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. Evaluación clínica, escalas
y diagnóstico
Clinical evaluation, scales &
diagnostic
Davide Pareyson
Fondazione IRCCS
Istituto Neurologico Carlo Besta.
Milan. Italia
International Symposium
Nerve biology and inherited peripheral neuropathy.
From biology to therapy
Madrid, December 11-12, 2014

3. CHARCOT-MARIE-TOOTH DISEASE
• Early onset, chronic course, slow progression
• Variability of expression (inter/intrafamilial)
• Inheritance: Autosomal Dominant ++++
X-linked +
Autosomal Recessive + - -
Sporadic cases (de novo) +

4. CMT1
PMP22 Duplication
(60-90%, 50% overall)
MPZ 3-5%, PMP22 1%
CMTX
GJB1/Cx32
(7-12% overall)
CMT2
MFN2 (≤20%)
MPZ (5%)
CMT4
GDAP1 – SH3TC2

6. CMT diagnosis
• Clinical picture, family history
• Define inheritance pattern
• Nerve conduction studies
– Presence and degree of conduction slowing
– Pattern: diffuse-homogeneous / asymmetric, non-homogeneous,
Conduction Blocks, Temporal Dispersion
• Molecular analyses
– Nerve biopsy
– (CSF examination)

7. CMT: ELECTROPHYSIOLOGY -
MCV VALUES (upper limbs)
CMTX1 30-45 m/s, intermediate (but wide range)
Abnormalities Males > Females
0 m/s
CMT1 (CMT4) <38 m/s,usually diffuse uniform slowing
I-CMT: rare intermediate forms
+ normal SAPs = dHMN (motor CMT)
70 m/s
CMT2 > 38 m/s

8. Main CMT types
CMT1A (PMP22) mild-to-moderate, slow NCV, onion bulbs
CMT1B (MPZ) early hypo-dismyelinating, variable severity
CMTX1 (GJB1) males > females, intermediate NCV,
asymmetry, median > ulnar, CNS involvement
CMT2A (MFN2) early severe motor (milder later onset)
CMT2I/J (MPZ) more axonal, late onset, may be severe,
pupillary, hearing loss
CMT4A (GDAP1) early onset, severe, vocal cords, > axonal
CMT4C (SH3TC2) scoliosis, cranial nerves, demyelinating

9. • Mild-to-moderate severity, +- early onset
• +(-) Family history
• Conduction velocities: 7-38 m/s (upper limbs)
– Conduction slowing diffuse and homogeneous
• Most frequent type (40-50% of all CMT cases)
• Variable severity = modifiers??
CMT1A• DNA analysis: PMP22 duplication

10. Pro70SerPro70Ser
• EARLY ONSET
• VERY LOW MCV, 5-25 m/s
CMT1B MPZ/PO
HYPO-DEMYELINATING
NEUROPATHIES OF
DIFFERENT SEVERITY
(CMT1B, DSN, CHN)
AD CMT1 = PMP22 (EGR2, LITAF)
or RECESSIVE CMT4

11. • Males more severely affected >
• Median nerve more affected than ulnar nerve
– males: intermediate 30-45 m/s; females: CMT2 range
– non-uniform conduction abormalities, median > ulnar
CMTX1 (Xq13.1 – GJB1/Cx32)

12. CMTX1 (Xq13.1 – GJB1/Cx32)
• 7-12 % of all CMT; no male-to-male transmission
• Cx32 expressed also in oligodendrocytes
• CNS involvement, usually subclinical
– Abnormal BAEP
– Few cases overt transient central involvement
– Stroke-like, ADEM-like
– Precipitating factors
– Connexin system failure
– Increased water content

13. • Aut. Dominant axonal CMT
• 10-20% of CMT2 cases
• Often severe & early onset, also
later onset and milder
• Often De novo mutations
• + Optic Atrophy (CMT6)
• + Pyramidal involvement (CMT5)
• Recessive. Complex phenotypes
CMT2A – Mitofusin 2
• Onset age 4-5, now 60 yrs
• Progressive course
• Aided walk-chairbound
• Severe Axonal SM neurop.
• Brother & daughter affected

14. Late-onset CMT: MPZ, MFN2, (MARS), …..

15. CMT4A, ARCMT2, I-CMT
• = autosomal recessive CMT
axonal > demyelinating
• Severe, early onset
• Loss of distal movements &
proximal weakness; wheel-
chair
• Vocal cords, diaphragm
CMT2K
• Autosomal dominant CMT
milder, later onset
GDAP1

16. - AR inheritance
- demyelinating pattern
- early onset
- moderate severity
- early scoliosis
-cranial nerve involvement
-basal lamina onion bulbs – outfoldings
CMT4C – SH3TC2
Opponente del pollice sin:
scariche ripetitive complesse
Ulnare dx:
after
discharges
Opponente del pollice sin: treni
di potenziali positivi di Jasper
HINT1 – AR CMT2

17. Additional specific findings
• Piramydal, CMT5: GJB1, BSCL2, MFN2, HSPB1, KIF5A, REEP1, SETX
• Upper limb predominance: GARS, BSCL2
• Optic Atrophy CMT6: MFN2, PRPS1 (+ deafness), C12orf65
• Glaucoma: MTMR13; Cataract: DNM2; Pigm Retin: MTATP6
• Hearing loss or tremor: many types, aspecific
• Vocal cord palsy: GDAP1, TRPV4, DCTN1
• Early severe scoliosis: SH3TC2
• Neuromyotonia: HINT1
• Dysautonomia, pain, disphagia: CMT2J (MPZ)
• Focal Glomerulosclerosis: IFN2
• Cognition: MTATP6, DNMT1, AIFM1
• Myelin Outfoldings: MTMR2/13/5; SH3TC2, FDG4
• Gypsies: NDRG1, HK1, SH3TC2, GDAP1 – Regional findings

18. ENG: demyelinating sensory-motor pattern
Is there male-to-male
transmission?
Myelin
outfoldings
on nerve
biopsy
Glaucoma
Gypsy
population
Spine deformities
Tongue atrophy
Sensory ataxia
17p12 duplication
CMT1A
MPZ
CMT1B
GJB1
CMTX1
PMP22 sequence
CMT1E
ERG2
CMT1D
LITAF/SIMPLE
CMT1C
Yes
No
Negative
Negative
Negative
Negative
GDAP1
CMT4A
Targeted Gene
Panel
(if available)
Autosomal Dominant,
Sporadic
or Recessive
(consanguineous parents)?
Dominant
NEFL
CMT1F
Recessive
MTMR2
CMT4B1
MTMR5
CMT4B3
MTMR13
CMT4B2
FDG4
CMT4H
FIG4
CMT4J
SH3TC2
CMT4C
NDRG1
CMT4D
HK1
CMT4G
PRX
CMT4F
ERG2
CMT4E
Negative
Negative
Negative
First to be
considered
May be rapidly
progressive
IFN2
DI-CMTE
Renal
Involvement
Reconsider
recessive forms
Early onset
Severe phenotype
Exome
Sequencing
(for research)
Reconsider intermediate
forms (see Fig.2)
Pareyson et al., Current Molecular Medicine, 2014 Oct 10

19. ENG: axonal or intermediate sensory-motor pattern
Is there male-to-male
transmission?
MFN2
CMT2A
MPZ
CMT2I/J
DI-CMTD
GJB1
CMTX1
Yes
No
Negative
Negative
Has the patient
predominant
motor involvement? HSPB1
CMT2F/dHMN-IIB
HSPB8
CMT2L/dHMN-IIA
Has the patient
predominant upper
limb involvement?
Has the patient
vocal cord
involvement?
Has the patient
severe sensory
involvement?
KIF5A
CMT2/SPG10
BSCL2
dHMN-VA/CMT2/SPG17
TRPV4
CMT2C/dHMN-VII
RAB7
CMT2B/HSAN-IB
GDAP1
CMT2K
Negative
Exome
Sequencing
(for research)
Negative
Negative
Late
onset
SPTCL1/2
HSAN-IA/IC
Negative
DominantDominant
RecessiveRecessive
NEFL
CMT2E
Has the patient
pyramidal signs?
Usually “axonal”
in females
MFN2
AR-CMT2A
Negative
Negative
HINT1
AR-CMT2
GDAP1
AR-CMT2
Common in
Middle-East
Europe
Most common
intermediate form
GARS
CMT2D/dHMN-I
Targeted Gene
Panel
(if available)
Consider
very rare forms
including
intermediate CMT
Consider
very rare forms
including
intermediate CMT
LMNA (CMT2B1)
MED25 (CMT2B2)
NEFL (CMT2B3)
LRSAM1 (CMT2P)
TRIM2 (AR-CMT2)
PLEKHG5 (RI-CMT)
AARS (CMT2N)
DYNC1H1 (CMT2O)
LRSAM1 (CMT2P)
DMN2 (CMT2M/DI-CMTB)
DHTKD1 (CMT2Q)
YARS (DI-CMTC)
GNB4 (DI-CMTF)
MTATP6
(CMT2/dHMN)

21. CHARCOT-MARIE-TOOTH DISEASE (CMT)
•Cellular and animal models
•Different compounds under investigation
• Difficulties in clinical trials:
•Slow progression
•Multiple reasons for disability: motor, sensory, foot
deformities
•Genetically highly heterogeneous
•Rare forms
•CMT1A most common form (50% all CMT) associated
with PMP22 duplication
•High variability of disease expression
•How to measure disease progression & intervention
efficacy?
PREPARE FOR CLINICAL TRIALS

22. CMT Neuropathy Score (CMTNS.v2)
• Composite score (Shy et al. Neurology 2005;64:1209;
version 2 = Murphy et al. JPNS 2011)
• Symptoms
– Sensory in legs only = 1
– Motor arms and legs =2
• Signs
– Sensory of vibration and pin = 2
– Motor arms and legs = 2
• Electrophysiology
– Motor (median or ulnar) and sensory (radial)
amplitude = 2

23. Murphy et al.
Reliability of the CMT
neuropathy score
(second version) in
Charcot-Marie-Tooth
disease.
JPNS 2011;16:191-8

24. Score 0-36

25. Score 0-40

28. 9 hole-peg test FDT
Foot posture
index
Lunge test
Strength
Myometer
Long jump
Balance - BOT-2
Sensation
6 min
walking
test

29. Clinical OM used in CMT-updated
• Impairment
– Strength assessment: MRC, myometers
– Sensory assessment: INCAT sensory sum score (ISS),
Semmes-Weinstein monofilaments
– Composite: CMTNS, CMTPedS, NIS
– VAS for pain, fatigue, cramps, etc.
• Disability
– Walking: 10 meter timed walking, 6-min walking test
(6MWT), Ambulation index, (activity monitors)
– Upper limbs: 9 hole peg test (9HPT), Box and Block test,
Functional dexterity test, Jebsen test, Sollerman hand
function test, Shape texture identification test, DASH
– Global: ONLS, Barthel Index, Rankin scale,
Novel = HMSN-R-ODS
• Qol
– SF36, RAND, pCMT-QOL

30. Minimal Dataset
Form of standardized
data collection
Modified from Reilly et al
168° ENMC workshop
on CMT. NMD 2010

31. HMSN–R-ODS
Disability scale
Rasch methodology
146 items
Rovekamp F et al.
Activities Difficulty performing this activity
Are you able to: Not possible
Possible with
effort
Easy to
perform
Not
applicable
1
Bend forward and pick something up
   
2
Remain standing for a short time
period, e.g. max 15 minutes
   
3
Remain standing for a long time
period, e.g. several hours
   
4
Stand on one leg
   
5
Stand up from a sitting position
   
6
Stand up from lying down
   
7
Get out of bed
   
8
Stand up from a squatting position
   
9
Kneel down
   
10
Sit down from a standing position
   
11
Lie down from a standing position
   
pCMT-QOL
Sindhu Ramchandren et al.
Infant-Toddler Scale
Sanmaneechai O et al.

32. MRI
BIOMARKERS
SKIN BIOPSY
Power
[W/kg]
Hip Knee Ankle
Moment
[Nm/kg]
Angle
[°]
flex
ext
ext
flex
prod
abs
Gait Analysis
Paraclinical outcome measures

33. Giuseppe Piscosquito
Daniela Calabrese
Paola Saveri
Sara Nuzzo
Anna Sagnelli
Graziana Scigliuolo
Ettore Salsano
Isabella Moroni
Claudia Gandioli
Emanuela Pagliano
Maria Foscan
Alessia Marchi
Stefania Magri
Daniela Di Bella
Micaela Milani
Franco Taroni
IRCCS Foundation,
“C.Besta” Neurological
Institute
Angelo Schenone
Lucilla Nobbio
GianMaria Fabrizi
Tiziana Cavallaro
Franco Gemignani
Isabella Allegri
Luca Padua
Costanza Pazzaglia
Lucio Santoro
Fiore Manganelli
Aldo Quattrone
Giuseppe Vita
Anna Mazzeo
Mary Reilly
Matilde Laurà
Julian Blake
Gita Ramdharry
Sinéad Murphy
Henry Houlden
RAC HughesITALIAN
CMT-NETWORK
MRC Centre for
Neuromuscular Disease
Mike Shy
Carly Siskind
Shawna Feely
Steve Scherer
Richard Finkel
Josh Burns
Michael
Sereda
M. Ferrarin
Polo Tecnologico
Don Gnocchi IRCCS
Foundation, Milan
Stefano Previtali,
Maurizio D'Antonio
HSR IRCCS
Foundation
Vidmer Scaioli
Claudia Ciano
Michela Morbin
Giuseppe Lauria
Raffaella Lombardi
Alessandra Solari
Irene Tramacere
Graziella Filippini
Luisa Chiapparini
Francisco Palau
José Berciano
Vincent
Timmerman
Jonat Baets
P De Jonghe