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Mecanismes moleculaires de la variabilite genetique d'expression de s hemoglobines majeures : Facteurs genetiques du pronostic et perspectives therapeutiques


- To understand the genetic and molecular bases of the variable phenotypic expression of major hemoglobinopathies and in particular sickle cell disease (SCD);
- To rationalise the therapeutic induction of foetal haemoglobin (HbF) in hemoglobinopathies by pharmacological means.
- In the social context of Benin, an affected new-born with SCD is rarely retrieved for regular clinical follow-up. We circumvented this difficulty by focusing our attention on identifying pregnancies' at-risk for giving birth to a child with SCD and by providing information and counselling. A total of 2300 pregnancies was followed : 5% of the pregnancies with SCD were managed clinically. 1028 new-borns were available for neonatal screening and 12% had SCD with 64% traits. 91 new-borns entered the clinical surveillance programme (75% compliance of the parents) which included prophylaxis against infections. Among them 25% had an associated G6PDH deficiency (G6PDA-). The outcome of these studies will be assessed only in year/3.

- Contribution to the culture of continuous learning : participation to the first regional specialised course of haematology on SCD held at Cotonou BENIN (12-16 Dec. 1995) with the aim of disseminating the state of the art of biological and clinical aspects of SCD to trainees from 11 different African countries. A "SCD network" among these countries has been created. The prevalence of G6PD deficiency by "spot test" in Mauritius is 5.5% (school and blood donor screening n = 1435). Molecular analysis (PCR RFLP, SSCP, Nucleotide sequencing) confirmed the phenotype data but also revealed the nature of mutant alleles (G6PD Orissa, Kerala Kalyan, Med-Union, Hammersmith, A-) consistent with the ancestral population input. 16 G6PD novel variants await characterisation. We could not observe SCD in association with G6PD deficiency in this population. More SCD cases need to be screened. Transfer of knowledge and know how was extremely efficient and a specialised centre for hemoglobinopathies was set up and now functions autonomously. Extensive comparison of regulatory region polymorphisms of the á-locus in Indian and different African sickle cell traits (taking into account the a globin gene status) revealed that the sickle cell gene from India has intrinsic thalassemic characteristics with resulting reduced expression of HbS and thus might contribute along with elevated HbF expression to the attenuated form of the disease in India as compared to severe form in Africa. A large three generation family consisting of 60 members with 16 presenting a á-globin gene cluster dependent HPFH (moderate increase in HbF in the basal state with further increase in response to anaemic stress) from Algeria is presently under investigation for defining the molecular basis of such forms of HPFH. Clinical trial of hydroxyurea (HU) treatment for the past 2 years of the first generation African SCD children followed at Paris (4 boys and 3 girls, age range 4-16 years) revealed :
- an excellent compliance;
- all were "responders" in terms of increase in HbF;
- SCD with "Senegal" haplotype had higher increment in HbF than others;
- absence of HU dose - dependence in HbF increase;
- beneficial affect of HU (in terms of hospitalisation for vaso occlusive crisis or acute thoracic syndrome/patienVyear is not limited to increment to HbF alone;
- HU caused reduction in serum iron, supplementation of which, further increased the HbF level all leading to the conclusion that UH treatment appears as an efficient cost-effective alternative for situations where exchange transfusion was the role (excepting strokes) and thus avoiding transfusion-associated risks.
- To appreciate :
- the feasibility of a comprehensive program on SCD based upon neonatal screening, parental education and early medical follow-up in an African setting;
- the impact of this program on the related morbidity and mortality (natural history).
- Epidemiology of G6PD deficiency and its interaction with SCD;
- Comparison of severe form of African sticklers with mild ones from India to assess the prognostic value of associated genetic modifiers (genetic polymorphism of the critical regulatory DNA elements of the alpha-globin gene cluster, alpha-globin gene status, genetic propensity to express HbF;
- Hydroxyurea treatment in paediatric SCD patients and follow up;
- Recruitment of families for studying genetic modifiers (unlinked to the alpha-globin gene cluster), involved in the genetic control of HbF expression (F-cell genetics).

Funding Scheme

CSC - Cost-sharing contracts


Institut National de la Sante et de la Recherche Medicale
48, Bd Serurier 48 - Batiment Ecran +4 Et +5, Adr 12 - Paris-nord
75019 Paris

Participants (7)

Centre National Hospitalier et Universitaire Cotonou

10 Cotonou
Centre de Recherches Médicales

Hôpital Robert Debré
48 Boulevard Serrurier
75935 Paris
Hôpital Tenon
4 Rue De La Chine
75970 Paris
Institut National d'Etudes Supérieures en Sciences Médicales d'Alger
Chu Mustapha
16000 Alger
Organisation de Lutte Contre les Endémies en Afrique Centrale

10 Yaoundé
Royal Postgraduate Medical School
United Kingdom
150,Du Cane Road
W12 0NN London