The Italian Mito-Patients Register: state of the

art and next steps

Michelangelo Mancuso

Gabriele Siciliano

Pisa

Original steering Committee

G Siciliano, Pisa

M Mancuso, Pisa

G Uziel, M Zeviani, Milano

E Bertini, Roma

GP Comi M Moggio, Milano

T Mongini,Torino

A Toscano, Messina

V Carelli, Bologna

C Angelini, Padova

S Servidei, Roma

P Tonin, Verona

C Minetti, Genova

Mitocon

Expanded Network

ºSiena

- Firenze Meyer

- Brescia

- Stella Maris Pisa

- Cagliari

- Siena

Italian Network of Mitochondrial Diseases

• Corrado Angelini

• Luca Bello

• Enrico Bertini

• Claudio Bruno

• Elena Caldarazzo Ienco

• Valerio Carelli

• Michela Catteruccia

• Giacomo Pietro Comi

• Maria Alice Donati

• Maria Teresa Dotti

• Antonio Federico

• Massimiliano Filosto

• Costanza Lamperti

• Michelangelo Mancuso

• Carlo Minetti

• MITOCON

• Maurizio Moggio

• Tiziana Mongini

• Isabella Moroni

• Olimpia Musumeci

• Daniele Orsucci

• Elena Pegoraro

• Dario Ronchi

• Filippo Maria Santorelli

• Mauro Scarpelli

• Monica Sciacco

• Serenella Servidei

• Gabriele Siciliano

• Paola Tonin

• Antonio Toscano

• Graziella Uziel

• Maria Lucia Valentino

• Liliana Vercelli

• Massimo Zeviani

The network has reached the following goals:

1.Establishment of an Italian network of clinical

centers with expertise on MM and cooperation

with MITOCON

2.Creation of a validated web based database,

harmonized with other European Databases and

Networks

3.Characterization of a big cohort of MM cases

4.Dissemination of our results

We have collected to date 1289

patients (June 2015), with both

adulthood and childhood onset of

the disease.

35.0 % 26.0 %

Molecular diagnosis

19%single

deletions 20% ?

Circa 200 pz con delezioni multiple

77 pz con diagnosi molecolare

38.5%

ANT1 2

C10orf2 (twinkle) 16

dGK 1

ECGF1 (Thymidine phosphorylase) 6

OPA1 27

POLG1 22

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

mtDNA point mutations

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%

Three well-defined phenotypes

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%)

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 %)

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% KSS n = 43 (white), PEO n = 66 (blue)

RESULTS: Neuroradiological features

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

“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.

‘MITOCHONDRIAL

NEUROPATHIES’

DATA FROM THE ITALIAN

NETWORK

DANIELE ORSUCCI (PISA)

IN BEHALF OF THE ITALIAN NETWORK OF MITOCHONDRIAL DISEASES

Mean age at onset 24.3 ± 20.1 years

Age at last evaluation 39.8 ± 22.3

years

Childhood onset [before age 16-yrs]

43.1%

Females 52.7%

RESULTS

Overall CNS involvement 334/1013 (33.0%) 82/143 (57.3%) <

0.0001

* Significance levels after Bonferroni’s correction 0.0036

*

If we exclude Leber patiens:

neuropathy in 142/1052

(13.5%)

* Significance levels after Bonferroni’s

correction 0.0042

*

Ongoing…

Development and validation of the mitochondrial disease quality of life (MitoQoL) questionnaire

Adulthood diagnostic criteria

Longitudinal studies

Clinical features and genotype\phenotype correlations: revision

Molecular studies and tissue biobank

Biomarkers consortium

Childhood diagnostic criteria

FUNDRISING

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)