Clinical features of Demyelinating CharcotMarieTooth disease

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Clinical features of Demyelinating
Charcot-Marie-Tooth disease

• Davide Pareyson
• C.Besta
• National Neurological Institute
• Milan, Italy

Prague May 25, 2004
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• CMT network in Italy
• Clinical studies of demyelinating CMT
• Role of gender and pregnancy in CMT1A
• Involvement of CNS in CMTX
• Examples of mutations in new genes
• Current studies
• Future therapies?

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Demyelinating CMT

• Autosomal dominant
• CMT1A PMP22 duplication (17p11.2) 60-90 PMP22
  point mutation 1-3
• CMT1B MPZ (P0) 4-5
• CMT1C LITAF/SIMPLE rare
• CMT1D EGR2 rare
• X-linked
• CMTX GJ1/Cx32 7-10 of all CMT

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Demyelinating CMT

• Autosomal recessive
• CMT4A GDAP1
• CMT4B1 MTMR2
• CMT4B2 MTMR13
• CMT4C KIAA1985
• CMT4D (DSD) PERIAXIN (PRX)
• HMSN-L NDRG1

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CMT1A (PMP22 duplication)

• MOST FREQUENT CMT SUBTYPE (40-50)
• CLINICAL PHENOTYPE
• relatively mild, although variable
• NERVE CONDUCTION mostly MCV 12-35 m/s
• diffuse uniform slowing, no conduction block
• NEUROPATHOLOGY
• diffuse onion bulbs,
• de-remyelination

MODIFIER FACTORS?
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Progesterone and derivates increase PMP22
expression
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Animal model of CMT1A worsening with
progesterone, improvement with its antagonist
onapristone (Sereda, 2003)
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EFFECTS OF PROGESTERONE ON CMT1A?

• Progesterone and derivates increases PMP22
  expression
• Animal model of CMT1A worsening with
  progesterone, improvement with its antagonist
  onapristone (Sereda, 2003)
• Reported cases of CMT worsening during pregnancy
  (dramatic increase in progesterone levels)

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Is there an effect of gender and pregnancy on
CMT1A severity?

• Retrospective evaluation of 84 CMT1A pts.
• Clinical and electrophysiologic data
• Rankin score presence and severity of clinical
  signs
• MCV, DL, CMAPs, F-lat, SCV, SAP ampl.
• Comparison between females and males
• Subgroup analysis for females in fertile age (15
  to 50-yr-old) vs males same age
• Retrospective interview about disease course
  during pregnancy

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Results. Clinical data

• Females 48, Males 36
• Age at onset was similar
• Females 10.9 10.8 Males 8.3 11.3 yrs.
• Age at evaluation higher in females
• Females 34.6 16.9 Males 26.5 17.5 yrs.
• Overall no difference in disease severity
• Upper limb sensory loss F gt M
• (p 0.05 p lt 0.03 for 15 to 50-year-old
  patients)

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CMT1A PREGNANCY

• N. pts. 20 pregnancy 44
• 4 patients had CMT worsening (gait
  disturbances, unsteadiness, weakness, sensory
  disturbances)
• 6 patients had minor complaints (paresthaesias,
  cramps, pain)

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Conclusions

• The effect of sex hormones on PMP22 does not
  result in relevant difference in disease severity
  between the two genders.
• Mild differences in upper limb clinical and
  electrophysiologic findings might be due to
  median nerve involvement at the carpal tunnel.
• Some female patients reported worsening of
  symptoms during pregnancy. Disease and normal
  controls need to be evaluated to establish
  whether this is truly a CMT1A-related phenomenon.

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X-linked Charcot-Marie-Tooth disease (CMTX)

• 2nd most common CMT variety (7-10)
• Connexin-32 (GJ1/Cx32) gene mutations, Xq13.1
• Hemizygous males more severely affected

• Isolated reports of central nervous system (CNS)
  involvement
• 9 patients with transient CNS symptoms
• few pts. abnormal examination (Babinski sign,
  etc)
• evoked potentials and brain MRI abnormalities

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PNS non-compact myelin gap-junctions in
Schwann cells CNS oligodendrocytes, some
neurons. function?
Connexin-32
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CNS involvement

• Clinic ex. (27 pts 13 M, 14 F, from 11
  families) 2 M Babinski, 2 (1 M 1 F) rest
  tremor

• Evoked potentials (central components)
• Brainstem acoustic BAEPs 18 pts.
• Visual Pattern-VEPs Flash-VEPs 16
• Somatosensory SEPs 16
• Motor MEPs 16

• Brain MRI 14

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Brainstem auditory evoked potential (BAEP)
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I
III
V
II
ms/D
V/D
Avg R1/R2
Left
(Cz-A1)
2
0.2u
5022/5213
Control
V
2
0.2u
5011/3866
Right
(Cz-A2)
III
II
I
V
Left
(Cz-A1)
1
0.5u
2133/2446
I
III
II
CMTX
V
Right
(Cz-A2)
2342/2377
1
0.5u
III
II
I
1 D

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BAEPs clear abnormalities 12/18 pts (8/9 M, 4/9
F) borderline 4 pts, normal 2 pts (2 F)

• I-V Interpeak time (ms)
• NORMAL 3.95 ? 0.17
• CMTX FEMALES 4.30 ? 0.43
• CMTX MALES 5.48 ? 0.9

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Somatosensory and motor evoked potential (SEP,
MEP)
SEP
MEP
N20
CCT
N13
registration
stimulus
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• SEPs N13-N20
• normal values ? 7.1 msec
• CMTX Right 7.6 ? 2.5 msec, range 5.1-13.6
  msec Left 7.4 ? 2.0 msec, range 5,3-11.5 msec

• MEPs CCT
• normal values ? 7.2 msec
• CMTX Right 7,1 ? 1,5 msec, range 5,5-10 msec
  Left 7,2 ? 1,8 msec, range 5,1-12 msec

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Evoked potential abnormalities

• E.P. tot M F
• BAEP 12/18 8/9 4/9
• SEP (N13-N20) 8/16 5/8 3/8
• MEP (CCT) 7/16 5/9 2/7
• VEP-pattern 1/16 1/8 0/8
• VEP-flash 9/15 4/7 5/8

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CMTX
NORMAL
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CMTX
Axial brain MRI, FLAIR sequence mild
hyperintensity in the piramidal tracts
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CMTX
A
B
Axial Brain MRI (A) Marked hypointensity in the
periferic portion of dentate nuclei on T2
w.i. Coronal MRI (B) Small foci of hyperintensity
in the hilum of the dentate nuclei on FLAIR
sequence
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CMTX
Hypointensity on T2 w.i. in the postero-lateral
aspect of the putamina
Normal
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NEURORADIOLOGY

• Pts. M F
• BRAIN MRI 14 6 8
• subtle abnormalities 9 3 6
• mild atrophy 4 2 2
• mild Corticospinal tract hyperintensity
  6 1 5
• hypointensity of dentate n. putamina
  2 0 2

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Arg164Gln Arg164Leu
Val181Met
Thr185Ile
Arg22Stop (2)
Leu9Trp
Arg220Stop (2)
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Conclusions

• Subclinical CNS involvement in 18/19 pts.
  (9/10 M, 9/9 F)
• BAEPs most reliable (overall 67 males 89)
• SEPs (50) MEPs (44) useful
• Flash-VEPs high abnormalities (73)
• role of MRI ?
• pathophysiology? Cx32 in CNS
• oligodendrocytes, neuronal populations of
  brainstem, cortex, basal ganglia, nigra
• interaction with other connexins?

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CNS involvement in CMT1A?Evoked potential
studies (central components)

• E.P. N exams abnormal
• BAEP 20 2 borderline
• SEP (N13-N20) 12 0
• MEP (CCT) 5 0
• VEP-pattern 5 0
• VEP-flash 5 0

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CMT1C

• Chr 16p13.3-p12
• LITAF LIPOPOLYSACCHARIDE-INDUCED TUMOR NECROSIS
  FACTOR-ALPHA FACTOR
• (SIMPLE SMALL INTEGRAL MEMBRANE PROTEIN OF
  LYSOSOME/LATE ENDOSOME)
• LITAF may play a role in protein degradation
  pathways
• Widely expressed, including cytoplasm of Schwann
  cells

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Severe CMT1 due to LITAF mutation (Thr49Met)
Marked motor and sensory impairment,
scoliosis NCV lt 35 m/s absent distal CMAPs SAPs
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PERIAXIN
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PERIAXIN

• PRX gene on 19q13.1-13.2 code for L e S-periaxin
• Interaction between L-periaxin, cytoskeleton
  membrane proteins like dystroglican-sarcoglican
  complex
• Necessary for PNS myelin maintainance
• Mutations in families with DSD CMT4
• PRX k.o. mouse develop a severe demyelinating
  neuropathy with allodinia e iperalgesia

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Recessive CMT4/DSD due to PRX gene mutations
(Glu547Stop - Pro807fs)
II-8. Early onset, delayed motor milestones,
severe sensory-motor impairment, scoliosis. MCV
5-9 m/s II-9. Later onset, less severe
involvement. MCV 12-16 m/s
5
3
II-8
II-9
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Ongoing studies

• Quality of life in CMT (funded by Telethon)

Future studies

• Therapy?
• Steroids I.V. Immunoglobulin (IVIG)
• NT3
• Progesterone antagonists
• Ascorbic Acid

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Franco Taroni Micaela Milani Matilde Laurà Angelo
Sghirlanzoni Vidmer Scaioli Claudia Ciano Michela
Morbin Isabella Moroni Alessandra Erbetta Luisa
Chiapparini
C.Besta National Neurological Institute, Milan
- Italy
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BAEPs clear abnormalities 12/18 pts (8/9 M, 4/9
F) borderline 4 pts, normal 2 pts (2 F)

• dx (ms) sin (ms) normal
• I wave 1,63 ? 0,14 1,67 ? 0,35 1,59
• III 4,12 ? 0,34 4,21 ? 0,49 3,70
• V 6,55 ? 1,05 6,65 ? 1,04 5,54
• I-III int. 2,51 ? 0,33 2,54 ? 0,37 2,10
• III-V 2,42 ? 0,73 2,44 ? 0,62 1,85
• I-V 4,92 ? 1,01 4,98 ? 0,92 3,95