Your SlideShare is downloading. ×
  • Like
Michelangelo Mancuso, Convegno Mitocon 2014
Upcoming SlideShare
Loading in...5

Thanks for flagging this SlideShare!

Oops! An error has occurred.


Now you can save presentations on your phone or tablet

Available for both IPhone and Android

Text the download link to your phone

Standard text messaging rates apply

Michelangelo Mancuso, Convegno Mitocon 2014



Published in Health & Medicine
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads


Total Views
On SlideShare
From Embeds
Number of Embeds



Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

    No notes for slide


  • 2. HISTORICAL STEPS Symposium Pisa Mitochondrial Medicine - ottobre 2006 AIM Pisa Giugno 2008: first steps Telethon-UILDM Grant 2008 Telethon-UILDM Grant 2009
  • 4. Original steering Committee G Siciliano, Pisa M Mancuso, Pisa G Uziel, Milano E Bertini, Roma GP Comi, Milano T Mongini,Torino A Toscano, Messina V Carelli, Bologna C Angelini, Padova S Servidei, Roma P Tonin, Verona C Minetti, Genova Mitocon
  • 5. Network ºSiena NEW ENTRY! - Siena - Firenze Meyer - Brescia - Stella Maris - Cagliari (in progress)
  • 6. Oversee Committee S DiMauro, Columbia University, New York G Logroscino, Bari J Montoya, Zaragoza, Spain RW Taylor, Newcastle
  • 7. Milan, 2010 May 5th
  • 8. Inter and intra-observer reliability will be tested with sub- samples of 15-20 patients (only with molecular diagnosis) per Center, evaluated simultaneously by two qualified neurologists VALIDATION Catania, 2010 October
  • 9. Time Table PHASE 3 – 12 months: Reassessment of all the cases in each center and build the clinical and laboratoristic register by developing the web−database
  • 10. Sul web…
  • 11. For each center involved in the project, a designated physician will be responsible for the data storage in the database.
  • 12. Cagliari, May 2011 Turin, November 2011 Verify that the data in the web log and start statistical analysis
  • 13. PHASE 4 – Disseminations of results (publications, meetings, workshops etc) and plans for future funding, crucial for future applications of the registry. TIME TABLE Inizio I annoTelethon
  • 14. The network has reached the following goals: 1. Establishment of an Italian network of clinical centers with expertise on MM 2. Creation of a validated web based database, harmonized with other European Databases and Networks 3. Characterization of a big cohort of MM cases
  • 15. We have collected to date 1250 patients (April 2014), with both adulthood and childhood onset of the disease.
  • 16. 33.0 % 23.0 % Molecular diagnosis 18%s.d. 20% ?
  • 17. PEO 28.3% Encephalo- myopathy 25.3% Leber/ADOA 15.3% MELAS 9.0% Leigh 7.3% KSS 2.1% MERRF 4.3% Others 8.4% Mitochondrial syndromes
  • 18. mtDNA point mutations
  • 19. nuclear point mutations OPA1 35.4% POLG1 20.5% Twinkle 11.8% ANT1 2.6% TYMP 5,1 SURF1 10.3% PDHA1 4.6% TK2 2.1% others 7.6%
  • 20. Data analysis Genotype-based approach Phenotype-based approach
  • 21. Mitochondrial DNA single deletion and related phenotypes: data of the Italian Network of Mitochondrial Diseases Italian Network of Mitochondrial Diseases SINGLE DELETION (N= 231 pts) THE BIGGEST COHORT SO FAR ANALYSED!
  • 22. BACKGROUND Mitochondrial DNA (mtDNA) single deletion is one of the major causes of mitochondrial disease. It is commonly associated with progressive external ophthalmoplegia (PEO), Kearns-Sayre syndrome (PEO with multisystem involvement and specific diagnostic criteria), and Pearson syndrome (pediatric refractory sideroblastic anemia associated with pancreatic insufficiency), but its variability is incompletely understood.
  • 23. A 25-year history…
  • 24. …pathogenicity studies…
  • 25. …pathogenicity studies…
  • 26. …but very few systematic clinical studies to date
  • 27. Three well-defined phenotypes
  • 28. AIMS Revision of the clinical data of the patients with a single large-scale mtDNA deletion Is the distinction in three phenotypes justified and clinically useful? How the classic diagnostic criteria could be updated?
  • 30. RESULTS 231 patients with mitochondrial disease due to a single mtDNA deletion have been identified among 1250 patients (18.5%) present in our database (April 15th, 2014). The clinical picture was not available for six patients, who have not been considered in the following analysis  225 patients
  • 31. RESULTS Mean age at onset was 24.3 ± 16.1 years (40.5% childhood onset: <16 years) Mean age at last control 41.7 ± 19.0 years Male-to-female ratio (M/F): 0.67 (slight female prevalence: 60% of all patients). The presence of ptosis and/or ophthalmoparesis was almost universal (212/225, 94.2%). “NEW” PEO AND “NEW” KSS?
  • 32. 0 10 20 30 40 50 60 70 80 90 100 PtosisOphthalmoparesisMuscleweaknessExerciseintol.HearinglossMusclewasting Ataxia DysphagiaIncreasedCK RetinopathyThrivefail./shortst. DiabetesConductiondefects HypotoniaIncreasedALT/AST Neuropathy Musclepain AnemiaCognitiveinv. % White: onset - Black: last evaluation
  • 33. RESULTS: Pearson syndrome (PS) • Six patients (2.6%) fulfilled the criteria for PS (refractory sideroblastic anemia associated with exocrine pancreatic insufficiency) • Mean age at onset 0.3 ± 0.8 years, M/F = 1 • Last control 4.2 ± 2.8 years (died 4/6 patients)
  • 34. RESULTS: Pearson syndrome (PS) Adjunctive clinical features: • 4/6 (67%) increased ALT/AST • 3/6 (50%) failure to thrive/short stature • 2/6 (33%) hypotonia; ptosis; ophthalmoparesis; diabetes mellitus; kidney involvement Lactic acid was increased in 4/6 (67%)
  • 35. RESULTS: “pure” PEO PEO as a purely myopathic disease Additional clinical features may include: • dysphagia • proximal limb weakness • exercise intolerance With these criteria: 121 subjects with “pure” PEO (54.6%), M/F 0.51 (female prevalence), age at onset 27.2 ± 13.9 years, last control 44.7 ± 14.4, died 2/121 (1.7%)
  • 36. Progressive external ophthalmoplegia plus: • pigmentary retinopathy • onset before age 20 Plus at least one of: • cerebellar ataxia • cardiac conduction block • CSF protein > 0.1 g/L RESULTS: Kearns-Sayre syndrome (KSS) With these criteria: 15 subjects with KSS (6.6%) M/F 0.88, age at onset 9.4 ± 4.8 years, last control 29.4 ± 18.0 years, died 2/15 (13.3%)
  • 37. RESULTS: retinopathy Is really retinopathy the pivotal predictor of multisystem involvement (KSS versus PEO)?
  • 38. RESULTS: ataxia …what about the secondary criteria for KSS diagnosis? Features with which ataxia is associated (in addition to retinopathy):
  • 39. RESULTS: cardiac conduction defects …what about the secondary criteria for KSS diagnosis? Features with which conduction defects are associated:
  • 40. KSS CLASSIC CRITERIA: TOO RIGID AND OUTDATED? KSS/PEO distinction should differentiate a multisystem from a purely or prominently myopathic disorder, reflecting the timing of the deletion propagation (Rowland, 1983; Pitceathly NMD 2012), BUT • limited use of CSF protein levels in the current clinical practice • The age limit of 20 years is arbitrary • Many patients with ptosis and/or ophthalmoparesis due to a mtDNA single deletion do not fulfill the criteria for KSS nor for “pure” PEO (77/212, 36.3% in our cohort) • Many multisystem clinical features strongly associated with the signs and symptoms defining KSS (= able to predict their presence or development) are excluded (hearing loss, failure to thrive/short stature, cognitive involvement, cardiomyopathy)
  • 41. “NEW” KSS CRITERIA WHICH WILL BE TESTED HERE Ptosis and/or ophthalmoparesis due to a mtDNA single large-scale deletion and at least one of the following: • Retinopathy • Ataxia • Cardiac conduction defects • Hearing loss • Failure to thrive/short stature • Cognitive involvement • Cardiomyopathy
  • 42. “NEW” SINGLE-DELETION PEO CRITERIA WHICH WILL BE TESTED HERE Ptosis and/or ophthalmoparesis due to a mtDNA single large-scale deletion not fulfilling the “new” KSS criteria
  • 43. With the new clinical definition, we were able to classify almost all (97%) our single-deletion patients: • 62.7% PEO (141/22), vs 54.6 NMD 2012 • 31.6% KSS (71/225), vs 6.6 NMD 2012 • 2.7% Pearson (6/225), NMD 2.7
  • 44. RESULTS: “new” KSS versus PEO General features:
  • 45. RESULTS: “new” KSS versus PEO “Muscular” clinical features:
  • 46. PEO multisystemic? “Multisystem” clinical features are possible (but rare): 6.4% Diabetes (9/141) 4.3% Neuropathy (6/141) 2.1% Migraine (3/141) 2.1% Psychiatric involvement (3/141) 2.1% Hypothyroidism (3/141) (the frequency of these clinical features is not different between KSS and PEO) Longitudinal studies are needed to understand the factors able to predict which PEO patients are at risk of developing KSS, if any.
  • 47. RESULTS: “new” KSS versus PEO Laboratory data: Heteroplasmy levels (muscle) were not different between the two groups (KSS 50.3 ± 16.1 %, PEO 51.2± 16.2 %)
  • 48. % KSS n = 43 (white), PEO n = 66 (blue) RESULTS: Neuroradiological features
  • 49. CONCLUSIONS With the new criteria, we were able to classify almost all (97%) our single-deletion patients: • 62.7% PEO (141/22) • 31.6% KSS (71/225) • 2.7% Pearson (6/225) (with the previous criteria: PEO 54.6%, KSS 6.6%, Pearson 2.7%  total 64%)
  • 50. CONCLUSIONS The new criteria of KSS and PEO which have been proposed here were able to distinguish two natural patient groups (the arbitrary parameter of onset before age 20 was excluded). The new criteria represent an extension of the old criteria, including the multisystem clinical features which are strongly associated with the “old” features (namely retinopathy, ataxia and conduction defects) and which therefore could predict their presence or development.
  • 51. CONCLUSIONS “New” KSS: multisystem involvement, more severe muscular impairment (weakness and wasting), MRI frequently abnormal (white matter, brainstem, basal nuclei), mean age at onset 21 years, worst prognosis. “New” single-deletion PEO: prominent myopathic involvement, MRI frequently normal, mean age at onset 27 years, better prognosis.
  • 52. CONCLUSIONS Lactate and CK, heteroplasmy levels and muscle histology were not different between the two groups. Further studies are needed to elucidate if the two groups reflect a different timing of the deletion propagation, and what other genetic and/or environmental factors may influence the natural history of mitochondrial disorders due to a single, large-scale mtDNA deletion.
  • 54. 0 10 20 30 40 50 60 70 80 90 100 Hearingloss Seizures Diabetes Ptosis/PEOStroke-likeep. MigraineExerciseintol.Muscleweakn.Heartdisease Cognitiveinv.Thrivefail./shortst.IncreasedCK MusclepainMusclewastingGastrointdysmotil. Neuropathy Ataxia HypotoniaPyramidalsigns % White: onset - Black: last evaluation
  • 55. RESULTS Stroke-like episodes are the core feature of MELAS Here we have confirmed that lactic acidosis (even if not mandatory) is associated with stroke-like episodes, confirming the validity of the acronym in A3443G patients A third strongly associated feature was the presence of generalized seizures (≈70%), which were rare in non- MELAS subjects (≈15%) Heteroplasmy levels and muscle histology could not predict stroke-like episodes.
  • 56. Other possibly associated features include cognitive involvement and hearing loss. RESULTS In our m.3243A>G cohort, MELAS was more frequent in males than females: at the mean age of ≈40 years, 53.6% of males had stroke-like episodes as opposed to 32.7% of females.
  • 57. Is the distinction in three phenotypes (MELAS; PEO; MIDD) somehow arbitrary?
  • 58. “pure” PEO rare; associated with heart disease and muscle weakness “pure” MIDD rare; commonly associated with the presence of stroke-like episodes and may be a clinical marker of multisystem impairment, i.e. heart disease, exercise intolerance, cognitive involvement, migraine MELAS CORRECT! UNCORRECT! UNCORRECT! RESULTS
  • 59. Rather than being associated with one of the previously mentioned discrete clinical syndromes, the m.3243A>G phenotypes seem a continuum from asymptomatic to lethal multisystem diseases; between these extremes there are all the possible expressivity degrees RESULTS
  • 60. Comparison with 8344 A>G mutation
  • 61. Possible future plans… Development and validation of the mitochondrial disease quality of life (MitoQoL) questionnaire Adulthood diagnostic criteria Longitudinal studies Clinical features and genotypephenotype correlations: revision Molecular studies and tissue biobank Biomarkers consortium Childhood diagnostic criteria FUNDRISING
  • 62. Global mt database
  • 63. International Registry network  Dr Carolyn Sue (Australia)  Dr Eino Palin (Finland)  Prof.Anu Suomalainen (Finland)  Dr MassimoZeviani (Italy)  DrVictoria Nesbitt (UK)  Prof. Jan Smeitink (Netherland)  Prof.T. Klopstock (Germany)  Dr M. Mancuso (Italy)  Dr Robert McFarland (UK)  Prof. DougTurnbull (UK)  Mr Simon Cockell (UK)  Dr Michio Hirano Dr S DiMauro (USA)  IMP delegates (Mitocon, DGM, UMDF)
  • 64. Italian Network of Mitochondrial Diseases • AntonioToscano • Olimpia Musumeci • Graziella Uziel • Isabella Moroni • PaolaTonin • Mauro Scarpelli • Massimiliano Filosto • Enrico Bertini • Filippo M Santorelli • Massimo Zeviani • Giacomo P. Comi • Costanza Lamperti • Serenella Servidei • Antonio Federico • MT Dotti E Cardaioli • Maurizio Moggio • Monica Sciacco • Tiziana Mongini • LilianaVercelli • Gabriele Siciliano • Michelangelo Mancuso • Daniele Orsucci • Elena Caldarazzo Ienco • CorradoAngelini • Elena Pegoraro • Claudio Bruno • Carlo Minetti • Valerio Carelli • MA Donati