Los días 11 y 12 de diciembre de 2014, la Fundación Ramón Areces celebró el Simposio Internacional 'Neuropatías periféricas hereditarias. Desde la biología a la terapéutica' en colaboración con CIBERER-ISCIII y el Centro de Investigación Príncipe Felipe. El tipo más común de estas patologías es la enfermedad de Charcot-Marie-Tooth, un trastorno neuromuscular hereditario con una prevalencia estimada de 17-40 afectados por 100.000 habitantes. Durante estos dos días, investigadores mostraron sus avances en la mejora del diagnóstico y el tratamiento y, por ende, de la aproximación clínica y la calidad de vida de las personas afectadas por estas patologías.

1. 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

2.  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"
FUNDACION RAMON ARECES: CMT's networks
TRANSLATIONAL MEDICINE:

3. 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

4. Now

5. 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.
FUNDACION RAMON ARECES: CMT's networks

6. No. 8 — Federico V.
Pallardó
Facultat de Medicina
Universitat de València
No. 8 — Federico V.
Pallardó
Facultat 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. Cuezva
Centro de Biología Molecular
“Severo Ochoa” (CBMSO)
Universidad Autónoma de
Madrid
No. 9 — José M. Cuezva
Centro 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
No. 5 — Celedonio Márquez
IIS Hospital Universitario
Virgen del Rocio
No. 4 — Samuel I. Pascual
IIS Hospital Universitario La
Paz
No. 4 — Samuel I. Pascual
IIS Hospital Universitario La
Paz
No. 3 — Carlos Casasnovas
Hospital Universitario de
Bellvitge, IDIBELL
No. 3 — Carlos Casasnovas
Hospital Universitario de
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. 6 — Carmen Espinós
Principe Felipe
Research Centre
No. 12 — M. Ibo Galindo
Principe Felipe
Research Centre
No. 12 — M. Ibo Galindo
Principe Felipe
Research Centre
No. 7 — José M. Millán
IIS Hospital Universitari i
Politècnic La Fe
No. 7 — José M. Millán
IIS Hospital Universitari i
Politècnic La Fe
No. 2 — Teresa Sevilla
IIS Hospital Universitari i
Politècnic La Fe
No. 2 — Teresa Sevilla
IIS Hospital Universitari i
Politècnic La Fe
12 clinical and basic12 clinical and basic
research groupsresearch groups
Treat-CMT Consortium partnersTreat-CMT Consortium partners

7. FUNDACION RAMON ARECES: CMT's networks
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

8. No. 5 — Celedonio Márquez
IIS Hospital Universitario
Virgen del Rocio
No. 5 — Celedonio Márquez
IIS Hospital Universitario
Virgen del Rocio
No. 4 — Samuel I. Pascual
IIS Hospital Universitario La
Paz
No. 4 — Samuel I. Pascual
IIS Hospital Universitario La
Paz
No. 3 — Carlos Casasnovas
Hospital Universitario de
Bellvitge, IDIBELL
No. 3 — Carlos Casasnovas
Hospital Universitario de
Bellvitge, IDIBELL
No. 2 — Teresa Sevilla
IIS Hospital Universitari i
Politècnic La Fe
No. 2 — Teresa Sevilla
IIS Hospital Universitari i
Politècnic La Fe
12 clinical and basic12 clinical and basic
research groupsresearch groups
Treat-CMT: Work package 1(WP1)Treat-CMT: Work package 1(WP1)

9. 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
FUNDACION RAMON ARECES: CMT's networks

10. FUNDACION RAMON ARECES: CMT's networks
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

11. 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
FUNDACION RAMON ARECES: CMT's networks

12. FUNDACION RAMON ARECES: CMT's networks
3. Integration of clinical databases and generation of a Spanish
database of CMT mutations

13. FUNDACION RAMON ARECES: CMT's networks
4. Setting up a distributed biobank of biological samples.
DONORDONOR
SAMPLESAMPLE
HOSPITALHOSPITAL
SAMPLESAMPLE
NATIONAL RESEARCH
GROUPS
NATIONAL RESEARCH
GROUPS
INTERNATIONAL
RESEARCH GROUPS
INTERNATIONAL
RESEARCH GROUPS

14. No. 8 — Federico V.
Pallardó
Facultat de Medicina
Universitat de València
No. 8 — Federico V.
Pallardó
Facultat de Medicina
Universitat de València
No. 9 — José M. Cuezva
Centro de Biología Molecular
“Severo Ochoa” (CBMSO)
Universidad Autónoma de
Madrid
No. 9 — José M. Cuezva
Centro de Biología Molecular
“Severo Ochoa” (CBMSO)
Universidad Autónoma de
Madrid
No. 5 — Celedonio Márquez
IIS Hospital Universitario
Virgen del Rocio
No. 5 — Celedonio Márquez
IIS Hospital Universitario
Virgen del Rocio
No. 4 — Samuel I. Pascual
IIS Hospital Universitario La
Paz
No. 4 — Samuel I. Pascual
IIS Hospital Universitario La
Paz
No. 3 — Carlos Casasnovas
Hospital Universitario de
Bellvitge, IDIBELL
No. 3 — Carlos Casasnovas
Hospital Universitario de
Bellvitge, IDIBELL
No. 6 — Carmen Espinós
Principe Felipe
Research Centre
No. 6 — Carmen Espinós
Principe Felipe
Research Centre
No. 7 — José M. Millán
IIS Hospital Universitari i
Politècnic La Fe
No. 7 — José M. Millán
IIS Hospital Universitari i
Politècnic La Fe
No. 2 — Teresa Sevilla
IIS Hospital Universitari i
Politècnic La Fe
No. 2 — Teresa Sevilla
IIS Hospital Universitari i
Politècnic La Fe
12 clinical and basic12 clinical and basic
research groupsresearch groups
Treat-CMT Work-package 2 (WP2)Treat-CMT Work-package 2 (WP2)

15. FUNDACION RAMON ARECES: CMT's networks
CMT: PHENOTYPICAL VARIABILITYCMT: PHENOTYPICAL VARIABILITY
1. Genetically heterogeneous: 80 genes CMT/related
disorders
Mutations ≠ genes = Phenotype
Still 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

16. FUNDACION RAMON ARECES: CMT's networks
GDAP1:AR

17. AD GDAP1 mutation
p.R120W (c.358C> T)

18. GDAP1AD:

19. CMT2A:
Mut MF2

20. 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
FUNDACION RAMON ARECES: CMT's networks

21. 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
FUNDACION RAMON ARECES: CMT's networks

22. FUNDACION RAMON ARECES: CMT's networks
Mouse models: Gdap1, Mfn2
Calcium homeostasis
Mouse iPS cells and
motor neurons
Drosophila models of
mitochondrial CMT and
related genes

23. WP1: Results &
future directions
Part.2:
Dr. SevillaDr. Sevilla
Part.3:
Dr. CasasnovasDr. Casasnovas
Part.4:
Dr. PascualDr. Pascual
Part.5:
Dr. Márquez
Part.6:
Dr. EspinosDr. Espinos
Wp1:
Results
Wp1:
Results

24. FUNDACION RAMON ARECES: CMT's networks
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

25. FUNDACION RAMON ARECES: CMT's networks
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

26. FUNDACION RAMON ARECES: CMT's networks
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

27. FUNDACION RAMON ARECES: CMT's networks
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

28. FUNDACION RAMON ARECES: CMT's networks
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

29. FUNDACION RAMON ARECES: CMT's networks8

30. FUNDACION RAMON ARECES: CMT's networks
Series1= IC series, total 1427 patients
Series 2= SC series, total 1044 patients
1 2 3

31. FUNDACION RAMON ARECES: CMT's networks
Series1= IC series, AD cases
Series 2= SC series, AD cases
1

32. FUNDACION RAMON ARECES: CMT's networks
Series1= IC series, AR cases
Series 2= SC series, AR cases
2

33. FUNDACION RAMON ARECES: CMT's networks
3
Series1= IC series, AR cases & rare mutations
Series 2= SC series, AR cases & rare mutations

34. FUNDACION RAMON ARECES: CMT's networks
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.

35. 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 2
Partners involved: 3, 4, 5
WP2
Translational
genomics
and
Biomarkers
development in
CMT diagnostics
Leader: Partner 6
Partners involved: 7, 8, 9
WP3
Cellular pathways,
pathophysiology and
therapeutics of
mitochondrial associated
CMT
Leader: Partner 1
Partners involved: 10, 11, 12
WP3
Cellular pathways,
pathophysiology and
therapeutics of
mitochondrial associated
CMT
Leader: Partner 1
Partners involved: 10, 11, 12
WP 4-5
Management
structure and
dissemination
activities
Coordinator:
Partner 1
Translational Research
DiagnosisTherapeutic targets & pathways

36. Thank you very much for
your attention
FUNDACION RAMON ARECES: CMT's networks

37. Scientific Advisory Board
 Dr. Mary Reilly
MRC Centre for Neuromuscular Diseases, Department of
Molecular Neurosciences, UK
 Prof.VincentTimmerman
Department of Molecular Genetics, University of Antwerp,
Belgium
 Dr. Davide Pareyson
Clinica delle neuropatie degenerative centrali e periferiche,
Fondazione IRCCS Istituto Neurologico Carlo, Italy
FUNDACION RAMON ARECES: CMT's networks