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Mancuso

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  • 1. “Presentazione Registro Nazionale Malattie Mitocondriali” Gabriele Siciliano Michelangelo Mancuso
  • 2. Steering CommitteeG Siciliano, PisaG Uziel, MilanoE Bertini, RomaGP Comi, MilanoT Mongini,TorinoA Toscano, MessinaV Carelli, BolognaC Angelini, PadovaS Servidei, RomaP Tonin, VeronaC Minetti, Genova Mitocon
  • 3. Oversee CommitteeG Logroscino, BariS. DiMauro, Columbia University, New YorkJ. Montoya, Zaragoza, SpainRW Taylor, Newcastle
  • 4. Time TablePHASE 1 INSTALLMENT OF THE STEERING COMMITTEEPHASE 2 DEVELOPMENT AND VALIDATION OF THE REGISTER
  • 5. Riunione S.C. Milano, 5 Maggio 2010
  • 6. Riunione Milano, 5 Maggio 2010
  • 7. Riunione Milano, 5 Maggio 2010
  • 8. Definitiva approvazione da parte dei centri Italiani e dell’Oversee Committee
  • 9. Time Table PHASE 1 INSTALLMENT OF THE STEERING COMMITTEE PHASE 2 DEVELOPMENT AND VALIDATION OF THE REGISTERPHASE 3 – 12 months: Reassessment of all the cases ineach center and build the clinical and laboratoristicregister by developing the web−database
  • 10. SienaCagliari
  • 11. Sul web…
  • 12. For each center involved in the project, adesignated physician will be responsible for thedata storage in the database.
  • 13. UNO SGUARDO DINSIEME... 1138 pazienti 7/5/2012
  • 14. UNO SGUARDO DINSIEME...(1) 48.4% 51.6%
  • 15. UNO SGUARDO DINSIEME... (2) 48% 52% Età esordio 23.8 ± 20.5 aa
  • 16. UNO SGUARDO DINSIEME... (3) CONFERMA MOLECOLAREConfermati “pathogenetic mutations” > 850 35.0 % 30 %
  • 17. Frequenza sindromi mitocondriali Others 8.4% KSS 2.1% MERRF 4.3% PEO 28.3% Leigh 7.3% MELAS 9.0% Leber/ADOA No specific 15.3% syndrome 25.3%
  • 18. Frequenza mutazioni puntiformi DNAmt Others 25.2% "Leber" 25.7% T8993G 5.7% A8344G 12.7% A3243 30.7%
  • 19. Frequenza mutazioni puntiformi nDNA others 7.6% TK2 2.1% PDHA1 4.6% OPA1 35.4% SURF1 10.3% TYMP 5,1 ANT1 2.6% Twinkle 11.8% POLG1 20.5%
  • 20. Mutazioni mtDNA340 pazienti con mutazioni puntiformiAnamnesi familiare negativa 36.9% Esordio pediatrico 44.0%, adulto 56.0% Età esordio: 21.5 ± 17.9 Lattato basale • alterato 34.3%
  • 21. Common mtDNA mutations
  • 22. A3243G91 pz (M 49, F 42) età esordio 24.5 ± 16.6 aa esordio adulto 42, pediatrico 39
  • 23. 0 10 20 30 40 50 60 stro ke seiz ures myo clon us atax hypo ia acu scogn ia i tive imp. ptos is/PE O reti n opat hy h e ar t di s . esordio (%) diab etes li pom atos is A3243G
  • 24. 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 stro ke seiz ures statu s ep myo i l. clon us atax hypo ia acu scogn ia i tive imp. ptos is/PE reti n O opat hy h e ar t di s . diab etes li pom atos quadro clinico (%) is A3243G
  • 25. 0 10 20 30 40 50 60 norm al stro ke-l i ke whi t e m at ter d i s. cort i cal atr o p hy subc ort . at ro phycere bella r atr op h y calc i fica ti ons caratteristiche neuroradiologiche (%) A3243G
  • 26. dati istologici (%)10090807060504030 A3243G2010 0 ag e al t ive s /RBF SSV norm stor a -neg RRF li pid COX
  • 27. A8344G42 patients (3.9% in our database May 1st,2012).They represented the 12.4% (42/340) of allmtDNA point mutations. 15/42 patients (35.7%)had childhood onset (<16 years).
  • 28. % White: onset; black: last evaluation.
  • 29. RESULTS: the A8344G mutationFisher’s exact test revealed no associationbetween myoclonus and generalized seizures inthe 38 adult (>16 years) A8344G mutationcarriers with known clinical picture.A significant association was observed betweenmyoclonus and cerebellar ataxia (P =0.0245; significance level 0.025 after Bonferroni’scorrection)
  • 30. T8993G17 casi (M 4, F 13; età esordio 6.5 ± 14.5; esordioadulto 2, pediatrico 15).T8993G esordio pediatrico: esordio 1.3 ± 2.4 anni
  • 31. 0 10 20 30 40 50 60 70 80 90 cogn i tive 100 imp. atax ia seiz ures d ystpyra oni a mida l sig hypo ns acu s ia hypo toni neur a opat resp irat o hy r y in ptos v. is/PE reti n O opat opti hy c ne ur. T8993G esordio pediatrico (%) esordio successiv.
  • 32. 0 10 20 30 40 50 60 70 80 90 100 b asa l nu clei inv. cort i cal atr o ph y cere bella r atr .whi t e m at ter a b n. norm al T8993G esordio ped. (%): neuroimmagini n = 13
  • 33. Nuclear DNA mutations
  • 34. mutazioni nDNA>200 pazienti con mutazioni identificate Anamnesi familiare negativa nel 37.5% Esordio pediatrico 61.0% adulto 39%
  • 35. mutazioni nDNA Età esordio: 18.2 ± 19.2(non differenza significativa rispetto mtDNA) Lattato basale: alterato 29.5%,
  • 36. others 7.6% TK2 2.1% PDHA1 4.6% OPA1 35.4%SURF1 10.3% TYMP 5,1 ANT1 2.6% Twinkle 11.8% POLG1 20.5%
  • 37. ADOA/LeberADOA 62 (1 asintomatico)Leber 91 (8 asintomatici) Ipotiroidismo segnalato nel 5-6% di ADOA e Leber, ma mai nella 3243 ed in un caso solo di 8344 Neuropatia periferica 7.8% ADOA, no LHON
  • 38. Sindrome di Leigh73 pazienti (esordio 0.7 ± 1.6 anni).M 42, F 31Mutazioni nucleari identificate 30 (41.1%),mitocondriali 23 (31.4%).Non identificate mutazioni 20 (27.5%)
  • 39. Sindrome di Leigh (%) Not identified SURF1 26.0% 27.5% PDHA1 4.1%mtDNA, others 13.7% nDNA, others T9176C 4.1% 11.0% G13513A 6.8% T8993G 6.8%
  • 40. Sindromi atassiche in età adulta
  • 41. esordio con atassia in età adulta POLG1 18.2% OPA1 4.5%Unknown 45.5% A8344G 18.2% A3243G 4.5% Single deletion 9.1%
  • 42. POLG141 casi (M 18, F 22)Età esordio 34.1 ± 18.2Esordio adulto 25 p, pediatrico 16 p) POLG1 esordio adulto: esordio 41.2 ± 13.2 anni POLG1 esordio pediatrico: esordio 7.5 ± 6.5 anni
  • 43. “Specific mitochondrial disorder” - POLG1 (%) Alpers 2.4% MELAS 2.4% MIRAS 2.4% SANDO 9.8% No specificsyndrome 17.1% PEO 65.9%
  • 44. 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 0 5 atax hypo ia acu s ia stro ke-l i park ke inso ni sm cogn i tive imp. seiz ures ptos is/PE neur O opat hy d ysp h ag ia optiGI d c ne ysm ur. oti l./ vo m it . POLG1 esordio adulto (%) esordio successiv.
  • 45. 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 0 5 atax ia hypo acu s ia stro ke-l i ke seiz ures ptos is/PE O neurGI d opat ysm hy oti l./ vo m hypo it . g on adis m li ver di s. kidn ey d is. POLG1 esordio pediatrico (%) esordio successiv.
  • 46. 100 0 10 20 30 40 50 60 70 80 90 cogn i tive imp. seizpyra ures mida l sig ns d yst oni a hypo toniresp irat o a r y im ptos p. is/PE neur O opat hy d ysp h ag hepa ia t opa thy kidn ey in v. an ae m ia Sindromi da deplezione/Alpers (%) esordio successiv.
  • 47. Sindromi da deplezione/Alpers - neuroimmagini (%)100 90 80 70 60 50 40 30 n=6 20 10 0 inv. n. phy . al r atr b norm ter a atr o clei bella m at l nu i cal cere b asa cort e whi t
  • 48. esordio con epilessia in età adulta (%) Multiple deletions 4.8% A8344G 9.5% Unknown 38.0% A3243G 42.9% T8356C 4.8%
  • 49. esordio con epilessia in età < 16 aa (%) mtDNA: others 13.8% Unknown 36.2% A3243G 31.6% Single deletion 2.6% PDHA 7.9% POLG1 7.8%
  • 50. Biomarkers
  • 51. LATTATO EMATICO (%) unknown 11.0%abnormal 32.3% not performed 30.7% normal 26.0%
  • 52. LATTATOEsordio pediatrico (lattato alterato 179/288 =62.2%) vs adulto (144/295 = 48.8%). P = 0.0016(chi-square test)mtDNA (104/165 = 63.0%) vs nDNA (52/36 =59.1%). P not significant.
  • 53. CSF LACTATE • NORMAL 32 • ABNORMAL 48 • N.P.UNKNOWN 820RC COMPLEXES • PERFORMED 26.3% • N.P.UNKNOWN 73.7
  • 54. PIRUVATE • NORMAL 117 PDH in muscle • ABNORMAL 92 • NORMAL 17 • N.P.UNKNOWN 791 • ABNORMAL 8 • N.P.UNKNOWN 975ORGANIC ACID • NORMAL 55 • ABNORMAL 70 • N.P.UNKNOWN 875
  • 55. Global mt database
  • 56. International Registry network• Dr Carolyn Sue (Australia)• Dr Eino Palin (Finland)• Prof. Anu Suomalainen (Finland)• Dr Massimo Zeviani (Italy)• Dr Victoria Nesbitt (UK)• Prof. Jan Smeitink (Netherland)• Prof. T. Klopstock (Germany)• Dr M. Mancuso (Italy)• Dr Robert McFarland (UK)• Prof. Doug Turnbull (UK)• Mr Simon Cockell (UK)• Dr Michio Hirano Dr S DiMauro (USA)• IMP delegates (Mitocon, DGM, UMDF)
  • 57. http://www.mitopatients.org/
  • 58. Others National Patients Registries ITALY GERMANY USA FranceType of Information (UMDF) N° (%) N° (%) N° (%) N° (%) N° of patients 1001 485 657 - Male (48,4%) (47,6%) 47.6% - Female (51,6%) (52,4%) 52.4% - 8.46 (male) -Average Age of onset 23,8 ± 20 y 22,8 ± 19,8y 17.67 (fem.) - Diagnosis PEO 28,3 % 20,4% 3,9% - Leber/ADOA 15,3 % 9,1% 1,2% - Leigh 7,3 % 3,7% 14,9% - MELAS 9,0 % 3,7% 11,0% - MERRF 4,3 % 1,6% 3,2% - KSS 2,1 % 1,9% 6,0% - Others 8,4 % 37,1% 11,8% (1) -
  • 59. Gruppi di lavoroDevelopment and validation Childhood diagnostic of the mitochondrial criteria disease quality of life (MitoQoL) questionnaire Molecular studies and tissue biobank Biomarkers consortium Longitudinal studies Adulthood diagnostic criteria Clinical features and genotypephenotype correlations: revision
  • 60. Partecipanti• Antonio Toscano • Maurizio Moggio• Olimpia Musumeci • Tiziana Mongini• Graziella Uziel • Liliana Vercelli• Paola Tonin • Gabriele Siciliano• Mauro Scarpelli • Michelangelo Mancuso• Massimiliano Filosto • Daniele Orsucci• Enrico Bertini • Corrado Angelini• Filippo M Santorelli • Elena Pegoraro• Massimo Zeviani • Marco Spinazzi• Giacomo P. Comi • Claudio Bruno• Costanza Lamperti • Carlo Minetti• Serenella Servidei • Valerio Carelli

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