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Dotti mngie 21 maggio

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  • 1. HSCT in un caso di MNGIE: follow up di un anno Maria Teresa Dotti Dipartimento di Scienze Neurologiche, Neurochirurgiche e del Comportamento Università di Siena
  • 2. Therapeutic approaches for LSDs Parenti, EMBO Mol Med 2010
  • 3. Stem Cell Transplantation 1968• The principle : hematopoietic stem cells of the patient are replaced by cells of a donor able to build up sufficient amounts of enzyme to correct the deficient activity and to be clinically efficient
  • 4. MNGIE (mitochondrial neurogastrointestinal encephalomyopathy)• Trasmissione AR• Mutazioni gene timidina fosforilasi (TYMP)• Alterazioni metaboliche: deficit enzima TP, aumento timidina (dThd) e deossiuridina (dUrd)• Danno mtDNA disfunzione catena respiratoria
  • 5. MNGIE/ quadro clinico• Esordio infantile-adolescenziale• Andamento progressivo• Manifestazioni cliniche multisistemiche (neurologiche ed gastrointestinali)• Disturbi gastrointestinali (vomito, dolore, gonfiore, pseudo- occlusione)• Cachessia• Ptosi/oftalmoparesi• Debolezza (miopatia)• Polineuropatia• Leucoencefalopatia
  • 6. MNGIE/ quadro clinico lieve
  • 7. MNGIE/ epidemiologia• Malattia rara• <200 casi descritti/incidenza sconosciuta• Sicuramente sottostimata
  • 8. Caso clinico• Sabrine, 21 anni• Genitori consanguinei• Incidente stradale cervicobrachialgia, parestesie• EMG: polineuropatia sensitivo-motoria• Esame neurologico: sfumata ptosi, areflessia• 37 kg (BMI 16,44), H 150 cm
  • 9. Caso clinico• Anamnesi: 15 a, episodi ricorrenti di dolore addominale, vomito, diarrea, stanchezza Lattato: 2.3 mmol/l TP: assente Timidina e deossiuridina: 9.0 µmol/ L e 1.15 µmol/L Analisi Genetica: mutazione c.1249 dupC gene TYMP
  • 10. Caso clinico/HSCT• Trapianto: 7 Aprile 2010, BM donatore il fratello sano, HLA compatibile• Trattamento mieloablativo (Busulfan e Fludarabina)• Profilassi GVHD : Ciclosporina e Metotrexate• Chimerismo 100% (giorno 30)• Follow up:• 1 mese, completa risoluzione disturbi gastrointestinali• 3 mesi, riduzione stanchezza• 12 mesi, 37 kg (34 kg post-trapianto), aumento forza (MRS: 80 prima e 96 dopo HSCT ), aumento VCs, lattato 1,5
  • 11. 2500 TP activity (normal, 75-1640) 2000Buffy Coat TP (nmol/h/mg-prot) 1500 1000 500 0 Time 0 16 days 35 days 45 days 60 days 3 months 6 months 8 months 10 months 12 months Time Post-Transplant
  • 12. Plasma dThd levels Plasma dUrd levels 18 16 14 12Nucleoside levels 10 (µM) 8 6 4 2 0 Time 0 15 days 30 days 45 days 60 days 3 months 6 months 8 months 10 months 12 months Time Post-Transplant
  • 13. 37th Annual Meeting of European Group for Blood and Marrow Transplantation – 3/6 aprile 2011 – Parigi•17 pazienti sintomatici trapiantati (19-41 anni)• 7 donatori familiari, 10 no• 10 BM, 5 PBSC, 2 CB• Mortalità: 8 pazienti• 9 tuttora viventi
  • 14. Mngie/terapia• Rimozione diretta metaboliti tossici  Dialisi peritoneale• Replacement enzima  trasfusione piastrine• HSCT
  • 15. As occurs with many monogenic disorders that can benefit from an allogeneic HSCT, MNGIE is probably a very good candidate for hematopoietic stem cell gene therapy (HSCGT)
  • 16. • …. the delay of mitochondrial DNA replication rate observed when dTTP is in excess is not caused by this excess in itself. Instead, the dTTP overload produces a secondary dCTP depletion that actually delays mitochondrial DNA replication….. This indicates that strategies to provide nucleotides to patients’ mitochondria should be explored as a possible treatment for these fatal disorders
  • 17. Selezione pazienti per nuove terapie• Diagnosi precoce  cruciale• Frequenti ritardi, errori diagnostici• Sforzi speciali per migliorare conoscenze cliniche e algoritmi diagnostici, soprattutto nelle forme late- onset
  • 18. UO Neurologia e Unità trapianto e Dipartimento Malattie Terapia cellulare Biotecnologie Neurometaboliche• A. Federico • G. Marotta • V. Micheli• F. Sicurelli • A. Bucalossi • G. Jacomelli• A. Carluccio • F. Toraldo• E. Cardaioli • M. Tozzi• M. Mondelli • M. Lenoci

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