Aggiornamento sul Registro Nazionale ed iAggiornamento sul Registro Nazionale ed iRegistri europei dei Pazienti:Registri e...
Steering CommitteeG Siciliano M Mancuso, PisaG Uziel, MilanoE Bertini, RomaGP Comi, MilanoT Mongini,TorinoA Toscano, Messi...
Oversee CommitteeG Logroscino, BariS. DiMauro, Columbia University, New YorkJ. Montoya, Zaragoza, SpainRW Taylor, Newcastle
SienaCagliari
Sul web…Sul web…
UNO SGUARDO DINSIEME...UNO SGUARDO DINSIEME...13001300 pazientipazienti
UNO SGUARDO DINSIEME...(1)UNO SGUARDO DINSIEME...(1)48.4%48.4% 51.6%51.6%
UNO SGUARDO DINSIEME... (2)UNO SGUARDO DINSIEME... (2)52%52%48%48%Età esordio 23.8 ± 20.5 aa
UNO SGUARDO DINSIEME... (3)UNO SGUARDO DINSIEME... (3)Confermati “pathogenetic mutations” > 85035.0 %35.0 % 30 %30 %CONFER...
PEO 28.3%No specificsyndrome 25.3%Leber/ADOA15.3%MELAS 9.0%Leigh 7.3%MERRF 4.3%KSS 2.1%Others 8.4%Frequenza sindromi mitoc...
"Leber" 25.7%A3243 30.7%A8344G 12.7%T8993G 5.7%Others 25.2%Frequenza mutazioni puntiformi DNAmtFrequenza mutazioni puntifo...
OPA1 35.4%POLG1 20.5%Twinkle 11.8%ANT1 2.6%TYMP 5,1SURF1 10.3%PDHA1 4.6%TK2 2.1%others 7.6%Frequenza mutazioni puntiformi ...
Mutazioni mtDNAMutazioni mtDNA380 pazienti con mutazioni puntiformiAnamnesi familiare negativa 36.9%Esordio pediatrico 44....
Common mtDNA mutations
The mitochondrial DNAm.3243A>G “MELAS”mutation in Italy
BACKGROUND (2)The clinical syndromes which have been,ascribed to this mutation include mitochondrialencephalopathy with la...
AIMSRevision of the clinical data of the subjects withthis mutationGenotype-phenotype correlations
PATIENTSBased on the database ofthe “Nation−wide ItalianCollaborative Networkof MitochondrialDiseases”, we reviewedthe dat...
RESULTS: the m.3243A>G mutation (1)• 118 patients harboring the A8344G mutation havebeen identified among the 1150 mitocho...
RESULTS: the m.3243A>G mutation (1)• 118 patients harboring the A8344G mutation havebeen identified among the 1150 mitocho...
RESULTS: the m.3243A>G mutation (1)• 118 patients harboring the A8344G mutation havebeen identified among the 1150 mitocho...
RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• ...
RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• ...
RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• ...
RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• ...
0102030405060708090100HearinglossSeizuresDiabetesPtosis/PEOStroke-likeep.MigraineExerciseintol.Muscleweakn.HeartdiseaseCog...
RESULTS: Stroke-like episodes (1)Stroke-like episodes are crucial for the syndromicdiagnosis of MELAS48/111 (43.2%) of m.3...
RESULTS: Stroke-like episodes (2)Heteroplasmy levels could not predict stroke-like episodes:“MELAS” “NON-MELAS” PBlood 35....
RESULTS: Stroke-like episodes (3)Lactate was associated with MELAS“MELAS” “NON-MELAS”Normal 6 17Increased 29 21Not availab...
A role for the gender?“MELAS” group: males 30/48 (67.6%)“non-MELAS” group: males 26/63 (42.9%)“MELAS” “NON-MELAS”Males 30 ...
Possible confounding factorsMales Females POnset 24.3±14.8 yrs 24.5±16.6 yrs n.s.Age* 37.4±17.0 yrs 42.2±19.9 yrs n.s.Het....
Gender effect: not a new concept inMitochondrial Medicine……but not previously reported for the m.3243A>Gmutation!
Stroke-like episodes are associated with…
RESULTS: “MIDD” syndromeAre diabetes and deafness specificallyassociated in m.3243A>G patients?Diabetes: Yes NoHearing los...
RESULTS: “MIDD” syndromeAre diabetes and deafness specificallyassociated in m.3243A>G patients?Diabetes: Yes NoHearing los...
Hearing loss is also associated with…
Diabetes is also associated with…
RESULTS: Progressive externalophthalmoplegiaKey point: «pure» PEO(3/111, 2.7%)
0102030405060708090100 Stroke-likeepis.CorticalatrophyCerebellaratrophyWithematterdid.SubcorticalatrophyCalcificationsNorm...
0102030405060708090100RRFsCOXnegativeLipidstorageSSVsNormal% n = 62RESULTS: Muscle biopsy
CONCLUSIONS (1)Stroke-like episodes are the core feature ofMELASHere we have confirmed that lactic acidosis (even ifnot ma...
CONCLUSIONS (1)Stroke-like episodes are the core feature ofMELASHere we have confirmed that lactic acidosis (even ifnot ma...
CONCLUSIONS (1)Stroke-like episodes are the core feature ofMELASHere we have confirmed that lactic acidosis (even ifnot ma...
CONCLUSIONS (2)Other possibly associated features include cognitive involvementand hearing loss.Heteroplasmy levels and mu...
CONCLUSIONS (2)Other possibly associated features include cognitive involvementand hearing loss.Heteroplasmy levels and mu...
CONCLUSIONS (2)Other possibly associated features include cognitive involvementand hearing loss.Heteroplasmy levels and mu...
Is the distinction in three phenotypes (MELAS; PEO;MIDD) somehow arbitrary?
CONCLUSIONS (3)“pure” PEO rare; associated with heart disease and muscle weakness“pure” MIDD rare; commonly associated wit...
CONCLUSIONS (4)Rather than being associated with one of the previouslymentioned discrete clinical syndromes, the m.3243A>G...
T8993GT8993G17 casi (M 4, F 13; età esordio 6.5 ± 14.5; esordioadulto 2, pediatrico 15).T8993G esordio pediatrico: esordio...
0102030405060708090100cognitiveimp.ataxiaseizuresdystoniapyramidalsignshypoacusiahypotonianeuropathyrespiratoryinv.ptosis/...
0102030405060708090100basalnucleiinv.corticalatrophycerebellaratr.whitematterabn.normaln = 13T8993G esordio ped. (%): neur...
Nuclear DNA mutationsNuclear DNA mutations
mutazioni nDNAmutazioni nDNA>200 pazienti con mutazioni identificateAnamnesi familiare negativa nel 37.5%Esordiopediatrico...
mutazioni nDNAmutazioni nDNAEtà esordio: 18.2 ± 19.2(non differenza significativa rispettomtDNA)Lattato basale: alterato 2...
OPA1 35.4%POLG1 20.5%Twinkle 11.8%ANT1 2.6%TYMP 5,1SURF1 10.3%PDHA1 4.6%TK2 2.1%others 7.6%
SURF1 26.0%PDHA1 4.1%nDNA, others11.0%T8993G 6.8%G13513A 6.8%T9176C 4.1%mtDNA, others13.7%Not identified27.5%Sindrome di L...
Sindromi atassiche in età adultaSindromi atassiche in età adulta
POLG1 18.2%OPA1 4.5%A8344G 18.2%A3243G 4.5%Single deletion9.1%Unknown 45.5%esordio con atassia in età adultaesordio con at...
PEO 65.9%No specificsyndrome 17.1%Alpers 2.4%SANDO 9.8%MIRAS 2.4%MELAS 2.4%““Specific mitochondrial disorder” - POLG1 (%)S...
0510152025303540455055606570758085ataxiahypoacusiastroke-likeparkinsonismcognitiveimp.seizuresptosis/PEOneuropathydysphagi...
05101520253035404550556065707580859095100ataxiahypoacusiastroke-likeseizuresptosis/PEOneuropathyGIdysmotil./vomit.hypogona...
A8344G 9.5%A3243G 42.9%T8356C 4.8%Unknown 38.0%Multiple deletions4.8%esordio con epilessia in età adulta (%)esordio con ep...
mtDNA: others13.8%A3243G 31.6%POLG1 7.8%Unknown 36.2%PDHA 7.9%Single deletion2.6%esordio con epilessia in età < 16 aa (%)e...
BiomarkersBiomarkers
unknown 11.0%not performed30.7%normal 26.0%abnormal 32.3%LATTATO EMATICO (%)LATTATO EMATICO (%)
LATTATOLATTATOEsordio pediatrico (lattato alterato 179/288 =62.2%) vs adulto (144/295 = 48.8%). P = 0.0016(chi-square test...
CSF LACTATECSF LACTATE• NORMAL 32• ABNORMAL 48• N.P.UNKNOWN 820RC COMPLEXESRC COMPLEXES• PERFORMED 26.3%• N.P.UNKNOWN 73.7
PIRUVATEPIRUVATE• NORMAL 117• ABNORMAL 92• N.P.UNKNOWN 791ORGANIC ACIDORGANIC ACID• NORMAL 55• ABNORMAL 70• N.P.UNKNOWN 87...
Global mt databaseGlobal mt database
International Registry network• Dr Carolyn Sue (Australia)• Dr Eino Palin (Finland)• Prof. Anu Suomalainen (Finland)• Dr M...
http://www.mitopatients.org/
Others National Patients RegistriesType of InformationITALY GERMANYUSA(UMDF)FranceN° (%) N° (%) N° (%) N° (%)N° of patient...
PUBLICATIONS
Myoclonus in MERRF & beyond. A clinical and genetic perspective from theItalian Collaborative Network of Mitochondrial Dis...
OTHER PUBLICATIONS…OTHER PUBLICATIONS…•Effects of aerobic training on exercise-related oxidative stress in mitochondrial m...
Phase II -Phase II - Future plansFuture plansDevelopment and validationof the mitochondrialdisease quality of life(MitoQoL...
COLLABORATORS• Antonio Toscano• Olimpia Musumeci• Graziella Uziel• Paola Tonin• Mauro Scarpelli• Massimiliano Filosto• Enr...
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
Michelangelo Mancuso, Convegno Mitocon 2013
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Michelangelo Mancuso, Convegno Mitocon 2013

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Aggiornamento sul Registro Nazionale ed i Registri Europei dei Pazienti: risultati e prospettive sui registri di ricerca e per la qualità della vita
Michelangelo Mancuso, Università di Pisa, Clinica di Neurologia

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Michelangelo Mancuso, Convegno Mitocon 2013

  1. 1. Aggiornamento sul Registro Nazionale ed iAggiornamento sul Registro Nazionale ed iRegistri europei dei Pazienti:Registri europei dei Pazienti:risultati e prospettive sui registri di ricerca erisultati e prospettive sui registri di ricerca eper la qualità della vitaper la qualità della vitaMichelangelo MancusoMichelangelo Mancuso
  2. 2. Steering CommitteeG Siciliano M Mancuso, PisaG Uziel, MilanoE Bertini, RomaGP Comi, MilanoT Mongini,TorinoA Toscano, MessinaV Carelli, BolognaC Angelini, PadovaS Servidei, RomaP Tonin, VeronaC Minetti, Genova Mitocon
  3. 3. Oversee CommitteeG Logroscino, BariS. DiMauro, Columbia University, New YorkJ. Montoya, Zaragoza, SpainRW Taylor, Newcastle
  4. 4. SienaCagliari
  5. 5. Sul web…Sul web…
  6. 6. UNO SGUARDO DINSIEME...UNO SGUARDO DINSIEME...13001300 pazientipazienti
  7. 7. UNO SGUARDO DINSIEME...(1)UNO SGUARDO DINSIEME...(1)48.4%48.4% 51.6%51.6%
  8. 8. UNO SGUARDO DINSIEME... (2)UNO SGUARDO DINSIEME... (2)52%52%48%48%Età esordio 23.8 ± 20.5 aa
  9. 9. UNO SGUARDO DINSIEME... (3)UNO SGUARDO DINSIEME... (3)Confermati “pathogenetic mutations” > 85035.0 %35.0 % 30 %30 %CONFERMACONFERMA MOLECOLAREMOLECOLARE
  10. 10. PEO 28.3%No specificsyndrome 25.3%Leber/ADOA15.3%MELAS 9.0%Leigh 7.3%MERRF 4.3%KSS 2.1%Others 8.4%Frequenza sindromi mitocondrialiFrequenza sindromi mitocondriali
  11. 11. "Leber" 25.7%A3243 30.7%A8344G 12.7%T8993G 5.7%Others 25.2%Frequenza mutazioni puntiformi DNAmtFrequenza mutazioni puntiformi DNAmt
  12. 12. OPA1 35.4%POLG1 20.5%Twinkle 11.8%ANT1 2.6%TYMP 5,1SURF1 10.3%PDHA1 4.6%TK2 2.1%others 7.6%Frequenza mutazioni puntiformi nDNAFrequenza mutazioni puntiformi nDNA
  13. 13. Mutazioni mtDNAMutazioni mtDNA380 pazienti con mutazioni puntiformiAnamnesi familiare negativa 36.9%Esordio pediatrico 44.0%, adulto 56.0%Età esordio: 21.5 ± 17.9Lattato basale• alterato 34.3%
  14. 14. Common mtDNA mutations
  15. 15. The mitochondrial DNAm.3243A>G “MELAS”mutation in Italy
  16. 16. BACKGROUND (2)The clinical syndromes which have been,ascribed to this mutation include mitochondrialencephalopathy with lactic acidosis and stroke-like episodes (MELAS), maternally inheriteddeafness and diabetes (MIDD) and progressiveexternal ophthalmoplegia (PEO).
  17. 17. AIMSRevision of the clinical data of the subjects withthis mutationGenotype-phenotype correlations
  18. 18. PATIENTSBased on the database ofthe “Nation−wide ItalianCollaborative Networkof MitochondrialDiseases”, we reviewedthe data of the subjects withthe m.3243A>G mutation
  19. 19. RESULTS: the m.3243A>G mutation (1)• 118 patients harboring the A8344G mutation havebeen identified among the 1150 mitochondrial patients(10.9%) present in our database (April 15th, 2013).• They represented the 34.2% (118/345) of all mtDNApoint mutations.• The clinical picture was not available for seven patients,who have not been considered in the following analysis 111 patients
  20. 20. RESULTS: the m.3243A>G mutation (1)• 118 patients harboring the A8344G mutation havebeen identified among the 1150 mitochondrial patients(10.9%) present in our database (April 15th, 2013).• They represented the 34.2% (118/345) of all mtDNApoint mutations.• The clinical picture was not available for seven patients,who have not been considered in the following analysis 111 patients
  21. 21. RESULTS: the m.3243A>G mutation (1)• 118 patients harboring the A8344G mutation havebeen identified among the 1150 mitochondrial patients(10.9%) present in our database (April 15th, 2013).• They represented the 34.2% (118/345) of all mtDNApoint mutations.• The clinical picture was not available for seven patients,who have not been considered in the following analysis 111 patients
  22. 22. RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• 5/111 (4.5%) subjects were asymptomatic carriers (age atlast evaluation 42.0 ± 27.1 years; range 7-77).• The mean age at onset of the 106 symptomatic patients was24.5 ± 15.7 years (38.6% childhood onset: <16 years).
  23. 23. RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• 5/111 (4.5%) subjects were asymptomatic carriers (age atlast evaluation 42.0 ± 27.1 years; range 7-77).• The mean age at onset of the 106 symptomatic patients was24.5 ± 15.7 years (38.6% childhood onset: <16 years).
  24. 24. RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• 5/111 (4.5%) subjects were asymptomatic carriers (age atlast evaluation 42.0 ± 27.1 years; range 7-77).• The mean age at onset of the 106 symptomatic patients was24.5 ± 15.7 years (38.6% childhood onset: <16 years).
  25. 25. RESULTS: the m.3243A>G mutation (2)• The mean age at the last control was 39.9 ± 18.7 years.• Males were 56/111 (50.5%).• 5/111 (4.5%) subjects were asymptomatic carriers (age atlast evaluation 42.0 ± 27.1 years; range 7-77).• The mean age at onset of the 106 symptomatic patients was24.5 ± 15.7 years (38.6% childhood onset: <16 years).
  26. 26. 0102030405060708090100HearinglossSeizuresDiabetesPtosis/PEOStroke-likeep.MigraineExerciseintol.Muscleweakn.HeartdiseaseCognitiveinv.Thrivefail./shortst.IncreasedCKMusclepainMusclewastingGastrointdysmotil.NeuropathyAtaxiaHypotoniaPyramidalsigns% White: onset - Black: last evaluation
  27. 27. RESULTS: Stroke-like episodes (1)Stroke-like episodes are crucial for the syndromicdiagnosis of MELAS48/111 (43.2%) of m.3243A>G carriers, at the mean ageof 40 yrs, had experienced stroke-like episodes and canbe defined “MELAS”Age at onset, age at last control and disease duration werenot different between “MELAS” and “non-MELAS” groups
  28. 28. RESULTS: Stroke-like episodes (2)Heteroplasmy levels could not predict stroke-like episodes:“MELAS” “NON-MELAS” PBlood 35.2±20.8 (n=20) 24.3±20.2 (n=36) n.sMuscle 66.6±19.2 (n=9) 62.6±22.0 (n=18) n.s.Urine 58.3±30.5 (n=8) 38.6±26.0 (n=21) n.s.No difference in the proportion of patients with ragged redfibers and COX-negative fibers between the two groups.
  29. 29. RESULTS: Stroke-like episodes (3)Lactate was associated with MELAS“MELAS” “NON-MELAS”Normal 6 17Increased 29 21Not available 13 25Total 48 63P = 0.013
  30. 30. A role for the gender?“MELAS” group: males 30/48 (67.6%)“non-MELAS” group: males 26/63 (42.9%)“MELAS” “NON-MELAS”Males 30 26Females 18 37P = 0.035
  31. 31. Possible confounding factorsMales Females POnset 24.3±14.8 yrs 24.5±16.6 yrs n.s.Age* 37.4±17.0 yrs 42.2±19.9 yrs n.s.Het.Muscle 67.8±16.5 (n=12) 60.8±23.9 (n=15) n.s.Het.Blood 28.4±20.0 (n=20) 28.1±21.7 (n=36) n.s.Het.Urine 49.5±32.5 (n=12) 40.2±25.0 (n=17) n.s.*Last control
  32. 32. Gender effect: not a new concept inMitochondrial Medicine……but not previously reported for the m.3243A>Gmutation!
  33. 33. Stroke-like episodes are associated with…
  34. 34. RESULTS: “MIDD” syndromeAre diabetes and deafness specificallyassociated in m.3243A>G patients?Diabetes: Yes NoHearing loss:Yes 38 30No 9 34P = 0.00035 YESKey point: «pure» MIDD syndrome
  35. 35. RESULTS: “MIDD” syndromeAre diabetes and deafness specificallyassociated in m.3243A>G patients?Diabetes: Yes NoHearing loss:Yes 38 30No 9 34P = 0.00035 YESKey point: «pure» MIDD syndrome (6/111, 5.4%)
  36. 36. Hearing loss is also associated with…
  37. 37. Diabetes is also associated with…
  38. 38. RESULTS: Progressive externalophthalmoplegiaKey point: «pure» PEO(3/111, 2.7%)
  39. 39. 0102030405060708090100 Stroke-likeepis.CorticalatrophyCerebellaratrophyWithematterdid.SubcorticalatrophyCalcificationsNormal% n = 77RESULTS: Neuroradiological features
  40. 40. 0102030405060708090100RRFsCOXnegativeLipidstorageSSVsNormal% n = 62RESULTS: Muscle biopsy
  41. 41. CONCLUSIONS (1)Stroke-like episodes are the core feature ofMELASHere we have confirmed that lactic acidosis (even ifnot mandatory) is associated with stroke-like episodes,confirming the validity of the acronym in A3443GpatientsA third strongly associated feature was the presence ofgeneralized seizures (≈70%), which were rare in non-MELAS subjects (≈15%)
  42. 42. CONCLUSIONS (1)Stroke-like episodes are the core feature ofMELASHere we have confirmed that lactic acidosis (even ifnot mandatory) is associated with stroke-like episodes,confirming the validity of the acronym in A3443GpatientsA third strongly associated feature was the presence ofgeneralized seizures (≈70%), which were rare in non-MELAS subjects (≈15%)
  43. 43. CONCLUSIONS (1)Stroke-like episodes are the core feature ofMELASHere we have confirmed that lactic acidosis (even ifnot mandatory) is associated with stroke-like episodes,confirming the validity of the acronym in A3443GpatientsA third strongly associated feature was the presence ofgeneralized seizures (≈70%), which were rare in non-MELAS subjects (≈15%)
  44. 44. CONCLUSIONS (2)Other possibly associated features include cognitive involvementand hearing loss.Heteroplasmy levels and muscle histology could not predict stroke-like episodes.In our m.3243A>G cohort, MELAS was more frequent in malesthan females: at the mean age of ≈40 years, 53.6% of males hadstroke-like episodes as opposed to 32.7% of females.
  45. 45. CONCLUSIONS (2)Other possibly associated features include cognitive involvementand hearing loss.Heteroplasmy levels and muscle histology could not predict stroke-like episodes.In our m.3243A>G cohort, MELAS was more frequent in malesthan females: at the mean age of ≈40 years, 53.6% of males hadstroke-like episodes as opposed to 32.7% of females.
  46. 46. CONCLUSIONS (2)Other possibly associated features include cognitive involvementand hearing loss.Heteroplasmy levels and muscle histology could not predict stroke-like episodes.In our m.3243A>G cohort, MELAS was more frequent in malesthan females: at the mean age of ≈40 years, 53.6% of males hadstroke-like episodes as opposed to 32.7% of females.
  47. 47. Is the distinction in three phenotypes (MELAS; PEO;MIDD) somehow arbitrary?
  48. 48. CONCLUSIONS (3)“pure” PEO rare; associated with heart disease and muscle weakness“pure” MIDD rare; commonly associated with the presence ofstroke-like episodes and may be a clinical marker of multisystemimpairment, i.e. heart disease, exercise intolerance, cognitiveinvolvement, migraineMELAS CORRECT!UNCORRECT!UNCORRECT!
  49. 49. CONCLUSIONS (4)Rather than being associated with one of the previouslymentioned discrete clinical syndromes, the m.3243A>Gphenotypes seem a continuum from asymptomatic to lethalmultisystem diseases; between these extremes there are all thepossible expressivity degrees
  50. 50. T8993GT8993G17 casi (M 4, F 13; età esordio 6.5 ± 14.5; esordioadulto 2, pediatrico 15).T8993G esordio pediatrico: esordio 1.3 ± 2.4 anni
  51. 51. 0102030405060708090100cognitiveimp.ataxiaseizuresdystoniapyramidalsignshypoacusiahypotonianeuropathyrespiratoryinv.ptosis/PEOretinopathyopticneur.esordiosuccessiv.T8993G esordio pediatrico (%)T8993G esordio pediatrico (%)
  52. 52. 0102030405060708090100basalnucleiinv.corticalatrophycerebellaratr.whitematterabn.normaln = 13T8993G esordio ped. (%): neuroimmaginiT8993G esordio ped. (%): neuroimmagini
  53. 53. Nuclear DNA mutationsNuclear DNA mutations
  54. 54. mutazioni nDNAmutazioni nDNA>200 pazienti con mutazioni identificateAnamnesi familiare negativa nel 37.5%Esordiopediatrico 61.0%adulto 39%
  55. 55. mutazioni nDNAmutazioni nDNAEtà esordio: 18.2 ± 19.2(non differenza significativa rispettomtDNA)Lattato basale: alterato 29.5%,
  56. 56. OPA1 35.4%POLG1 20.5%Twinkle 11.8%ANT1 2.6%TYMP 5,1SURF1 10.3%PDHA1 4.6%TK2 2.1%others 7.6%
  57. 57. SURF1 26.0%PDHA1 4.1%nDNA, others11.0%T8993G 6.8%G13513A 6.8%T9176C 4.1%mtDNA, others13.7%Not identified27.5%Sindrome di Leigh (%)Sindrome di Leigh (%)
  58. 58. Sindromi atassiche in età adultaSindromi atassiche in età adulta
  59. 59. POLG1 18.2%OPA1 4.5%A8344G 18.2%A3243G 4.5%Single deletion9.1%Unknown 45.5%esordio con atassia in età adultaesordio con atassia in età adulta
  60. 60. PEO 65.9%No specificsyndrome 17.1%Alpers 2.4%SANDO 9.8%MIRAS 2.4%MELAS 2.4%““Specific mitochondrial disorder” - POLG1 (%)Specific mitochondrial disorder” - POLG1 (%)
  61. 61. 0510152025303540455055606570758085ataxiahypoacusiastroke-likeparkinsonismcognitiveimp.seizuresptosis/PEOneuropathydysphagiaopticneur.GIdysmotil./vomit.esordiosuccessiv.POLG1 esordio adulto (%)POLG1 esordio adulto (%)
  62. 62. 05101520253035404550556065707580859095100ataxiahypoacusiastroke-likeseizuresptosis/PEOneuropathyGIdysmotil./vomit.hypogonadismliverdis.kidneydis.esordiosuccessiv.POLG1 esordio pediatrico (%)POLG1 esordio pediatrico (%)
  63. 63. A8344G 9.5%A3243G 42.9%T8356C 4.8%Unknown 38.0%Multiple deletions4.8%esordio con epilessia in età adulta (%)esordio con epilessia in età adulta (%)
  64. 64. mtDNA: others13.8%A3243G 31.6%POLG1 7.8%Unknown 36.2%PDHA 7.9%Single deletion2.6%esordio con epilessia in età < 16 aa (%)esordio con epilessia in età < 16 aa (%)
  65. 65. BiomarkersBiomarkers
  66. 66. unknown 11.0%not performed30.7%normal 26.0%abnormal 32.3%LATTATO EMATICO (%)LATTATO EMATICO (%)
  67. 67. LATTATOLATTATOEsordio 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.
  68. 68. CSF LACTATECSF LACTATE• NORMAL 32• ABNORMAL 48• N.P.UNKNOWN 820RC COMPLEXESRC COMPLEXES• PERFORMED 26.3%• N.P.UNKNOWN 73.7
  69. 69. PIRUVATEPIRUVATE• NORMAL 117• ABNORMAL 92• N.P.UNKNOWN 791ORGANIC ACIDORGANIC ACID• NORMAL 55• ABNORMAL 70• N.P.UNKNOWN 875PDH in musclePDH in muscle• NORMAL 17• ABNORMAL 8• N.P.UNKNOWN 975
  70. 70. Global mt databaseGlobal mt database
  71. 71. 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)
  72. 72. http://www.mitopatients.org/
  73. 73. Others National Patients RegistriesType of InformationITALY GERMANYUSA(UMDF)FranceN° (%) N° (%) N° (%) N° (%)N° of patients 1001 485 657 -Male (48,4%) (47,6%) 47.6% -Female (51,6%) (52,4%) 52.4% -Average Age of onset 23,8 ± 20 y 22,8 ± 19,8y8.46 (male) -17.67 (fem.) -DiagnosisPEO 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) -
  74. 74. PUBLICATIONS
  75. 75. Myoclonus in MERRF & beyond. A clinical and genetic perspective from theItalian Collaborative Network of Mitochondrial Diseases.Under revision Movement DisordersIn a given patient with a mitochondrial disorder, myoclonus can be part of a morecomplex encephalopatic mitochondrial syndrome ore can be the prominent clinicalfeature (i.e., MERRF), possibly associated with other signs and symptoms such asataxia and seizures. 8344A>G mutation is the major cause of MEERF, but it onlyexplains about one out of three cases. Furthermore, it is frequently associated withdifferent phenotypes. Other mtDNA or nDNA mutations are associated with myoclonusin the frame of MERRF or of another encephalopatic syndrome.
  76. 76. OTHER PUBLICATIONS…OTHER PUBLICATIONS…•Effects of aerobic training on exercise-related oxidative stress in mitochondrial myopathies. Neuromuscul Disord.2012•Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc. 2012•Progressive cavitating leukoencephalopathy associated with respiratory chain complex I deficiency and a novelmutation in NDUFS1. Neurogenetics. 2011•Next-generation sequencing reveals DGUOK mutations in adult patients with mitochondrial DNA multipledeletions. Brain. 2012•Clinical and molecular features of an infant patient affected by Leigh Disease associated to m.14459G>Amitochondrial DNA mutation: a case report. BMC Neurol. 2011•May "mitochondrial eve" and mitochondrial haplogroups play a role in neurodegeneration and Alzheimersdisease? Int J Alzheimers Dis. 2011•Optimization of respiratory chain enzymatic assays in muscle for the diagnosis of mitochondrial disorders.Mitochondrion. 2011•Quality of life in adult patients with mitochondrial myopathy. Neuroepidemiology. 2012•Psychiatric involvement in adult patients with mitochondrial disease. Neurol Sci. 2013•Cardiological manifestations of mitochondrial respiratory chain disorders. Acta Myol. 2011•Current and emerging treatment options in the management of Friedreich ataxia. Neuropsychiatr Dis Treat. 2010•The novel mitochondrial tRNAAsn gene mutation m.5709T>C produces ophthalmoparesis and respiratoryimpairment. Eur J Hum Genet. 2012•POLG1-related and other "mitochondrial Parkinsonisms": an overview. J Mol Neurosci. 2011•Drugs and mitochondrial diseases: 40 queries and answers. Expert Opin Pharmacother. 2012•TMEM70: a mutational hot spot in nuclear ATP synthase deficiency with a pivotal role in complex V biogenesis.Neurogenetics. 2012•Pontocerebellar hypoplasia type 6 caused by mutations in RARS2: definition of the clinical spectrum andmolecular findings in five patients. J Inherit Metab Dis. 2013•EPI-743 reverses the progression of the pediatric mitochondrial disease--genetically defined Leigh Syndrome.Mol Genet Metab. 2012•Novel large-range mitochondrial DNA deletions and fatal multisystemic disorder with prominent hepatopathy.Biochem Biophys Res Commun. 2011•Optic atrophy plus phenotype due to mutations in the OPA1 gene: two more Italian families. J Neurol Sci. 2012
  77. 77. Phase II -Phase II - Future plansFuture plansDevelopment and validationof the mitochondrialdisease quality of life(MitoQoL) questionnaireAdulthood diagnosticcriteriaLongitudinal studiesClinical features andgenotypephenotypecorrelations: revisionMolecular studies andtissue biobankBiomarkers consortiumChildhood diagnosticcriteria
  78. 78. COLLABORATORS• Antonio Toscano• Olimpia Musumeci• Graziella Uziel• Paola Tonin• Mauro Scarpelli• Massimiliano Filosto• Enrico Bertini• Filippo M Santorelli• Massimo Zeviani• Giacomo P. Comi• Costanza Lamperti• Serenella Servidei• Maurizio Moggio• Monica Sciacco• Tiziana Mongini• Liliana Vercelli• Gabriele Siciliano• Michelangelo Mancuso• Daniele Orsucci• Elena Caldarazzo Ienco• Corrado Angelini• Elena Pegoraro• Marco Spinazzi• Claudio Bruno• Carlo Minetti• Valerio Carelli

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