaemia Major Showing reduced stature Height 134cms and delayed pubertal development. Since circulating growth hormone levels are usually normal, the lack of growth is due to endocrine organ failure.

21. Skeletal Changes The Bone Marrow expands greatly as it tries (uselessly) to make red cells. This weakens and distends the bones, particularly the bones of the face and skull. This is why the children with Thalassaemia Major develop a characteristic facial appearance.

23. Splenic Changes During the course of the disease the spleen, which normally destroys the old red blood cells begins to destroy young red blood cells worsening the anaemia.

25. Mortality Most untreated children die from anaemia or infections before 2 and at most 5 years of age. Treatment The current treatment for Thalassaemia Major is blood transfusions every 4 weeks for life. This results in good health mainly in the short term.

26. Side effects of this treatment Blood contains a great deal of iron which gradually accumulates in the body. Iron can damage the liver, heart and other major organs. Unless it is removed it can cause premature death through organ failure. The most common being Heart failure, this occurs between 16-30 years of age.

27. Drug Treatment Iron can be removed by a drug called Desferrioxamine, it is infused subcutaneously through a fine needle attached to a small pump or syringe driver. Its action is to bind with the iron and then be excreted in the urine. This procedure takes 8-12 hours and has to be carried out 5-6 times a week.

28. Compliance Having the treatment regularly patients with Thalassaemia Major can live up to 50 years plus leading a reasonably normal life. However this form of treatment is very hard to comply with and as no ill effects are experienced until organ damage is sustained the main factor contributing to premature death particularly in young people is Organ failure due to Non-compliance.

29. Innovations in current Drug Therapy Oral chelator’s _ L1 Deferiprone and the latest Exjade Deferasirox. (L1 has been on the market for 10 years initially on a named patient basis only but is now available and commonly used in combination therapy with Desferioxamine Exjade has recently been developed and trialled, relatively free of side effects, the iron is excreted predominately in the faeces.

30. Innovations in Current Treatment Combination drug therapy specific to the individual as need. MRI and more recently the Ferriscan technique specific in identifying organs which are affected by iron overload Baxter Pumps Home delivery of equipment and preparations ready to use

31. Bone Marrow Transplant This procedure is available to children preferably below 7 years of age who have a Matching HLA (Human Leucocyte Antigen). Genotypically matched sibling only About 30% of patients will have a sibling match

32. Complications Arise due to Graft V Host Disease, which may be acute or chronic. A life threatening disorder affecting the skin, gastro-intestinal tract, liver and with rejection of the bone marrow. The mortality and morbidity rate is between 93% and 91% transplant related mortality of 7% At risk factor ( Liver disease) & poor chelation history, disease free survival 79% & 58% with 10% risk of death during proceedure

33. Alpha Plus Thalassaemia (Otherwise known as Alpha Thalassaemia Trait) A carrier state of one or two gene deletion This is a mild form of Alpha Thalassaemia It can be difficult to identify as the haemoglobin is only minimally lowered and electrophoresis is normal Definitive diagnosis requires DNA analysis

34. Alpha Zero Thalassaemia Major Otherwise known as Hydrops Fetalis or Bart’s Hydrops Fatalis This occurs when the fetus inherits Alpha zero Thalassaemia from both parents The fetus has no Alpha genes and can not make an alpha chains This means that it cannot make any fetal haemoglobin.

35. Alpha Zero Thalassaemia This is a fatal anaemia The Fetus Develops normally for the first 5 months of pregnancy, sometimes longer then growth slows, its heart begins to fail and its body and the placenta becomes swollen with fluid.

36. The Mother Can develop Pre-Eclampsia or even Eclampsia The baby may be born at any time between the 28 th and 42 nd week of pregnancy Complications at delivery Include obstructed labour and excessive bleeding, if the baby has not died in the womb it will die shortly after birth.

37. Alpha Zero Thalassaemia Major. There is no treatment For couples at risk of having a baby with this disorder, there is a 1 in 4 chance of a still birth or neonatal death in every pregnancy

38. PREGNANCY Early booking with joint management by the Obstetrician and Haemotologist Correction and prevention of anaemia Serial scans for fetal growth Prompt treatment of infection Beta Thalassaemia Major

39. The Fetus The fetus is not directly affected in Utero by Beta Thalassaemia as it is protected by fetal haemoglobin. Symptoms start to arise when the infant is unable to produce normal adult haemoglobin from six months of age

40. Ante- Natal Diagnosis If both partners are Carriers Pregnancy identified as “At Risk” Chorionic villus sampling carried out between 10-12 weeks Amniocentesis from 15 weeks Fetal blood sampling some times carried out in late pregnancy for rapid DNA analysis

41. Pre-Natal Diagnosis It is well documented that the most important factors influencing a couples choice for or against PND Severity of the disorder Stage of pregnancy at counselling

42. Counselling Sensitive to the Needs of the couple Issues such as Level of Risk Pre -natal diagnosis and in the case of an affected child informed choice and support Preferably before Pregnancy