Charcot-Marie-Tooth Syndrome - A Neurologic Disease

A presentation on CMT

1. CHARCOT-MARIE-CHARCOT-MARIE-
TOOTH SYNDROMETOOTH SYNDROME

2. Objectives
• to present an interesting case of Hereditary
Motor Sensory Neuropathy or Charcot-
Marie-Tooth Syndrome
• to discuss its clinical manifestations,
diagnostic modalities, and advances in
genetic investigations

3. General Data
• MGM
• 11-year-old female
• right-handed
• from Novaliches, QC

4. Chief Complaint
progressive weakness

5. History of Present Illness
• 6 years PTA, at the age of 5 years:
• frequent trips and falls when running
• clumsiness
• consulted at QCGH
• left leg was shorter than her right leg

6. History of Present Illness
• No laboratory exams
• No definite diagnosis was given
• No plan of management was advised

7. History of Present Illness
• At age 6 years:
• persistence of symptoms
• trips and falls now also noted even
when just walking
• difficulty in standing up from a sitting
position
• no report of any pain or numbness

8. History of Present Illness
• At age 6 years:
• POC: X-ray of the legs
• left leg was shorter than the right
• No definitive management was
advised.

9. History of Present Illness
• At age 7 years:
• difficulty in climbing up the stairs
• At age 8 years:
• progression in difficulty in ambulation
• had to hold on to her classmates or
other objects when walking

10. History of Present Illness
• At age 9 years:
• handwriting was deteriorating
• difficulty in extending her right ring and
little fingers
• feet are starting to invert

11. History of Present Illness
• At age 10 years:
• unable to ambulate alone
• feet have become more inverted
• fingers, more claw-like in appearance
• note of thinning of the legs
• no consultation was done

12. History of Present Illness
• At age 11 years, 3 months PTA:
• QCGH because of an asthma attack
• noted her progressive weakness as well
as the deformity of her feet
• low potassium
• EMG-NCV was requested: done at
PCMC
• on regular check-up but no definite
plan was advised

13. History of Present Illness
• 2 months PTA:
• JRRMMH: Neurology and Orthopedics
• X-ray: scoliosis
• advised to have a brace fitted
• plan: to perform surgery on her feet,
pending clearance

14. History of Present Illness
• 2 months PTA:
• meanwhile, patient’s condition
persisted
• had to stop going to school
• could still move within short distances
• left ring finger is now starting to
contract
•  PCMC-OPD

15. Review of Systems
• (-) fever
• (-) cough/colds/dyspnea
• (-) bowel/bladder disturbance
• (-) numbness/paresthesias/pain

16. Past Medical History
• no previous hospitalizations
• asthma, intermittent

17. Birth and Maternal History
• born to a then 20-year-old primigravid,
with intake of herbal abortifacients
• no MV’s/FeSo4
• no pre-natal check-up
• UTI at 2 months AOG and varicella at 8
months AOG

18. Birth and Maternal History
• delivered full term at a clinic with good
cry and activity
• no cyanosis, jaundice
• no perinatal complications

19. Immunization History
• (+) BCG, DPT3, OPV3, measles, Hepa B3
(given at their Local Helath Center)

20. Developmental History

21. Developmental History

22. Family History

23. Physical Examination
• Weight: 27.3 Kgs (p25)
• Height: 130 cm. (p50)
• HC: 53 cm. (p50)
• BP: 90/60 mmHg
• HR: 88/min.
• RR: 20/min.

24. Physical Examination
• Conscious, coherent, non-ambulatory
• Pink conjunctivae, anicteric sclerae, no
cervical lymphadenopathy, no
tonsillopharyngeal congestion

25. Physical Examination
• (+) levoscoliosis, clear breath sounds,
no rales, no wheezes
• adynamic precordium, regular
rhythm, no murmurs
• flat abdomen, normoactive bowel
sounds, no organomegaly
• Full pulses, no edema
• easily palpable ulnar nerve

26. Physical Examination
• good sphincter tone
• Tanner’s Stage: Stage III (breast
mound, curly pubic hair)

27. Physical Examination

28. Physical Examination

30. Neurologic Examination
• Conscious, coherent, oriented to
person, place and time, no right-left
disorientation, appropriate affect, intact
recent and remote memory, no
dyscalculia

31. Neurologic Examination
• Pupils 2mm, equally brisk reaction to
light, both direct and consensual
• Visual acuity: 20/20, OU
• No visual field cuts
• OU: (+) ROR/AV 2:3/clear media/
distinct disc borders/no
hemorrhages/exudates
• Full extra ocular Muscle movements

32. Neurologic Examination
• Intact V1-3, good masseter and
temporalis tone
• No facial asymmetry
• No lateralization on Weber’s
• Rinne’s: AC>BC
• Good gag reflex
• Equal shoulder elevation, good
sternocleidomastoid tone
• Midline tongue, no fasciculations

33. Neurologic Examination
• Sensory:
• Intact sensation to pain and
temperature
• Intact vibratory and position sense

34. Neurologic Examination
• Atrophic muscles with hypothenar and
thenar atrophy and stork-like appearance
of the legs
• No fasciculations
• No involuntary movements

35. MUSCLE RIGHT LEFT
Neck, flexors 5 5
Neck, extensors 5 5
Arm elevation 4 4
Arm adduction, downward 4 4
Arm adduction across the chest 4 4
Elbow flexors 4 4
Elbow extensors 4 4
Wrist flexors 4 4
Wrist extensors 3 3
Finger flexion (PIP/DIP) 2 2
Finger extension (PIP/DIP) 2 2
Finger Abduction-Adduction 2 2

36. MUSCLE RIGHT LEFT
Hip flexion 4 4
Hip extension 4 4
Thigh abduction 4 4
Thigh adduction 4 4
Knee flexion 3 3
Knee extension 3 3
Dorsiflexion 1 1
Plantarflexion 1 1
Toe Flexion 1 1
Toe Extension 0 0

37. Neurologic Examination
Muscle Stretch Reflexes Right Left
Biceps + +
Triceps + +
Brachioradialis + +
Quadriceps 0 0
Achilles 0 0

38. Neurologic Examination
• No superficial abdominal reflex
• No extensor toe signs
• No clonus
• No dysmetria, dysdiadochokinesia
• No nystagmus
• Supple neck

39. Salient Features:
• chronic progressive weakness
• gait disturbance
• deformity of hands and feet
• atrophy of muscles
• strong family history of similar symptoms
• muscle weakness: distal more than proximal
• hyporeflexia to areflexia

40. Localization: LMN vs. UMN?
CHARACTERISTICS LMNUMNPX
Paralyzes movements ---+ ---
hemiplegig, quadriplegic or
paraplegic distribution;
not individual muscles
Paralyzes individual muscles
or sets of muscles in root or
peripheral nerve distributions + ---+

41. Localization: LMN vs. UMN?
CHARACTERISTICS LMNUMNPX
Atrophy of disuse only
(late and slight) ---+ ---
Atrophy of denervation
(early and severe) + ---+
Fasciculations and fibrillations+ ------
Hyperactive MSR’s ---+ ---
Hypoactive MSR’s + ---+

42. CHARACTERISTICS LMNUMNPX
Clonus ---+ ---
Spasticity ---+ ---
Hypotonia + ---+
Extensor toe sign ---+ ---
Localization: LMN vs. UMN?

43. Localization: LMN vs. UMN?
Lower Motor
Neuron

44. Clinical signs
Ant
Horn
Cell
Dorsal
root
ganglion
Axons
of PN
NM
Junction

Muscle

Patient
Weakness + - + + + +
Hypotonia + + + +/- + +
Atrophy + - + - + +
Hyporeflexia/areflexia + + + +/- - +
Fascisulations/
fibrillations
+ - + - - -
Percussion myotonia - - - - + -
Sensory loss - + + - - -

Localization: Neuropathy,
Myopathy, NM Junction?

45. Localization: Neuropathy,
Myopathy, NM Junction?

46. Acquired or Hereditary?
Hereditary
 Acquired:
 infectious
 toxic exposure
 autoimmune diseases such as GBS
 drug interactions
 others

47. Hereditary
Charcot-Marie-Tooth I:
most common form of hereditary neuropathy
onset: 5 years old
 progressive weakness and atrophy
 hand and foot deformities, scoliosis
 no sensory complaints

48. Hereditary
Charcot-Marie-Tooth II:
progressive weakness and atrophy
hand and foot deformities, scoliosis
 onset: 20-30 years
 severe sensory complaints

49. Hereditary
Dejerine-Sotas:
progressive weakness and atrophy
hand and foot deformities, scoliosis
 severe sensory deficits
 delayed motor milestones

50. Hereditary
Giant Axonal Neuropathy:
progressive weakness and distal atrophy
hypo/areflexia
profoundly impaired vibratory and
proprioceptive sensations
 Early onset: 3 years

51. Hereditary
Metachromatic Leukodystrophy:
progressive weakness and distal atrophy
hypo/areflexia
 Cerebral demyelination  Dementia,
spasticity and blindness

53. Hereditary
Other Leukodystrophies: weakness and
hyporefelxia are not presenting symptoms
Krabbe disease: psychomotor retardation
 Cockayne syndrome: progeria, small stature,
ataxia

54. Course
NCV:
• SNAP: moderately to severely reduced
• SNC: mildly to moderately slowed
• CMAP: moderately to severely reduced
• MNC: moderately slowed

55. Course
EMG:
• increased insertional activity
• fibrillations
• normal to large amplitude, normal to prolonged
duration MUAP’s in all muscles with many
serrated potentials
• moderate to severe reduction of recruitment

62. IMPRESSION
Chronic Hereditary Polyneuropathy:
Charcot-Marie-Tooth Syndrome or
Hereditary Motor-Sensory Neuropathy

63. Course at the OPD
• for sural nerve biopsy
• physical/occupational therapy
• orthopedic referral

64. Historical Background
•1873: Eichhorst provided a more
complete description of a 6-generation
family with weakness and atrophy of the
feet and hands
•1885: Virchow described a young man
with progressive weakness with
abnormally thickened nerves

65. Historical Background
• 1886: Jean Martin Charcot and Pierre Marie
of France described 5 children with an inherited
form of peroneal muscular atrophy characterized
by a progressive weakness and atrophy of distal
muscles, usually originating in the feet and lower
legs and progressing to the arms and forearms
• "Concerning a Special Form of Progressive
Muscular Atrophy Often Familial, Starting in the
Feet and Legs, and later Reaching the Hands“

66. Historical Background
• Howard H. Tooth: a student at Cambridge
University, was independently working on his
thesis for the MD degree
• The Peroneal Type of Progressive Muscular
Atrophy
•Tooth correctly hypothesized that the disorder
was caused by peripheral nerve dysfunction
• Thus, the eponym Charcot-Marie-Tooth

67. Historical Background
• 1912: Hoffman described a case of peroneal
muscular atrophy with thickened nerves
• late 1950’s: Gilliatt and Thomas noted that
some patients with CMT had slow nerve
conduction velocities

68. Historical Background
• 1960’s: Dyck and Lambert classified CMT into 2
pathologically and electrophysiologically distinct
subsets:
• CMT1 with slow NCV and nerve hypertrophy
• CMT2, normal NCV without nerve hypertrophy
• eventually developed a characterization with
seven subtypes called Hereditary Motor and
Sensory Neuropathies (HMSN).
• This name is more commonly seen in European
journals.

69. Historical Background
• 1980: Harding and Thomas, demonstrated further
that CMT1 and CMT2 both segregated mainly as an
autosomal dominant trait
• 1982: Lewis and Sumner showed that patients with
CMT1 have uniformly slowed NCV’s in contrast with
patients with acquired demyelinating neuropathies
such as GBS

70. Historical Background
• Recent advances in genetics have shown rapid
progress in identifying specific genes responsible for
various subtypes of this disorder.

71. Definition
• Charcot-Marie-Tooth Syndrome, or as others may
prefer to call it Hereditary Motor and Sensory
Neuropathy, refers to a pathologically and
genetically heterogenous group of motor and
sensory neuropathies
• It is a collection of diseases with similar signs and
symptoms rather than a single disease entity.

72. Epidemiology
• one of the most common degenerative neurological
disorders with a prevalence of 1 in 2500
• most common inherited neuropathy and CMT
disorders comprise about 80 to 90% of all genetic
neuropathies Kamholz, et. al, 2000, Brain
• In the US: incidence of more than 42 per 100,000
which represents more than 250,000 cases
nationwide Lovelace, 1999, Motor Disorders

73. Epidemiology
• Various epidemiological studies worldwide showed
the following rates:
• 28.2/100,000 (Cantabria)
• 19/100,000 (Sweden)
• 16.7/100,000 (South Wales)
• 20.1/100,000 (North Sweden)
• 17.5/100.000 (Molise, Italy) Morocutti, et. al, 2002,
Neuroepidemiology
• No racial nor gender predilection exists

74. Epidemiology
• Dyck and Lambert in 1975: credited for the first
comprehensive classification of the syndrome
• distinguished different types on the basis of clinical,
genetic, electrophysiological and histological
characteristics
• Charcot-Marie-Tooth disease in the genetic
nomenclature
• Hereditary Motor and Sensory Neuropathy which is
more often used in neurologic literature Ouvrier, 1996,
Journal of Child Neurology

75. CMT I or HMSN I
• most common form
• early age of onset (first or second decade of life)
• corresponds to a DEMYELINATING type
• slow NCVs of less than 38m/sec
• hypertrophic nerves are secondary to segmental
demyelination/remyelination and the subsequent
formation of onion bulbs seen in nerve biopsies
• visible in light and electron microscope as
concentrically laminated Schwann Cell cotyledons in
layers

76. CMT I or HMSN I
• In all CMT1 genotypes, 50-75% of affected
individuals present with pes cavus and hammertoes
• 65% of the cases have distal upper limb
involvement
• Distal sensory impairment is present, but is
usually asymptomatic
• vibratory sensation is typically diminished
• Gene penetrance is complete, but exhibits variable
phenotypic expression and age of onset

77. CMT II or HMSN II
• AXONAL type
• usually normal nerve conduction velocities
• basic problem is thought to lie within the axon and
not the myelin covering
• nerve conduction velocities are greater than 38 m/s
• biopsies are characterized by chronic axonal loss
• Clinical symptoms usually develop in the second
decade

78. CMT III or Dejerine-Sotas
• Dejerine-Sotas disease
• severe demyelination and is characterized by
infantile onset with delayed motor skills
• Nerve conduction velocities of < 10m/s is a
hallmark of this condition
• Marked segmental demyelination and thinning of
the myelin around the nerve is observed on
histologic examination
• Onion bulb formations are always seen, often with
double basal laminae Dubourg, et. al., 2001, Brain

79. CMT IV or HMSN IV
• rare form of demyelinating CMT
• characterized by progressive motor/sensory
neuropathies
• autosomal recessive inheritance
• typical CMT phenotype of distal muscle weakness
and atrophy associated with sensory loss and,
frequently, pes cavus, although it is usually more
severe and the onset is earlier
• comprises six subtypes (CMT4 A, B, C, D, E and F)
• usually marked by slow (15-30 m/s) NCVs

80. CMT I-X
• X-linked form
• inherited dominantly or, rarely, recessively
• clinical features overlap with those of CMT1
• males are more severely affected than females
• affected males have childhood or adolescent onset
of a slowly progressive motor/sensory neuropathy
associated with foot drop, pes cavus and distal limb
atrophy
• affected females exhibit milder symptoms or may
be asymptomatic

81. CMT I-X
• primary axonopathy with secondary demyelination,
although a mixed picture (myelinopathy/axonopathy)
• NCVs of affected males are typically faster (20-30
m/s) than those of individuals affected by CMT1, but
there is an overlap in NCV ranges between the two
types
• mild slowing of NCVs is typical in affected females

82. Hereditary neuropathy with liability
to pressure palsies (HNPP)
• episodes of numbness, weakness, and muscular
atrophy
• mildly slowed NCVs and conduction blocks at
entrapment sites
• clinical presentations overlap with Multifocal Motor
Neuropathy (MMN), Chronic Inflammatory
Demyelinating Polyneuropathy (CIDP), and
Hereditary Neuralgic Amyotrophy (HNA; Brachial
Plexus Neuropathy)

83. Hereditary neuropathy with liability
to pressure palsies (HNPP)
• In a study (by Harding, A.E. et al.) of 51 patients
with a clinical diagnosis of multifocal neuropathies,
24 (47%) were found to have the 1.5 mb deletion
linked to HNPP
• In the same study, it was recommended that
molecular testing be considered in patients with
multifocal neuropathies that do not conform to the
classical clinical presentation of HNPP.

84. Hereditary neuropathy with liability
to pressure palsies (HNPP)
• caused by a deletion of the same region of
chromosome 17 that is duplicated in CMT1A
• typically present as focal symptoms of weakness or
sensory loss following compression of individual
nerves
• symptoms are usually transient, lasting from hours
to days
• pure carpal tunnel syndrome (CTS) presentation is
only rarely, if ever, a presentation of HNPP
• occasionally, a brachial plexopathy may be the
presenting symptom

85. Clinical Manifestations
• significant family history of the disorder
• varies depending on the mode of inheritance and
penetrance pattern of the particular disorder

86. Clinical Manifestations
• Slow progressing weakness beginning in the distal
limb muscles generally is noted
• occurring in the lower extremities before the upper
extremities
• CMT type 1A may present with proximal muscle
wasting and weakness
• onset of symptoms usually occurs in the first or
second decades of life

87. Clinical Manifestations
• initially may complain of difficulty walking and
frequent tripping due to foot and distal leg weakness
• frequent ankle sprains and falls are characteristic
• parents may report that a child is clumsy or simply
not very athletic

88. Clinical Manifestations
• foot drop commonly occurs
• Steppage gait: in which the individual must lift the
leg in an exaggerated fashion to clear the foot off of
the ground Intrinsic foot muscle weakness
• commonly results in the foot deformity known as
pes cavus
• symptoms related to structural foot abnormalities
include calluses, ulcers, cellulitis, and lymphangitis

89. Clinical Manifestations
• Hand weakness results in complaints of poor finger
control, poor handwriting, difficulty using zippers and
buttons, and clumsiness in manipulating small
objects
• usually do not complain of numbness
• may be because patients with CMT never had
normal sensation and, therefore, simply do not
perceive their lack of sensation

90. Clinical Manifestations
• pain, both musculoskeletal and neuropathic types,
may be present
• muscle cramping is a common complaint
• autonomic symptoms usually are absent, but a few
men with CMT have reported impotence.

91. Physical Examination
• Distal muscle wasting: stork leg or inverted
champagne bottle appearance
• pes cavus (high arch foot), probably analogous to
development of claw hand in ulnar nerve lesion,
has a 25% occurrence rate in the first decade of
life and a 67% occurrence rate in later decades
• other foot deformities also can occur
• Spinal deformities (eg, thoracic scoliosis)
occur in 37-50% of patients with CMT type 1
• recurrent patellar dislocations, developmental
dysplasia of the hip

92. Physical Examination
• DTRs: diminished to absent
• Vibration sensation and proprioception: typically
diminished
• patients usually have no sensory symptoms
• pain and temperature is usually intact
• essential tremor is present in 30-50% of patients
with CMT and this combination is sometimes
referred to as Roussy-Levy Syndrome
• Sensory neuronal hearing loss is observed in 5%
of patients

93. Physical Examination
• Enlarged and palpable peripheral nerves are
common
• Phrenic nerve involvement with diaphragmatic
weakness is rare but has been described in
HMSN III
• Vocal cord involvement can occur

94. Genetics
• molecular genetics has more clearly defined the
clinical and genetic diversity of CMT
• Autosomal dominant, autosomal recessive, and X-
linked families have been documented

95. Genetics

96. Genetics
• Recent molecular investigations have given further
insight into the heterogeneity of CMT and in some
instances, allowed the localization and identification
of the defective genes
• To date, more than 20 subtypes of CMT have been
identified

97. Genetics
• CMT 1A, the most common form of CMT 1, was
shown to be caused by a duplication on
chromosome 17 in 70-90% of cases
• Chromosome 17 contains the gene encoding
for peripheral myelin protein 22kD (PMP22)
• two copies of this gene are present on one
chromosome 17 instead of the usual one copy
• causes too much of the PMP22 protein to be
made in the Schwann cells (cells that make
myelin)

98. Genetics
• the other 10 to 30 percent of people with
CMT1A have a point mutation within the PMP22
gene
• the mutation affects a single base or letter in the
DNA
• It is believed that PMP22 plays a role in
communication between the myelin and the axon
• exactly how these mutations lead to the
symptoms associated with CMT is unclear

99. Genetics
• Interestingly, a deletion of exactly the same 1.5
Mb region containing PMP22 is now known to
cause HNPP
• People with CMT1A have a duplication of the
PMP22 gene for a total of three copies, on the
other hand, individuals with HNPP have a
deletion of the PMP22 gene for a total of only one
copy
• CMT1A and HNPP are inherited in an
autosomal dominant manner

100. Genetics
• Missense mutations in the major PNS myelin
protein gene, on chromosome 1, encoding
myelin protein zero (MPZ), cause CMT1B
• MPZ is a member of the immunoglobulin
superfamily, has a single transmembrane
domain, and is necessary for the adhesion of
concentric myelin wraps in the PNS internode

101. Genetics
• Missense mutations in the early growth
response 2 (EGR2, also called krox20), on
chromosome 10, cause CMT1D
• EGR2 is a transcription factor involed in the
regulations of as yet unspecified genes in the
myelinating Schwann cell.

102. Genetics
• Sequence variations in the MPZ, Cx32 and
KIF1B (Kinesin Superfamily Protein) genes
have been associated with CMT2
• NEFL gene has been identified as a cause of a
CMT2 subtype
• product of this gene, neurofilament light chain
protein, forms the cytoskeletal component of the
myelinated axon

103. Genetics
• X chromosome and is called connexin 32
• important in forming links between nerves
• CMTX is inherited in an X-linked pattern that is
different from CMT type 1 and 2

104. Genetics

105. Genetics
• In a few people with CMT, the pattern of
inheritance is autosomal recessive
• This type of CMT does not clearly fall under
type 1 or type 2
• Chromosomal areas where the genes that
cause the autosomal recessive types of CMT
have been found, although the specific genes
have not yet been identified.

106. Genetics

109. Pathology
• No inflammatory infiltrate should be present, indicating
an autoimmune demyelinating process
• Other findings according to types of CMT disease are as
follows:
• CMT type 1: peripheral nerves contain few
myelinated fibers, and intramuscular nerves are
surrounded by a rich connective tissue and
hyperplastic neurilemma. Lengths of myelin are
atrophic along the fibers. Concentric hypertrophy of
the lamellar sheaths is seen. Formation of the typical
onion bulb is noted and is made of circumferentially
directed Schwann cells and their processes.

110. Pathology

111. Pathology

112. Pathology
• CMT type 2: axonal degeneration
• CMT type 3 or Dejerine-Sottas disease:
demyelination with thinning of the myelin
sheath can be seen

113. Diagnosis: EMG-NCV
• EMG-NCV:
• Electromyography/nerve conduction study
(EMG/NCS) should be performed if CMT is
suggested
• Findings vary depending on the type of CMT
• In Demyelinating types such as CMT 1:
diffuse and uniform slowing of nerve
conduction velocities is observed

114. Diagnosis: EMG-NCV
• Harding and Thomas criteria for diagnosing
CMT 1 include:
• median motor nerve conduction velocity
less than 38 meters per second (m/s) with
compound motor action potential (CMAP)
and amplitude of at least 0.5 millivolts (mV)
• no focal conduction block or slowing
should be present unless associated with
other focal demyelinating processes

115. Diagnosis: EMG-NCV
• All nerves tested, both sensory and motor,
show the same degree of marked slowing.
• Absolute values vary, but they are
approximately 20-25 m/s in CMT 1 and less
than 10 m/s in Dejerine-Sottas disease
• Slowing of nerve conduction also can be
found in asymptomatic individuals

116. Diagnosis: EMG-NCV
•In a study of 119 CMT1-A patients:
•Motor nerve conduction velocity was
uniformly reduced in all nerves
•</= 33 m/s in the median nerve for all
patients
•Sensory potentials were abnormal in all
cases, even when there is no clinical
sensory loss
•Needle EMG recruitment was reduced in
distal muscles for all patients Birouk, et. al, 1997,
Brain

117. Diagnosis: EMG-NCV
• Neuronal (ie, axonal) types:
• nerve conduction velocity is usually normal
• markedly low amplitudes are noted in both
sensory (ie, sensory nerve action potential
[SNAP]) and motor nerve (ie, CMAP) studies
• increased insertional activity is evident as
fibrillation potentials and positive sharp waves
are observed
• motor unit potentials show decreased
recruitment patterns and neuropathic changes
in morphology

118. Diagnosis: Genetics
• CMT 1A:
• Pulsed field gel electrophoresis and a
specialized fluorescent in situ
hybridization (FISH) assay are the most
reliable genetic tests, but they are not
widely available.
• DNA-based testing through polymerase
chain reaction for the PMP-22 duplication
(CMT 1A) is widely available and detects
more than 98% of patients with CMT 1A

119. Diagnosis: Genetics
• CMT 1B: Genetic testing is performed primarily
on a research basis, but it is available from a few
commercial laboratories.
• CMT 1C: No genetic test is available at this time.
Causative gene(s) and chromosomal assignments
are not known.

120. Diagnosis: Genetics
• CMT 2: The 4 subtypes of CMT 2 are clinically
indistinguishable and are distinguished solely on
genetic linkage findings.
• CMT X: DNA-based testing detects a mutation in
the connexin 32 gene. The test detects 100% of
cases and is commercially available.
• Genetic testing currently is not available for other
types of CMTs.

121. Diagnosis: Genetics
• Genetic testing for CMT has several benefits
including establishment of a specific diagnosis
and to answer questions for other family
members.
• Testing is ideally first performed on an affected
family member
• If the mutation causing CMT is found, the
diagnosis is confirmed and other family members
can be offered testing.
• Intra-partum testing is also available

122. Diagnosis: Nerve Biopsy
• Nerve biopsy indicates the degree of neuropathy
and reveals morphologically specific alterations,
including demyelination, remyelination, and onion
bulb formation as described previously.
• The latter are visible by light and electron
microscopy.
• The sural nerve is usually sampled although the
fibular nerve may also be used.

123. Treatment
• Currently, no treatment exists to reverse or slow
the natural disease process for the underlying
disorder
• evaluated and treated symptomatically by a team
that includes a neurologist, physiatrist, orthopedic
surgeon, physical therapist, and occupational
therapist

124. Treatment
• Orthopedic surgery is required to correct severe
pes cavus deformities, scoliosis, and other joint
deformities
• Surgery is determined by the age of the patient
and the cause and severity of the deformity.

125. Treatment
• Daily heel cord stretching exercises to prevent
Achilles' tendon shortening
• Special shoes, including those with good ankle
support
• Exercise is encouraged within the patient's
capability and many individuals remain physically
active
• Important career and employment implications
exist because of the persistent weakness of hands
and/or feet.

126. Treatment
• Gene therapy is a possible method of treating
genetic diseases by replacing, changing, or
supplementing genes that do not work properly
• Although there is much promise in using gene
therapy to treat genetic conditions such as CMT, it
is not yet available.

127. Treatment
• important to advise patients to avoid drugs and
medications known to cause nerve damage (eg,
vincristine, isoniazid, nitrofurantoin)
• Pain:
Musculoskeletal pain may respond to
acetaminophen or nonsteroidal anti-inflammatory
drugs (NSAIDs).
Neuropathic pain may respond to tricyclic
antidepressants or antiepileptic drugs such as
carbamazepine or gabapentin.

128. Treatment
• Krajewski et al in 2000, Brain
• Evaluated 42 patients to understand further
the molecular pathogenesis of CMT1A as well
as to determine which features correlate with
neurological dysfunction and might be
amenable for treatment
• In these patients, muscle weakness, CMAP
amplitudes and motor unit number estimates
correlated with clinical disability while motor
NCV did not

129. Treatment
• Krajewski et al in 2000, Brain
• In addition, loss of joint position sense and reduction
in SNAP correlated with clinical disability while sensory
NCV did not
• Together, these data strongly support the hypothesis
that neurological dysfunction and clinical disability in
CMT1A are caused by loss or damage to large caliber
motor and sensory axons
•Therapeutic approach should be directed towards
preventing axonal degeneration and/or promoting
axonal regeneration

130. Prognosis
• Generally, CMT is a slowly progressive
neuropathy that causes eventual disability
secondary to distal muscle weakness and
deformities
• CMT does not shorten the expected life span

131. Prognosis
• functional disability as well as emotional
stress that comes with the disorder is
substantial
• Pfeiffer et al in 2001 did a report on disability and
quality of life in CMT 1
• Disability and ambulation of 50 patients were scored by the
Hauser ambulation and Rankin scale
• The sickness impact profile was assessed and compared
with patients 6 months after stroke
• To define at which the degree sickness and disability
become relevant for genetic counselling, the patients were
asked whether they would refrain from childbearing if the
children were at risk of inheriting a disease that caused so
much disability as they experienced themselves

132. Prognosis
• High disability significantly predicted an attitude
against childbearing
• Thirty six percent of the patients voted against
childbearing
• Psychosocial impact was comparable with patients
with stroke and similar disability
• Depression was present in 18% of the patients
• In conclusion, disability becomes relevant for the
attitude towards childbearing as soon as everyday
activities become markedly slow

133. Prognosis
• Emotional stress in CMT is similar to that of
patients with stroke and comparable disability
•genetic counseling
• informed decisions regarding potential risks of
passing the disease to their children