dra. teresa sevilla - 'neuropatías periféricas hereditarias

Dr. Teresa Sevilla

CIBERER - HOSPITAL UNIVERSITARI I POLITÈCNIC LA FE

11th-12th December 2014

Valencia

Traslational Research, Experimental Medicine and Therapeutics

of Charcot-Marie-Tooth Disease

FUNDACION RAMON ARECES: CMT's networks

Discipline in biomedical research which aims to expedite the discovery of new diagnostic tools and treatments by using a multi-disciplinary, highly collaborative, "bench-to-bedside" approach

La disciplina en la investigación biomédica y su objetivo es acelerar el descubrimiento de nuevas herramientas de diagnóstico y tratamientos mediante el uso de un enfoque multidisciplinario, altamente colaborativo, "del laboratorio a la cabecera"


TRANSLATIONAL MEDICINE:

IRDiRC Funding Member of Spain:IRDiRC Funding Member of Spain:

Spanish Call for IRDiRC Collaborative Research Joint Projects

Spanish Call for IRDiRC Collaborative Research Joint Projects

TREAT-CMT

Spanish consortium on Charcot-Marie-Tooth disease (CMT) set up in march of 2012.

Based on the multidisciplinary integrationist cooperation of 12 clinical and basic research groups

Translational research

To improve the diagnosis and treatment of the disease and thus of the quality of life of people affected by CMT and their relatives.


No. 8 — Federico V. PallardóFacultat de Medicina Universitat de València


No. 10 — Jorgina Satrústegui

Centro de Biología Molecular “Severo Ochoa” (CBMSO)Universidad Autónoma de Madrid

No. 10 — Jorgina Satrústegui

Centro de Biología Molecular “Severo Ochoa” (CBMSO)Universidad Autónoma de Madrid

No. 9 — José M. CuezvaCentro de Biología Molecular “Severo Ochoa” (CBMSO)Universidad Autónoma de Madrid


No. 11- José Manuel Torres Universitat de València

No. 11- José Manuel Torres Universitat de València

No. 5 — Celedonio Márquez IIS Hospital Universitario

Virgen del Rocio


Virgen del Rocio

No. 4 — Samuel I. Pascual IIS Hospital Universitario La

Paz


Paz

No. 3 — Carlos CasasnovasHospital Universitario de

Bellvitge, IDIBELL


Bellvitge, IDIBELL

No.1 — Francesc Palau Principe Felipe Research Centre

No.1 — Francesc Palau Principe Felipe Research Centre

No. 6 — Carmen Espinós Principe Felipe Research Centre


No. 12 — M. Ibo GalindoPrincipe Felipe Research Centre

No. 12 — M. Ibo GalindoPrincipe Felipe Research Centre

No. 7 — José M. Millán IIS Hospital Universitari i Politècnic La Fe


No. 2 — Teresa Sevilla IIS Hospital Universitari i Politècnic La Fe


12 clinical and basic 12 clinical and basic research groups research groups

Treat-CMT Consortium partnersTreat-CMT Consortium partners


1. Investigation of natural history, clinical phenotyping and generation of clinical tools.

2. Translational genetics and genomics research for the discovery of new CMT genes and identification of biomarkers.

3. Pathophysiology and Therapeutics forms mitochondrial associated CMT

TREAT-CMT3: goalsTREAT-CMT3: goals

3 work package3 work package


Virgen del Rocio


Virgen del Rocio


Paz


Paz


Bellvitge, IDIBELL


Bellvitge, IDIBELL




Treat-CMT: Work package 1(WP1)Treat-CMT: Work package 1(WP1)

1. Establishment of common criteria and procedures for research on natural history and the phenotype of patients with specific clinical forms of CMT

2. Neuropathological phenotyping

3. Integration of clinical databases and generation of a Spanish database of CMT mutations

4. Setting up a distributed biobank of biological samples.

Objectives WP 1



1.Establishment of common criteria and procedures for research on natural history and the phenotype of patients with specific clinical forms of CMT

1. Implement commons clinical evaluation /Neuropathy score protocols

CMT Neuropathy score CMTNS v1 and v2 FSD: Ranking functional lower extremity 9HPT: Standardized, quantitative test of upper extremity function INCAT scale

2. Neuropathological phenotyping

Morphological study of sural nerve biopsy when there is clinical indication (in rare forms)

Skin biopsy was used for investigation of biomarkers (proteome and metabolome analysis), these studies are also engaged in blood samples

Objectives WP 1



3. Integration of clinical databases and generation of a Spanish database of CMT mutations


4. Setting up a distributed biobank of biological samples.

DONORDONOR

SAMPLESAMPLE

HOSPITAL HOSPITAL

SAMPLESAMPLE

NATIONAL RESEARCH GROUPS

NATIONAL RESEARCH GROUPS

INTERNATIONAL RESEARCH GROUPS

INTERNATIONAL RESEARCH GROUPS






Virgen del Rocio


Virgen del Rocio


Paz


Paz


Bellvitge, IDIBELL


Bellvitge, IDIBELL








Treat-CMT Work-package 2 (WP2)Treat-CMT Work-package 2 (WP2)


CMT: PHENOTYPICAL VARIABILITYCMT: PHENOTYPICAL VARIABILITY

1. Genetically heterogeneous: 80 genes CMT/related disorders

Mutations ≠ genes = PhenotypeStill there are families without mutation

2. Phenotypically heterogeneous

Mutations of the same gen ≠ differents phenotypes

Same mutation (same gen) leads to interfamiliar and intrafamiliar variability

Unknown genes

Biomarkers


GDAP1:AR

AD GDAP1 mutationp.R120W (c.358C> T)

GDAP1AD:

CMT2A:Mut MF2

1. Genomic mapping and exome sequencing.

a. Characterising new genes and new mutations involved in CMT and developing tools for exhaustive global diagnosis.

b. Identifying genetic modifiers in patients and their families with mutations in the

GDAP1 gene and carriers of the CMT1A duplication and GJB1 female carriers.

2. Biomarkers in CMT neuropathy

a. Identifying marker proteins of CMT neuropathy connected with oxidative stress & energy metabolism.

b. Identifying metabolites acting as biomarkers in CMT neuropathy.

Objectives WP 1


1. Generation and characterization of models of mitochondrial CMT disease models.a. Human and mouse cell culture models (GDAP1 RNAi, Gdap1loxP

knock-out and Mfn2R94Q transgenic mice)

b. Mouse (Conditional KO Gdap1loxP knock-out and Mfn2R94Q transgenic mice)

c. Drosophila (knock-down & overexpression)

a. Calcium metabolism and preclinical tests in mitochondrial CMT.

Objectives WP 1



Mouse models: Gdap1, Mfn2

Calcium homeostasis

Mouse iPS cells and motor neurons

Drosophila models of mitochondrial CMT and related genes

WP1: Results & future directions

Part.2: Dr. SevillaDr. Sevilla

Part.3: Dr. CasasnovasDr. Casasnovas

Part.4:

Dr. PascualDr. PascualPart.5: Dr. Márquez

Part.6:

Dr. EspinosDr. Espinos

Wp1: ResultsWp1: Results


Total cases partner 2: Hospital La Fe

n=536

Hospital U La Fe N (%)

CMT1 208 (39%)

CMT2 114 (21%)

CMT4 60 (11%)

CMTX 56 (10,5%)

HNPP 31 (6%)

DHMN 67 (12,5%)

TOTAL 536


Total cases partner 3: Hospital Bellvitge

Hospital U de Bellvitge

N (%)CMT1 85 (39%)

CMT2 38 (18%)

CMT4 4 (2%)

CMTX 7 (3%)

HNPP 73 (34%)

DHMN 9 (4%)

TOTAL 216

CMT1, 85

CMT2, 38

CMT4, 4

CMTX, 7

DHMN, 9

HNPP, 73

n=216


Total cases partner 4: Hospital U La Paz

Hospital Universitario

La Paz N (%)

CMT1 65 (51,58%)

CMT2 38 (30,15%)

CMT4 13 (10,31%)

CMTX 6 (4,76%)

HNPP 3 (2,38%)

DHMN 1 (0,79%)

TOTAL 126


Total cases partner 5: Hospital U V. Rocío

Hospital U Virgen del Rocío N (%)

CMT1 93 (56%)

CMT2 37 (22%)

CMT4 14 (8,4%)

CMTX 15 (9%)

HNPP 6 (3,6%)

DHMN 1 (0,6%)

TOTAL 166


TREAT-CMT Total

CMT1 451 (43%)

CMT2 227 (21,7%)

CMT4 91 (8,7%)

CMTX 84 (8%)

HNPP 111 (10,6%)

DHMN 78 (7,5%)

TOTAL 1044

Genetic diagnosis(%)

Unknown genetic diagnosis(%)

CMT1 87,80% 12,19%

CMT2 33,48% 66,51%

CMT4 100% 100%

CMTX 100% 100%

HNPP 100% 0

DHMN 10,56% 89,44%

CMT1, 451

CMT2, 227

CMT4, 91

CMTX, 84

HNPP, 111

DHMN, 79

TREAT-CMT Spanish consortium: total series & genetic diagnosis

n:1044

FUNDACION RAMON ARECES: CMT's networks 8


Series1= IC series, total 1427 patientsSeries 2= SC series, total 1044 patients

1 2 3


Series1= IC series, AD casesSeries 2= SC series, AD cases

1


Series1= IC series, AR casesSeries 2= SC series, AR cases

2


3

Series1= IC series, AR cases & rare mutationsSeries 2= SC series, AR cases & rare mutations


Summary

The most frequent mutations of genes have a similar prevalence in all countries.

In our series there is a relatively high prevalence of AR mutations, probably due to bias introduced Roma population.

We have a very high percentage of rare mutations, probably due to exhaustive genetic study (35 genes) in 50% cases.

Working programme: Contribution of the partners to each work package and their interactions

WP1

Natural history, in-depth phenotyping and clinical

research tools

Leader: Partner 2Partners involved: 3, 4, 5

WP2

Translational genomics

and

Biomarkers development in

CMT diagnostics


WP3

Cellular pathways, pathophysiology and

therapeutics of mitochondrial associated

CMT


WP3

Cellular pathways, pathophysiology and

therapeutics of mitochondrial associated

CMT


WP 4-5 Management structure and dissemination

activities

Coordinator: Partner 1

Translational Research

DiagnosisTherapeutic targets & pathways

Thank you very much for your attention


Scientific Advisory Board

Dr. Mary ReillyMRC Centre for Neuromuscular Diseases, Department of Molecular Neurosciences, UK

Prof. Vincent Timmerman

Department of Molecular Genetics, University of Antwerp, Belgium

Dr. Davide PareysonClinica delle neuropatie degenerative centrali e periferiche, Fondazione IRCCS Istituto Neurologico Carlo, Italy


dra. teresa sevilla - 'neuropatías periféricas hereditarias

Health & Medicine

genomics research

valenciatraslational

biomedical research

fe12 clinical

clinical phenotyping

cabecerafundacion ramon

generation of clinical

politcnic la fe