Conference Papers
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This collection contains abstracts of conference papers, presented at local and international conferences by the staff of the Faculty of Medicine
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Item Chracterisation of beta giobin mutations in Sri Lankan patients with betathalassaemia intermedia(Sri Lanka Medical Association, 2013) Perera, S.; Silva, D.P.S.I.; Hapugoda, M.; Wickramarathne, M.N.; Wijesirwardhena, I.; Efremove, D.G.; Fisher, C.A.; Weatherall, D.J.; Premawardhena, A.P.INTRODUCTION AND OBJECTIVES: Patients with beta thalassaemia intermedia account for a third of patients attending thalassaemia clinics in Sri Lanka. They show immense phenotypic diversity, the genetic basis for which has not been identified so far. Objective were to characterise beta globin gene mutations in Sri Lankan thalassaemia intermedia patients and to determine how it to influences disease severity. METHODS: We identified 64 thalassaemia intermedia patients from the five main thalassaemia centers; Anuradhapura (n= 6), Kuruncgala (n= 4), Ragama (n= 42), Badulla (n=7) and Chilaw (n=5). Their beta globin DNA sequences were analyzed using ABI PRISM 313lx genetic analyser. RESULTS: Of sixteen patients identified to be homozygous for beta mutations, eleven carried mild beta alleles, IVSI 5 G_C (n= 10) and a rare homozygous promoter mutation - 90 C_T (N=l). Other five were shown to have different types of severe iputations in homozygous state. Nearly half the sample (n=39) was heterozygous for beta mutations. Of them 33 showed mild to severe mutation in one of the alleles IVSI-5 G_C (n=12), IVSI-1 G_A (n= 11) were the commonest. Two patients who were hetcrozygones for beta mutation had a highly unstable Hb variant haemoglobin Mizuho causing severe haemolytic anacma. Hb variants Hb G-Szuhu and Hb G-Coushatta were identified in two patients. CONCLUSIONS: We identified types of beta mutations in some patients with thalassaemia intermedia, which account for the clinical severity.Item Paraspinal extramcduallry erythropoiesis- a rare cause of spinal cord compression: two case reports(Sri Lanka Medical Association, 2004) Arambepola, M.; Premawardhena, A.P.; de Silva, S.; Olivieri, N.; Weatherall, D.J.INTRODUCTION: Extrameduallry erythropoiesis (EME) is characterized by the appearance of haemopoietic tissue outside the bone marrow. When EME occurs, albeit rarely, outside the liver and spleen problems may occur. We describe two patients with haemoglobin E- [β thalassaemia who had spinal cord compression, due to EME masses which was reversed with treatment with hydroxyurea and hypertransfusion. PATIENT A: Was a 27year old with HbE -(β thalassaemia. His mean pre transfusion haemoglobin level was 5.5 g/dl. He presented with a six-month history of progressive numbness of his legs. On examination he was found to be paraparetic. The magnetic resonance scan (MRI) showed external compression of the spinal cord between the 4th and 8th thoracic vertebrae. Patient was put on a hypertransfusion regimen and hydroxyurea and made a complete recovery within 4 weeks. Patient B: Was a 9 year old boy with a diagnosis of Haemoglobin E [β thalassaemia who presented with paraplegia which had developed over 3 months. His spinal MRI showed two masses one in the upper thoracic vertebrae and the other at the 1st lumbar level. He was commenced on hydroxyurea and hypertransfusiion to maintain pre-transfusion haemoglobin at >9.5g/dl) and his neurological recover was remarkable. Six months later he had no neurological deficit. DISCUSSION: The above cases highlight the potentially dangerous complications of EME when it involves the spinal cord. They also highlight that even lesions which are sufficiently large to cause complete paraplegia are potentially reversible. Hypertransfusion, hydroxyurea, surgery and previously been used with varying success. The problem remains in deciding the optimal method of management.Item An islandwide hospital based epidemiological survey of haemoglobinopathies and an assessment of standards of care in 23 centres(Sri Lanka Medical Association, 2017) Premawardhena, A.P.; Mudiyanse, R.M.; Jifri, M.N.; Nelumdeniya, U.B.P.; Silva, D.P.S.I.; Nizri, A.H.M.; Rajiyah, M.O.F.; de Silva, T.U.N.; Pushpakumara, K.R.C.; Dissanayake, D.M.R.; Jansz, M.; Rifaya, M.I.; Navarathne, N.M.U.S.B.; Arambepola, W.W.M.M.; Thirukumaran, V.; Mendis, D.; Weerasekara, K.P.; de Silva, N.N.; Vaidyanatha, U.S.de.S.; Mettananda, D.S.G.; Oliveri, N.F.; Weatherall, D.J.INTRODUCTION & OBJECTIVES: There is no database for haemoglobinopathy patients in Sri Lanka resulting in imprecise knowledge about the distribution and standards of care among patients managed in different centres in the island. The prevention programme commenced in 2007 is not centrally monitored. METHODS: We carried out centre-wise visitation and data gathering of patients with haemoglobinopathies in 2015. 23 centres were visited by researchers who gathered information from patient records. RESULTS: Data was obtained of 1768 patients. Three centres had over 200 patients each and another three centres had between 50-100 patients. There were 8 centres with less than 10 patients each. Beta thalassaemia major (BTM) accounted for 1207 (68.26%) patients. There were 363 patients (20.53%) with Haemoglobin E-β thalassaemia. Sickle cell-β thalassaemia accounted for 51 patients (2.88%). The mean age of BTM patients was 13 years (range 2-44). Ethnic distribution of the haemoglobinopathies (82.5% Sinhalese, 12% Muslims and 5.2% in Tamils) was discrepant to the national ethnic data. Islandwide mean number of new births of all thalassaemics recorded showed a reduction from 66/year between 2004 - 2009 to 48/year between 2010 to 2015.Clinical record keeping was not systematic in most units thus complication rates were hard to obtain. Death data were available only in two units. CONCLUSION: This study identified significant inconsistencies in haemoglobinopathy care between centres. Existence of small centres needs to be recognized by the Ministry of Health. A reducing trend of new births over the last decade was observed.Item “Silent” white matter changes in brain MRI in patients with haemoglobinopathies and their clinical significance(Sri Lanka Medical Association, 2016) Premawardhena, A.P.; Ranawaka, U.R.; Hapangama, A.; Pathmeswaran, A.; Hettiarachchi, S.; Salvin, K.A.; Pilapitiya, T.; Sanjaya, G.; Oilvieri, N.F.; Weatherall, D.J.INTRODUCTION AND OBJECTIVES: Increasing interest has been directed to the study of white matter changes and lacunar infarcts in patients with haemoglobinopathies which are thought to be clinically silent. Previous studies suggest an association with splenectomy and thrombocytosis. The objective was to assess the association of white matter changes in patients with haemoglobinopathies. METHOD: Older patients with haemoglobinopthies attending the Hemals Thalassaemia Unit were assessed by a specialist neurologist and simultaneously had MRI brain. Relevant clinical, biochemical and hematological data were collected. A non-thalassaemic control group (age and sex matched) too were assessed. RESULTS: There were 82 patients (25 Thalassaemia Major,24 Intermedia and 33 Haemoglobin E b thalassaemia) and 19 controls. Mean age of the study group was 32yrs. 21 patients (26%) had MRI changes (20%,29%,27% in the three groups respectively) (p=0.73). 10% of controls had MRI changes. 12 (60%) of the patients with MRI changes were asplenic whilst 53.2% without changes were asplenic (P=0.138). There was no difference in the two groups with platelet counts. (Mean platelet count 581 Vs. 452 (p= 0.709) 58% of patients and 53% of controls had headache as a symptom. Headache was commoner among those with MRI changes (85% vs 51.6%; p=0.008). CONCLUSIONS: The white matter changes in MRI occurred in all three sub groups of thalassaemic patients studied in high frequency. To our knowledge, this is the first report of the association of MRI changes with neurological symptoms in thalassaemic patients. The higher frequency of headache in those with MRI changes suggest that these changes may not be silent as previously believed.Item The clinical effects of excessive a globin genes : two family studies(Sri Lanka Medical Association, 2003) Premawardhena, A.P.; Fisher, C.A.; Rugless, M.; de Silva, S.; Perera, A.W.V.S.; Olivien, N.F.; Weatherall, D.J.INTRODUCTION: Globin chain imbalance is the central pathogenic abnormality in the thalassaemias, a condition where globin gene expression is reduced. Conversely, the inheritance of excess globin genes too may affect the phenotype. However such examples are rarely found. OBJECTIVES: To describe two families in whom the co-existence of excess a genes was noted together with p - thalassaemia trait. METHODS: During the routine P - globin gene analysis in patients attending the Thalassaemia Unit of the Kurunegala Hospital, two patients were identified to have thalassaemia intermedia phenotype, but with just one (3 - thalassaemia mutation. The clinical details of these patients and their families were studied in detail as was their h'aematological and genetic data. RESULTS: We describe two families in which the propositus had inherited six and eight a - genes respectively together with a single p - thalassaemia mutation. Both patients had the thalassaemia intermedia phenotype. The family members who did not inherit any thalassaemic mutations too had varying, but often marked hypochromic microcytosis. DISCUSSION: We describe the first ever family study of a patient with the combination of 8 a - genes and p - thalassaemia trait. We also describe another family where a member had 6 a - genes together with p thalassaemia trait. This highlights yet another mechanism for the intermedia phenotype in patients with a solitary (3 - globin gene mutation. It also highlights the need for the study of a globin genes in patients with unexplained hypochromic microcytic anaemia.Item The worldwide prevalence of the UGT-1A1 promoter polymorphism as a contributor for phenotypic variability in thalassaemia(Sri Lanka Medical Association, 2003) Premawardhena, A.P.; Lilt, Y.T.; Fisher, C.A.; Clegg, J.B.; Weatherall, D.J.INTRODUCTION: The number of TA repeats in the promoter region of the UGTIA1 gene is involved in fine-tuning of the serum bilirubin level. People who inherit more TA repeats than in the wild type (6), tend to have higher than normal Serum bilirubin levels. When homozygosity for 7 repeats is co-inherited with hereditary anaemias the patients have an elevated serum bilirubin level and an increased incidence of gallstone formation. OBJECTIVES: To investigate the pattern of UGTIAI promoter genotype in several diverse populations across the world. METHODS: A fluorescent labeled PCR method was designed which would amplify the region of interest of the UGTIAI gene. The PCR products were separated using (PAGE) polyacrelymide gel electrophoresis. DNA samples for the study were collected from people from 15 countries, from 5 continents. RESULTS: We found remarkable diversity of the UGTIAI polymorphism amongst people of African origin. The haplotype 7/7 was found in very high frequencies in India. Sri Lanka and Bangladesh, and was extremely rare amongst people of Southeast Asian origin. The Europeans and the Africans had intermediate frequencies. DISCUSSION: These results suggest that in people of Southeast Asian origin, a group that has a high prevalence of thalassaemia and other heamoglobinopathies, the UGTIAI polymorphisms are unlikely to be important genetic modifiers of the phenotype. However, Sri Lankans and other South Asians are very likely to be influenced by this polymorphism. These results also support the theory of African origins of Homo sapiens.Item Response of jaundice to phenobarbitone in thalassaemic patients co-inheriting Gilbert syndrome(Sri Lanka Medical Association, 2004) Premawardhena, A.P.; Arambepola, M.; Fisher, C.A.; Oliveiri, N.F.; Weatherall, D.J.INTRODUCTION: Genetic mutations causing Gilbert's syndrome are found in up to 20% of Sri Lankans. The co-existence of Gilbert's syndrome together with haemolytic anaemias can lead to significantly higher level of serum bilirubin and also an increased risk of gall stone formation. In such patients persistent jaundice can be a distressing symptom. We used the hepatic enzyme inducer, phenobarbitone in a pilot study to treat symptomatic hyperbilirubinaemia in patients with haemoglobin E- p thalassaemia and Gilbert' syndrome. MATERIAL AND METHODS: Seven haemoglobin E (3 thalassaemia patients attending the Thalassaemia Unit of the Teaching Hospital Kurunegala in whom jaundice was a significant symptom and Gilberts syndrome mutations had been previously detected were started on phenobarbitone (15mg tds). No patients with predominant direct hyperbilirubinaemia were included in this study. Bilirubin levels were noted prior to the commencement of the study and were repeated 3 months later. RESULTS: Of the 110 patients with haemoglobin E [3 thalassaemia 26 were positive for the Gilberts syndrome mutation. Seven patients were concerned about the excessive yellow discoloration of their sclerae and skin. Their ages ranged from 15 to 24 years. The mean pre-treatment serum total and indirect bilirubin were 137.8 and 113.8 /xmol/1 and the post treatment mean 68.35 and 52.6 jimol/1 respectively (a mean reduction of 49%). The biochemical result was associated with a remarkable clearance of jaundice. The quality of life of these patients significantly improved as a result. There were no drop outs from the study and no side effects were noted in any of the participants. DISCUSSION: Phenobarbitone used at 15 mg tds seems an effective and safe method for treating the aesthetically unacceptable symptom of jaundice in patients with Gilberts syndrome. The lack of complete normalisation of the bilirubin levels may suggest the effect of the underlying haemolysis, the inadequacy of the dosage of phenobarbitone or the co-existence of mutations causing non-inducible hyperbilirubinaemia.Item Correlation of genotype with phenotype in beta thalassaemia intermedia in Sri lanka(Thalassaemia International Federation, 2015) Perera, P.S.; Silva, D.P.S.I.; Hapugoda, M.; Wickramarathne, M.N.; Wijesiriwardena, I.; Efremov, D.G.; Fisher, C.A.; Weatherall, D.J.; Premawardhena, A.Abstract AvailableItem Clinical and molecular heterogeneity among Beta Thalassaemia Intermedia in Sri Lanka(Sri lanka Medical Association, 2015) Perera, P.S.; Silva, D.P.S.I.; Hapugoda, M.; Wickramarathne, M.N.; Wijesiriwardena, I.; Efremov, D.G.; Fisher, C.A.; Weatherall, D.J.; Premawardhena, A.INTRODUCTION AND OBJECTIVES: Patients with beta thalassaemia intermedia (Tl) unrelated to haemoglobin E/beta thalassaemia account for an important minority in thalassaemia clinics in Sri Lanka. We investigated the genotypic/phenotypic diversity of this small group of patients. METHOD: Fifty Tl patients identified from five thalassaemia centers were clinically assessed and divided in to severity groups based on agreed criteria. Genetic analysis was done by PCR based techniques. RESULTS: There were 26 mild, 12 moderate and 12 in the severe groups. Ages ranged from 5-65 years. Mean haemoglobin of the whole group was 7.8g/dl. Age at presentation ranged from 3 months - 57 years (mean 16.8yrs) and varied according to severity; 17.8 years in mild to 4.8 years in severe group. 86% were on intermittent transfusions whilst 14% were never transfused. Mean total transfusion load in the three groups ranged from 6, 28 to 89. Majority (60%) had splenomegaly and 12% were splenectomised. The median spleen size of each severity group was 0, 4.5 and 7.5 cm respectively. Thalassaemicfacial features were not_ demonstrable in the majority (86%). Genetic analysis identified the commonest mechanism for Tl to be coexistence of a single beta mutation with excess alpha genes (56%). None of these patients had severe phenotype. Coexistence of two beta mutations with alpha thalassaemia invariably gave rise to severe phenotype. Other mechanisms gave rise to varying disease severity. CONCLUSION: This study highlights the remarkable phenotypic variations in beta Tl in Sri Lanka and identifies some genetic mechanisms which can explain this variation.Item Micro mapping of common alpha thalassaemia deletions (3.7 kb, 4.2 kb) in Sri Lanka and assessment of the contribution of alpha thalassemia to hypochromic microcytosis(Sri Lanka Medical Association, 2014) Rodriao, B.K.R.P.; Perera, H.L.; Branava, U.; Manamperi, A.A.P.S.; Weatherall, D.J.; Premawardhena, A.P.INTRODUCTION AND OBJECTIVES: The exact prevalence and distribution of a thalassaemia in Sri-Lanka is not known, and it is widely believed that single gene deletion of a thalassaemia does not cause hypochromic rnicrocytic anaemia. To micro map the distribution of the common athalassaemia deletions in Sri Lanka and to assess its contribution to hypochromic microcytosis in the community. METHODS: A national survey on haemoglobin disorders was carried out between 2009-2010 covering all 25 districts where 300 school children of each district were screened for haemoglobin disorders and anaemia. As part of the survey 3.7 kb and 4.2 kb common alpha plus deletions were analysed using polymerase chain reaction (PCR) Gap PCR in two groups. Group 01,,2038 subjects with hypochromTc rnicrocytic anaemia [MCV < 80 fl; MCH < 27 pg], Group 02, 1305 subjects with normal MCV and MCH. RESULTS: Overall prevalence of a thalassaemia in Sri-Lanka was 9.49 % of which 3.7kb was the commonest deletion (8.27%) whilst the 4.2kb deletion accounted for 1.14%. The distribution of a thalassaemia showed remarkable variabiiity within the districts in Sri Lanka ranging from (16.33%) in Kurunegala to (3.86%) in Galie. Contrary to the present belief a thalassaemia due to single gene deletions is most often associated with hypochromic microcytic anaemia (95%) than not (5%).