Thalassemias:general aspects and molecular pathology

Transcription

1 Thalassemias:general aspects and molecular pathology Prof. Renzo Galanello Pediatric Clinic 2 University of Cagliari Ospedale Regionale Microcitemie-ASL8

2 HEMOGLOBINOPATHIES CLASSIFICATION Structurally abnormal hemoglobins silent symptomatic Reduced synthesis of normal globin(s) thalassemias Reduced synthesis of abnormal globin(s) thalassemic hemoglobinopathies

3 Classification of carrier for most common hemoglobinopathies β-thalassaemia typical atypical α-thalassaemia typical: homozygous and heterozygous α +, heterozygous α, non- deletion defects silent: heterozygous α + δβ-thalassaemia δβ + δβ 0 Hereditary persistence of fetal haemoglobin pancellular heterocellular Haemoglobin variants: common variants (Hb S, Hb E, Hb C) unstable hyperunstable altered oxygen affinity M haemoglobins asymptomatic

4 Thalassemia and malaria

5 Hereditary transmission of β-thalassemia 50% 50% 50% 25% 25% trait normal affected β-thalassemia trait

6 Epidemiology of thalassemia: global estimate Carrier rate 4.9% of world populat. Total carriers 300,000,000 Newborn carriers with Hb disorders 6.1% Newborns with a major Hb disorders 2.1/1000 Affected births/year 307,000 (WHO 1998)

7 CARRIERS FOR BETA -THALASSEMIA IN ITALY 2.4 % 0.4 % 4.5 % 12.0 % 2.0 % ~ 3.0 % 0.8 % 2.0 % 5.9 % 5.0 % 8.0 % 10.3 % 3.0 % ~ 9.0 % 7.0 %

8 RELEVANT DEMOGRAPHIC DATA OF SARDINIAN POPULATION (Year 1974) number inhabitants number of newborn/yr birth rate of thalassemia major 1:250 total number new cases of thalassemia major/yr 120

9 Main reasons for changing of thalassemia epidemiology Fall in total birth rate Prevention programs Population movements

10 β Τhal carriers in EU : autoctonous and in ethnic minorities 5% 4% 3% 2% 1% 0% 5% 4,80% 3,80% 3% 3% 1,50% 1% 0,70% DE ES UK NL FR IT Natives Ethnic min. Source : Prevention of Thalassemias and other Haemoglobin Disorders.Vol 1 TIF

11 Organization and ontogenesis of globin genes LCR CHROMOSOME 11 ε G γ A γ δ β CHROMOSOME 16 ζ α α Hb Gower I ζ 2 ε 2 Hb Gower II α 2 ε 2 Hb Portland ζ 2 G γ 2 ζ 2 A γ 2 Hb F α 2 G γ 2 α 2 A γ 2 HbA 2 HbA α 2 δ 2 α 2 β 2 Embryos Fetus Adult

12 Model of the structure af a typical globin gene LCR β globin gene GT ATG AG GT TGA or TAA or TAG AG AATAAA E CACCC CCAAT ATA CA (A/T)GATA(A/G) (A/T)GATA(A/G)

13 Schematic representation of the process of β-globin gene expression β globin gene pre mrna initial transcription NUCLEUS post-transcriptional transcriptional modifications mrna cap cap Poly A Poly A Globin chain CYTOPLASM

14 Type And Distribution Of β-thalassemia Mutations CCAAT CACCC CACCC UTR IVS 1 IVS 2 3 UTR CATG ATAAA GT AG GT AG TAA ATAA Promoter 5 & 3 UTR RNA Processing ATG Nonsense codons Frameshifts Β + Β + Β +, βº βº βº βº Thein et al

15 PATHOPHYSIOLOGY OF β THALASSEMIA α β mrna α globin Excess α globin + heme β globin Ineffective erythropoiesis Intramedullary distruction

16 The timeline of the expression of the human globin genes from early stages of fetal development to the changes that occur at birth and in the first year of life Schechter, A. N. 2008

17 Globin chain synthesis with β-thalassemia mutations α γ α HbA β γ HbF 4 weeks Brith 1year

18 Pathophysiology of β-thalassemia Normal production alpha chains Absent or decreased beta chains Excess unstable alpha tetramers Ineffective erythropoiesis Absent or decreased Hemoglobin A Hemolysis ANEMIA 18

19 Peripheral Blood Smear β-thalassemia major normal

20 β-thalassemia: Clinical Phenotypes Silent Carrier with normal phenotype Requires DNA testing for detection Trait Slight anemia with low MCV Intermedia Major Late onset: > 2 years of age Moderate anemia: Hb > 7-10 g/dl Minimal or sporadic transfusions Diagnosis in first 2 years Severe anemia: Hb < 7 g/dl Lifelong transfusions MCV = mean corpuscular volume; Hb = hemoglobin.

21 Beta-thalassemia:genotypic/phenotypic heterogeneity genotype heterozygote homozygote/genetic compounds phenotype silent haematologic phenotype thalassemia intermedia thalassemia major mild severe sporadic tfx tfx dependent