dotti mngie 21 maggio
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HSCT in un caso di MNGIE:HSCT in un caso di MNGIE:follow up di un annofollow up di un anno
Maria Teresa DottiMaria Teresa Dotti
Dipartimento di Scienze Neurologiche, Neurochirurgiche Dipartimento di Scienze Neurologiche, Neurochirurgiche e del Comportamentoe del Comportamento
Università di SienaUniversità di Siena
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Therapeutic approaches for LSDsTherapeutic approaches for LSDs
Parenti, EMBO Mol Med 2010
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Stem Cell TransplantationStem Cell Transplantation
• 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
1968
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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
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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
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MNGIE/ quadro clinico lieve
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MNGIE/ epidemiologia
• Malattia rara
• <200 casi descritti/incidenza sconosciuta
• Sicuramente sottostimata
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Caso clinicoCaso 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
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Caso clinicoCaso 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
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Caso clinico/HSCTCaso 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
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0
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Time 0 16 days 35 days 45 days 60 days 3 months 6 months 8 months 10 months 12 months
Time Post-Transplant
Buf
fy C
oat T
P (
nmol
/h/m
g-pr
ot)
TP activity (normal, 75-1640)
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Time 0 15 days 30 days 45 days 60 days 3 months 6 months 8 months 10 months 12 months
Time Post-Transplant
Nuc
leos
ide
leve
ls
(µM
)
Plasma dThd levels Plasma dUrd levels
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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
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Mngie/terapiaMngie/terapia
• Rimozione diretta metaboliti tossici Dialisi peritoneale
• Replacement enzima trasfusione piastrine
• HSCT
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As occurs with many monogenic disorders that can benefit from As occurs with many monogenic disorders that can benefit from anan
allogeneic HSCT, MNGIE is probably a very good candidate forallogeneic HSCT, MNGIE is probably a very good candidate forhematopoietic stem cell gene therapy (HSCGT)hematopoietic stem cell gene therapy (HSCGT)
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• …. 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
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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
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UO Neurologia e Malattie Neurometaboliche
• A. Federico• F. Sicurelli• A. Carluccio• E. Cardaioli • M. Mondelli
Unità trapianto e Terapia cellulare
• G. Marotta• A. Bucalossi• F. Toraldo• M. Tozzi• M. Lenoci
Dipartimento Biotecnologie
• V. Micheli• G. Jacomelli