CHARCOT

MARIE-TOOTH
DISEASE
Sakunrat Sarikit, M.D.
REFERENCES
SCOPE
01. Overview
02. Clinical Manifestation
03. Electrophysiology and electrodiagnosis
04. Genetic pathogenesis
05. Treatment
 CHARCOT-MARIE-TOOTH DISEASE

● The most common inherited peripheral neuropathy

● Syndrome of many genetically distinct hereditary
neuropathies
● Hereditary motor and sensory neuropathy
● Prevalence of 17 to 40 per 100,000
● Onset starting in the 1st -2nd decades of life
● Slow progession
HSMN classification
Inheritedhypertrophic
Demyelinating form, AD

Inheritedneuronal
neuropathies
Axonal form ,AD
Hypertrophicneuropathy
Early onset with severe form
Demyelinating form, AR

Hypertrophicneuropathy
with Phytanic acid excess
Demyelinating form, AR
 MAJOR TYPE OF CMT

Based on inheritance pattern : 40 difference gene and

loci
● CMT 1 (HSMN-I) : most common 40-50%
● CMT 2 (HSMN-II) : neuronal
● CMT 3 (HSMN-III) : Dejerine-Sottas disease
● CMT 4 (HSMN-IV) : Refsum’s disease
● CMT X : X-linked demyelination neuropathies 10- 15%
Genetic pathogenesis
 P MP22, MPZ, GJB1,
MFN2, and GDAP1
 The most important
genes for diagnostic
purposes
= mutation gene
 DIAGNOSTIC APPROACH

● Clinical phenotype
● Identification of inheritance pattern
● Electrophysiological examination
● Molecular analyses
● Nerve biopsy
 INVESTIGATION

● Elevated protein level in CSF (50% of

demyelinating patient)
● Imaging : MRI may showed enlarged lumbosacral
nerve root
Charcot-Marie
Tooth Disease
Type 1
 Charcot-Marie-Tooth Disease
Type 1

● The demyelinating autosomal dominant form

● Most common hereditary neuropathy (1 per 50,000
to 1 per 250,000)
● Onset 1st- 3rd decade of life
● 6 subtype (CMT1A 70-80%,1B,1C,1D,1E,1F)
● all patients remain ambulatory throughout their life
 CLINICAL OF CMT Type 1

● onset commonly early childhood

● Motor symptom > sensory symptom
● Distal lower limb : especially peroneal nerve
innervation muscle
● Clinical Typically presentation : Foot deformity or
delayed motor milestones in child
 MUSCLE WASTING AND WEAKNESS

● Weakness and atrophy of the distal leg muscles

● Predominant effect intrinsic foot and peroneal
innervated
● Thigh and intrinsic hand muscle in late phase
● Foot drop Steppage gait
● Diaphragm and intercostal muscle weakness
 INVERTED CHAMPAGNE BOTTLE SIGN
atrophy of the lower limbs muscles
 STEPPAGE GAIT
Excessive hip flexion and Knee flexion in swing phase
 SKELETAL DEFORMITY

Skeletal deformities are seen in 66%

 Foot deformity : imbalance in strength of the foot
intrinsic and leg muscles
- Pes cavus or Equinovarus, Hammer toes, callus
 Claw hand deformity : Symmetrical distal muscle atrophy
and weakness
 Scoliosis occurring less
 FOOTDEFORMITY
FOOT DEFORMITY

Exuberantcallous
Pes cavus: formation
high arched foot
 Intrinsic hand atrophy

 Neuromuscular scoliosis

 Claw hand deformity

 NERVE ENLARGEMENT

 Hypertrophic nerves
 Palpation of this nerve reveals a
rather firm substance
 CMT 1 > CMT 2
 SENSORY SYMPTOM

 Less prominent than motor symptoms

 Negative symptom > Positive symptom
 Negative symptom : loss of sensation for pain, touch, and
vibration is seen in the feet, with clinical proprioception
relatively preserved.
 Positive sensory symptoms : pain or paresthesia less
common
 Complaints of cold feet and muscle cramps
 REFLEX

 Decrease or absent muscle stretch reflexes (DTR)

 Particularly Ankle reflex always absent
 ELECTROPHYSIOLOGY

 NCV
- Born with normal or only minimally slowed
- Rapidly decline of NCV when the child is 3-5 years of age
- Markedly slow NCV
 The CMAP amplitudes continue to diminish over time,
indicative of axon loss
 DML at birth are commonly borderline abnormal.
- increase until 10 years, at which time there is little
further prolongation of the distal latencies
 NERVE CONDUCTION STUDY IN CMT1

Motor response : usually abnormal

 NCV: >60% reduction when compared normal values
Distal motor latency : prolong in both UE & LE
 Reduced pulmonary function significantly prolonged phrenic
CMAP latencies
CMAP amplitudes
 Very low or absent in EDB & AH muscles
 Slightly decreased early in UE
No evidence of conduction block or temporal dispersion
 NERVE CONDUCTION STUDY IN CMT1

Sensory response : usually abnormal (secondary axonal

loss)
 SNAP amplitudes low or absent
 Prolong DSL & nerve conduction velocity <60% of normal
Late response
 F-waves : latencies are usually absent or extremely
prolonged
 NEEDLE EMG IN CMT1

 Evidence of “distal reinnervation with signs of chronic denervation”

 Often little spontaneous activities (The best muscle= tibialis anterior)
- Fibrillation potentials and positive waves
- CRD and fasciculation
 Reduced recruitment
 The MUAP –long duration, high amplitude & polyphasis
+/- satelite potential
HISTOPATHOLOGY

 Hypertrophic nerve
 CMT1a-“Onion blub formation”
Schwann cell perforation
 CMT1b-“tomacula & uncompact myelin”
Charcot-Marie
Tooth Disease
Type 2
 Charcot-Marie-Tooth Disease
Type 2 (Neuronal CMT)
 The axonal autosomal dominant form
 CMT2 : characterized by more neuronal or axonal
involvement than is seen in CMT1
 Onset 2nd decades of life
 6 subtype (CMT2A, 2B, 2C, 2D, 2E, 2X)
CMT2A,2B - common
CMT2C – occur vocal cord paralysis
 Charcot-Marie-Tooth Disease
Type 2 (Neuronal CMT)
 Clinical similar CMT1 , differential with CMT1 by NCS
 In CMT2A/B compared to CMT1
- Less severe involvement of the intrinsic hand muscles
- More significant atrophy of the distal lower limbs &
weakness of the posterior tibial and calf muscles
- Complete lack of deep tendon reflex is found in only a small
percentage (20-50%)
- Pes cavus and hammer toe deformities are less common in CMT2A/B
 ELECTROPHYSIOLOGIC FINDING IN CMT2

 Evidence of axonal degeneration

 Sensory NCS
- Reduced or absent SNAP amplitudes in UE & LE
- NCV well preserved (greater than 70% of the lower limit
of normal)
- Distal sensory latencies are normal or only mildly
prolonged
 ELECTROPHYSIOLOGIC FINDING IN CMT2

Motor NCS
 NCV normal or only mildly reduced (usually in excess of
70% of the lower limit of normal or >38 m/s)
 Distal motor latencies : normal or only mildly prolonged
 CMAPs are usually absent or reduced in peroneal and
posterior tibialis m. (often preserved in the upper limbs)
 NEEDLE EMG IN CMT2

 Evidence of “distal reinnervation with signs of chronic

denervation” liked CMT1
 CMT1 :Uniform CMT2 : Axonal loss
Demyelination motor > sensory

● SNAP – unobtainable ● Reduced

or very low amplitude SNAP,CMAPs
● CMAP – slightly amplitudes with
decrease amplitude ● mildlyprolonged DSL
DML
● Slow NCV(20-25m/s)
● No conduction block
● NCV normal or only
mildly reduced
(no temporal dispersion)

Needle examination demonstrates signs of chronic

denervation (distally > proximally) in all types of CMT
 Charcot-Marie-Tooth Disease
Type 2 (Neuronal CMT)

Histopathology
 small clusters of thinly myelinated fibers
 loss of the large myelinated fibers
 Axonal atrophy
 Wallerian degeneration
 Onion bulbs (rare)
Charcot-Marie
Tooth Disease
Type 3
 Charcot-Marie-Tooth Disease
Type 3 (Dejerine-Sottas disease)
 Congenital hypomyelination neuropathy
 The most severe form of demyelinating CMT
 Early onset with severe “hypertrophic” demyelination and
remyelination
 Onset infancy or early childhood
 Autosomal recessive (mutations in either the PMP-22, P0,
or EGR2 genes)
 Charcot-Marie-Tooth Disease
Type 3 (Dejerine-Sottas disease)
Clinical presentation
 Generalized weakness (distal muscles >proximal muscles)
or Hypotonia at birth
 Arthrogryposis multiplex
 In less severe case
- Delay in motor development, difficulty running and
jumping,and weakness(LE >UE)
- Weakness can progress Wheelchair dependent
 Charcot-Marie-Tooth Disease
Type 3 (Dejerine-Sottas disease)
Clinical presentation
 Peripheral nerve enlargement is noted in the majority of
patient
 reduction in all sensory especially large myelinated fibers (i.e.,
vibration, proprioception)
 limb and truncal ataxia (lack of sensory input)
 Sensorineural hearing loss
 Abnormal pupillary reaction to light
Arthrogryposis multiplex
 ELECTROPHYSIOLOGIC FINDING IN CMT3

 Evidence of demyelination feature

 Sensory NCS
- Absent SNAP amplitudes in UE & LE
 Motor NCS
- NCV are typically 5-10 m/s or less
- Distal motor latencies : dramatically increased
- CMAPs are usually absent or reduced in size
 NEEDLE EMG IN CMT3

 Different findings depending upon the muscle sampled

 In proximal muscles (less severe)
- Increased insertional activity with variable degrees of
positive sharp waves and fibrillation potentials
- The abnormal MUAPs are increased in amplitude and
duration with more polyphasic potentials noted than
normally found
- Reduced recruitment
 NEEDLE EMG IN CMT3

In distal muscles (terminal stages of the disorder)

 reduction in insertional activity with little spontaneous
fibrillation potentials and positive sharp waves.
 The terminal stages low-amplitude MUAPs with long or short
durations
 Reduced recruitment
Charcot-Marie-Tooth Disease
Type 3

Histopathology
 Hypomyelination with basal
lamina onion bulbs
 Hypomyelination with
 classic onion bulbs
 Amyelination
Charcot-Marie
Tooth Disease
Type 4
 Charcot-Marie-Tooth Disease
Type 4 (Refsum’s disease)

 Hypertrophic neuropathy associated with Phytanic acid

storage disease
 Autosomal recessive demyelinating form
 Rare, more severe course than CMT1
 Earlier onset the first 2 years of life
 Charcot-Marie-Tooth Disease
Type 4 (Refsum’s disease)

Clinical Features
 Classical syndrome
- Peripheral polyneuropathies
- Retinitis pigmentosa
- Cerebellar ataxia
- Elevated protein content in CSF
- Associate Liver, kidney, and heart
disease may also develop
 Vocal cord paresis &
sensorineural deafness, facial
and diaphragmatic weakness
 Scoliosis and skeletal
deformities
 Many children become
wheelchair-dependent
 Charcot-Marie-Tooth Disease
Type 4 (Refsum’s disease)

Clinical
 Motor development is generally delayed
 Weakness and atrophy are more prominent in the distal limbs.
 Proximal muscles become affected by the end of the first decade
 Mild sensory loss
 Areflexia
 ELECTROPHYSIOLOGIC FINDING IN CMT4

NCS are markedly abnormal in CMT4A26 and CMT4B and CMT4F

 SNAPs are generally unobtainable
 CMAPs are usually reduced in amplitude
 NCV
- Less than 20 m/s, and not infrequently less than 10 m/s in CMT4A
and CMT4B
- Slightly faster (ranging from 14 to 32 m/s, mean 24 m/s in the
median nerve) In CMT4C
- NCV were less than 5 m/s in CMT4F
 DML are significantly prolonged
 NEEDLE EMG IN CMT4

 Fibrillation potentials, positive sharp waves, large

polyphasic MUAPs, and decreased recruitment
 Charcot-Marie-Tooth Disease
Type 4 (Refsum’s disease)
Histopathology
 Hypomyelination with basal lamina onion bulbs
Charcot-Marie
Tooth Disease
Type X
 Charcot-Marie-Tooth Disease
Type X
 X-linked dominant (point mutation in the connexin-32 gene on the X
chromosome)
 Intermediate form
 10-15% of the overall CMT cases
 Clinical features similar to CMT1
Except
- Much more severe in men than in women
- Men usually occurs in the first two decades of life
- Women most asymptomatic or mild disease
- The nerves are not profoundly hypertrophic
 ELECTROPHYSIOLOGIC FINDING IN CMT X

 Abnormalities of demyelination and axonal degeneration (Male>Female )

 Sensory NCS
- SNAPs are reduced in amplitude or absent
- The distal latencies and conduction velocities of the SNAPs are slow
- Peroneal CMAPs are absent
- Median and ulnar CMAPs can usually be obtained but the amplitudes
may be diminished
 ELECTROPHYSIOLOGIC FINDING IN CMT X

Motor NCS
 DML are more prolonged (Male >female)
 Temporal dispersion
- Non uniform slowing of NCV between different nerves
 NEEDLE EMG IN CMT X

 Fibrillation potentials, positive sharp waves, large polyphasic MUAPs and

decreased recruitment
 Charcot-Marie-Tooth Disease
Type X

Histopathology
 Mix axonal and demyelinating feature
 few onion bulbs
 ELECTROPHYSIOLOGIC FINDING IN CMT X

 Uniform Demyelinating Neuropathies : NCV slowing is uniform in all

nerve
 Without evident of temporal dispersion or conduction block
 Motor Greater than Sensory Axon Loss
Differential diagnosis
 Between the different CMT types
 Other inherited neuropathies
 Acquired neuropathies
 Distal myopathies
 Motor neuron diseases
 Hereditary ataxias
 Mitochondrial disorders
 Hereditary spastic paraplegias
 Leucodystrophies
TREATMENT
 TREATMENT

 There is still no effective drug therapy for CMT

 Supportive treatment
- Rehabilitative therapy
- Surgical treatment
 REHABILITATION

 Evidence of mild to moderate exercise is effective and safe

- Significant improvement in walking ability and lower limb strength
 Aerobic exercise might improve functional ability and aerobic capacity
 High-resistance training should be avoided
 REHABILITATION

 Shoe modifications, plantar, orthoses and assistive device

 AFO prescribed to overcome foot drop and facilitate walking
- uncomfortable
- poorly tolerated
 Custom-fitted AFO are more comfortable, better compliance, relieve
painful pes cavus
 Bracing orthotics are useful when upper limb involvement is severe
 ”
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