Charcot-Marie-Tooth Neuropathies:

Diagnosis and Management

Agnes Jani-Acsadi, M.D.,1 Karen Krajewski, M.S.,1 and Michael E. Shy, M.D.1

ABSTRACT

Charcot-Marie-Tooth (CMT) disease is caused by mutations in several genes

expressed in myelinating Schwann cells and the axons they ensheathe. Typical patients
present with distally accentuated motor weakness, muscle wasting, and sensory loss leading to
significant and progressive clinical morbidity and impaired quality of life. The wealth of recent
information regarding genotype-phenotype correlations, recognition of disease heterogeneity, and newly characterized animal models provide exciting insights into the molecular
disease-related pathogenetic and pathophysiologic mechanisms. These advances at the same
time also represent a challenge for the diagnosis and management of these patients, with no
presently available specific curative or disease modifying treatments. A better understanding
of the pathogenesis of peripheral neuropathies is an invaluable tool in developing future
supportive and curative therapies for patients with CMT disease that will improve their
quality of life. In this review, we provide practical insights on current diagnostic and
therapeutic modalities and suggest future diagnostic and therapeutic directions.
KEYWORDS: Charcot-Marie-Tooth disease, heterogeneity, diagnosis, treatment

harcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited, nonmetabolic neuropathies afflicting
1 in 2500 people worldwide.13 This
disease was first referred to as peroneal muscular atrophy
by Charcot, Marie,4 and Tooth5 in 1886 and was
considered until recently as one specific disease entity.
Advances in the field of clinical and molecular diagnosis
and in genetic and electrophysiological testing have
enhanced our understanding of the syndrome of Charcot, Marie, and Tooth, and have led to the development
of new diagnostic and treatment possibilities.

HISTORICAL NOTES
The term CMT disease is broadly interchangeable with
hereditary motor-sensory neuropathies (HMSNs). The
1

Department of Neurology, Wayne State University School of

Medicine, Detroit, Michigan.
Address for correspondence and reprint requests: Agnes
Jani-Acsadi, M.D., Assistant Professor of Neurology, Department
of Neurology, Wayne State University School of Medicine, 8A
UHC, 4201 St. Antoine, Detroit, MI 48201 (e-mail: aacsadi@med.

typical clinical presentation of these patients is well

recognized: progressive, distally accentuated weakness
and atrophy of muscles innervated by the peroneal nerve
followed by weakness and atrophy of hands, sensory loss,
and characteristic foot abnormalities. The disease is
most often passed from one generation to the other.
The clinical heterogeneity of this peripheral nerve disease was recognized at the turn of the century when
Dejerine and Sottas (1893) described cases that were
more severe and had an onset in infancy,6 and later when
Roussy and Levy7 (1926) described cases associated with
tremor, ataxia, areflexia, and pes cavus. First attempts at
classification were based on clinicopathological and inheritance patterns,8,9 but the real breakthrough came
with the introduction of nerve conduction testing in the
1960s. Early electrodiagnostic studies suggested that
wayne.edu).
Neuromuscular Disorders; Guest Editor, Ted M. Burns, M.D.
Semin Neurol 2008;28:185194. Copyright # 2008 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY
10001, USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2008-1062264. ISSN 0271-8235.

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most patients with CMT could be divided into two

groups, one with slow nerve conduction velocities and
pathological evidence of a hypertrophic demyelinating
neuropathy (CMT type 1 [CMT1]), and another with
relatively preserved nerve conduction velocities with
pathological evidence of axonal loss (CMT type 2
[CMT2]).1013 Patients with CMT1 were found to
have median motor nerve conduction velocities below
38 m/s, whereas median motor nerve conduction velocities were greater than 38 m/s in patients with CMT2.
Approximately 75% of the patients belonging to the first
group, similar to the ones described by Charcot, Marie,
and Tooth, were found to have an autosomal-dominant
pattern of inheritance, weakness, and sensory loss predominantly in the distal legs, and muscle wasting in the
distribution of weakened muscles. Most patients presented within the first two decades of life. However,
sporadic occurrence observed in 25% of patients suggested a different inheritance pattern, such as autosomalrecessive or potentially new dominant mutations.

RECLASSIFICATION OF CHARCOT-MARIETOOTH DISEASE: THE MOLECULAR ERA

The electrophysiological dichotomy of demyelinating
and axonal CMT neuropathies (as reflected in the
original classification by Dyck and Lambert [Table 1])
was supported by early experimental data from transgenic animal models,14,15 which linked the demyelinating and axonal forms of CMT to primary defects in
Schwann cell and axonal function. This concept had to
be revised, however, when it was recognized that despite
obvious similarities among patients with CMT1, the
group is genetically heterogeneous. The most common
form of CMT1, CMT1A, was associated with a 1.4 Mb
duplication at chromosome 17p11.2.16,17 Reports of
other genetic defects associated with hereditary neuropathies soon followed. CMT1B, linked to chromosome 1, is caused by mutations in the gene of myelin
protein zero (MPZ) glycoprotein; X-linked neuropathy,
CMTX1, is due to mutations in the gap junction (GJB1)
on the X chromosome encoding the gap junction protein, connexin 32. Deletion of the identical 1.4-Mb
region responsible for CMT1A is associated with hereditary neuropathy with susceptibility to pressure palsies (HNPPs). Dejerine-Sottas disease (DSD), a severe
infantile neuropathy, is associated with mutations or
deletions in peripheral myelin protein 22 (PMP22),
MPZ, early growth response gene 2 (EGR2), and
several other dominantly and recessively inherited
genes. To date, at least 40 different forms of CMT
have been described (http://www.molgen.ua.ac.be/
CMTMutations). This diversity also reflects a challenge
in diagnosis and therapy, and has consequently led to the
need to modify the traditional classification system.
Genotype-phenotype studies have been an invaluable

Table 1 Frequently Applied Classification Parameters

of Charcot-Marie-Tooth Disease
1. Pattern of Inheritance
Autosomal dominant
Autosomal recessive
X linked
2. Gene Involved
Myelin genes
PMP22
Duplication
Mutation
Deletion
MPZ
LITAF/SIMPLE
EGR2
GJB1
PRX
GDAP1
MTMR2
Neuronal genes
KIF1Bb
RAB7
GARS
NFL
3. Electrophysiology
Demyelinating

Axonal
Intermediate (2540 m/s)

Disease
CMT1A-D, CMT2A-E, DSD
DSD, CMT4A-C
CMTX

CMT1A
CMT1A, DSD
HNPP
CMT1B, DSD
CMT1C
CMT1D, DSD
CMTX
DSD
CMT4A
CMT4A
CMT2A
CMT2B
CMT2C
CMT2E
CMT1A, CMT1B,
CMT4A/B, HNPP
CMTX
CMT2
CMT2, CMT4C
Dominant IM
Recessive IM

4. Type of Nerves Involved

Motor
HMN
Sensory
HSN
Sensorimotor
HMSN
Autonomic
HAN
Sensory and autonomic
HSAN
5. Syndromic Hereditary Neuropathies
Demyelinating/dysmyelinating
Globoid cell
syndrome
leukodystrophy
Cockayne syndrome
SOX10
Refsum disease
Axonal
Friedreich
AOA2
Giant axonal
Neuroaxonal
CMT, Charcot-Marie-Tooth disease (followed by type designations);
DSD, Dejerine-Sottas disease; PMP22, peripheral myelin protein
gene; HNPP, hereditary neuropathy (with susceptibility to) pressure
palsy; MPZ, myelin protein zero gene; LITAF, lipopolysaccharideinduced tumor necrosis factor-alpha factor gene; EGR2, early growth
response gene 2; GJB1, gap junction protein, beta-1 gene; PRX,
periaxin gene; GDAP1, ganglioside-induced differentiation-associated
protein 1 gene; MTMR2, myotubularin-related protein 2 gene; KIF1B,
Kinesin family member 1B gene; RAB7, RAS-associated protein gene;
GARS, glycyl tRNA synthetase gene; NFL, neurofilament light chain
gene; IM, intermediate; HMN, hereditary motor neuropathy; HSN,
hereditary sensory neuropathy; HMSN, hereditary motor-sensory
neuropathy; HAN, hereditary autonomic neuropathy; HSAN, hereditary sensory and autonomic neuropathy; SOX10, SRY-box containing
gene 10; AOA2, ataxia-oculomotor apraxia 2 gene.

CHARCOT-MARIE-TOOTH NEUROPATHIES/JANI-ACSADI ET AL

aid in describing the clinical variability associated with

identical pathogenic mutations, such as is seen in the
different phenotypes associated with pathogenic mutations in major peripheral myelin genes like MPZ or
PMP22. For example, most patients with MPZ mutations fall into two major groups, one with a severe early
onset neuropathy with extremely slow nerve conduction
velocity (NCV) (less than 10 m/s) and a later onset,
milder form that fits the typical CMT1 phenotype.18
Many early onset cases present sporadically with no
family history and would have traditionally been diagnosed as HMSN-III or DSD. Different mutations in
the same gene, such as MPZ, may also lead to near
normal velocities more characteristic of CMT2. Early on
it was also recognized that there was a group of neuropathies that had nerve conduction velocities falling in the
intermediate range.19,20 We know now that most of
these neuropathies are related to mutations in the
GJB1 gene causing X-linked CMT.21,22 More recently,
both dominant and recessive forms have been identified.
These neuropathies do not fit easily into the original
Dyck and Lambert classification scheme because of their
X-linked inheritance and intermediately slow NCV.
Classification schemes modified to accommodate the
genetic causes of the neuropathy and inheritance pattern
have been published.2 CMT4 is used to classify the
recessive forms of CMT, regardless of whether they
are demyelinating or axonal. Another reason the classification schemes remain a challenge is that pathogenic
mutations in the same genes are associated with different
inheritance patterns, such as is seen in mutations in the
PMP22 gene. A change from threonine to methionine at
position 118 (Thr118Met) may appear to cause recessively inherited neuropathies, when in fact it is a dominantly inherited neuropathy where the mutation leads
to partial gain of function of the affected gene.23 Clinical
variability related to mutations involving identical genes
and phenotypical similarities noted in mutations associated with different genes invariably lead to challenges
not only in classification, but also, consequently, in
diagnosis and patient management. Table 1 presents
some of the useful parameters that have been applied
to classify CMT neuropathy.

EPIDEMIOLOGY
Early data on epidemiology of CMT were obtained
before the era of molecular testing. Estimated prevalence
of CMT neuropathies has been reported as 23 to 46 per
100,000 people in Northern Europe,1 with comparable
numbers reported by Dyck and colleagues in southeastern Minnesota.13,24 Harding and Thomass cohort of
227 patients with CMT was comprised of 76% (173)
CMT1 and 24% CMT2.13 This correlates well with data
reported by Dyck and Lambert in 1968.10,11 Increasing
availability of commercial genetic testing allowed for

Table 2 Frequency of Charcot-Marie-Tooth Disease*

Type of CMT

Percentage of Patients
with Type (%) (n 224)

CMT1A

45

CMT1B

CMTX

CMT2

18

Unknown

15

*Based on genetic classification in the first 224 patients seen at the

Wayne State University CMT Clinic.
CMT, Charcot-Marie-Tooth disease (followed by type designations).

new data about mutational frequencies worldwide. Databases from both North America and Europe previously
have put the frequency of the most common form of
CMT1, CMT1A, at
60 to 70%; CMTX accounts for

10 to 20%, and CMT1B for up to 5%.22,25,26 HNPP
is caused in
80% of cases by chromosome 17p11.2
deletion,22 with most remaining cases likely to be related
to point mutations in the PMP22 gene.27,28 More recent
reports showed comparable mutation frequency in Chinese patients.3 CMT2 accounts for
22% of dominantly
inherited neuropathies in the series of Inonasescu et al.29
Distribution of CMT mutations in the database at the
CMT Clinic at Wayne State University is shown in
Table 2. These data are similar to mutational frequencies
reported by other groups cited previously.

CLINICAL FEATURES OF INHERITED

NEUROPATHY
Clinical classification of patients with CMT is based on
establishing identifying features of an inherited peripheral neuropathy based on typical presentation, family
history, and supporting electrophysiological and genetic
testing. Making a clinical diagnosis in typical cases is no
challenge for the experienced neurologist. Phenotypic
variability of CMT neuropathies and scarce availability
of natural history data are increasingly recognized,
however. Taken together with newly presenting mutations, variable penetrance and progression rates between and within the same generations may lead to
diagnostic challenges and ultimately the need for referral of these patients to special tertiary neurological
centers for diagnosis and management. Clinical
features of the different CMT phenotypes are presented in Table 3.

PATHOGENESIS: GENOTYPE-PHENOTYPE
CORRELATIONS
Many recent studies have investigated the molecular
pathways underlying various forms of CMT. Understanding how different genetic defects lead to the

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Table 3 Features of Charcot-Marie-Tooth Disease

Neuropathy
1. Classic CMT phenotype
Age: < 20 y
Progression: slow
Skeletal abnormalities: pes cavus, hammer toes, scoliosis
Muscle weakness: foot drop/peroneal atrophy, steppage gait
Sensory dysfunctions: large and small fibers affected,
glove and stocking
Reflexes: reduced or absent
Tremor: variable
2. Variant forms
a) Infantile forms:
Dejerine-Sottas Neuropathy
Muscle weakness manifesting as delayed motor
milestones
Severe at onset but may retain ambulation into adulthood
Proximal muscle involvement
May be fatal
Onset

(below 38 m/s) are indicative of demyelination or a

dysmyelination process, whereas normal motor nerve
conduction velocities with markedly reduced nerve action
potential amplitudes signal axonal pathology. However,
recent data highlight the dynamic interaction between
Schwann cell and axon during development; MPZ
mutations may lead to a typical axonal CMT,18 and
primary disturbance of axonal signaling pathways may
lead to hypomyelinated/dysmyelinated nerve fibers with
slow nerve conductions, such as has been shown in the
transgenic NRG1 mice.36,37 Axonal CMT and axon-glia
interactions in various CMTs have been reviewed in
detail elsewhere.31 Table 4 lists the different mechanisms
that are currently implicated in the pathogenesis of
demyelinating and axonal CMT. Recognizing molecular
mechanisms, how mutated proteins contribute to the
clinical phenotypes, and in particular distinguishing
the exact contribution of individual Schwann cell and
neuronal genes to clinical disability may provide a
means to further treatments.

Sensory dysfunction severe, ataxia

Skeletal abnormality: scoliosis
NCV very slow
Nerve biopsy: demyelinating or axon loss
Congenital Hypomyelination
Hypotonia/floppy infant
Developmental failure of myelination
Onset
May be fatal
NCV
Nerve biopsy similar to DSD
b) Early onset forms (may overlap with above)
Muscle weakness: may be severe at onset, with delayed
motor development in infancy, toe walking
Sensory dysfunction: may be severe or absent
c) Late onset forms
May resemble acquired forms: CIDP, diabetic neuropathies,
or critical illness neuropathy
Muscle weakness: milder at onset but may progress to
wheel chair
Sensory dysfunction: positive and negative symptoms
CMT, Charcot-Marie-Tooth disease; NCV, nerve conduction velocity;
DSD, Dejerine-Sottas disease; CIDP, chronic inflammatory demyelinating polyneuropathy.

development of disease phenotypes is a challenging,3032

but potentially very rewarding task because effective
novel therapies may someday be developed based on
these new discoveries.
Normal myelination implies the well-coordinated
interaction of Schwann cells and axons.3335 Traditional
classifications of CMT have emphasized the primarily
demyelinating or axonal features of CMT based on
the changes noted in nerve conduction velocities. In a
very simplistic approach, this means that markedly
reduced forearm motor nerve conduction velocities

DOES THE ELECTROPHYSIOLOGY

REFLECT THE PATHOPHYSIOLOGY?
Introduction of nerve conduction studies (NCS) into
neurological diagnosis has revolutionized the diagnosis
of neuropathies. The obtained nerve conduction parameters provide valuable clues as to whether neuropathies
are primarily demyelinating or axonal processes. Nerve
conduction studies remain the primary test used to
classify CMT because they are easily performed and
minimally invasive. The principle that inherited and
acquired demyelinating neuropathies could be distinguished in most cases by their nerve conduction velocities was introduced by Lewis and Sumner31 with their
recognition that inherited demyelinating neuropathies
have uniformly slow nerve conduction velocities,
whereas acquired demyelinating neuropathies, such as
chronic inflammatory demyelinating polyradiculoneuropathy, have asymmetric or nonuniform slowing. Recent
studies have pointed to some exemptions to this principle; even though most patients with CMT1, particularly
those with CMT1A, have uniformly slow motor nerve
conduction velocities of
20 m/s, values as high as
42 m/s have been reported (Fig. 1), and are sometimes
used as a cut-off value. Also, HNPP has been recognized for an asymmetric electrophysiological pattern.
Asymmetric nerve conduction velocities may also be
found in patients with missense mutations in PMP22,
MPZ, EGR2 and GJB1.38
The usefulness of electrophysiology to guide the
clinician in obtaining an accurate diagnosis is increasingly being reevaluated. Fig. 2 presents a possible guide
for the clinician in making a diagnosis. Early on it was
recognized that there is a group of CMT that is
frequently referred to as intermediate CMT.19,39,40

CMT1C

CHM, DSD, CMT1D

LITAF/SIMPLE

EGR2/Krox20

CMTX1

CMT4B

CMT4F, DSD

CMT4D/HMSN-Lom

GJB1/Cx32

MTMTR2

PRX

NDRG1

CMT2A

CMT2B

CMT2B1

KIF1B

RAB7

LMNA

/

Missense

Loss/function

Mutation

Missense

Dom-neg toxic gain

NAB co-repressor

Gain-of-function Dom-neg

Point mutations Deletions

Thr128Met

Severe axonal

Severe axonal

Axonal

NCV

Severe

Sensory

AO milder

EO slow

25 to 38 m/s

AO: axonal/IM

EO: < 10 m/s

< 38 m/s

Variable, < 10 to 38 m/s

Axonal forms

Slow, < 10 m/s

< 38 m/s, focal slowing

trafficking

Intracellular membrane

Axonal organellar
Mitochondrial transport

Pathomechanism

Focally folded myelin

Demyelin

Onion bulbs axonal

Demyelin

EO: dysmyelin
AO: demyelin onion bulbs

Dysmyelin

Tomacula

Onion bulb

Histology

Lamin A/C, IF/transcriptional regulation

Endosomal protein

Kinesin superfamily

Role

Protein degradation/stress responses/cell growth

Dystroglycan/DRP complex

PDZ domain

Membrane signaling/gap junction

Neuronal membrane recycling, transport

Transmembrane domain

Detox/reactive oxygen species

Myelin gene transcription

Zinc finger transcription factor

Lysosomal function/protein degradation

Myelin compaction (homophilic adhesion)

Signaling function

ER retention, abnormal aggregation

Gene dosage effect

Intercellular junction

Cell proliferation, death, differentiation

Membrane trafficking

Compact myelin development, maintenance

Putative Role of Protein

NCV, nerve conduction velocity; PMP22, peripheral myelin protein gene; CMT, Charcot-Marie-Tooth disease (followed by type designations); abnl, abnormal; fx, function; ER, endoplasmic reticulum;
EO, early onset; AO, adult onset; dysmyelin, dysmyelination; demyelin, demyelination; dom-neg, dominant negative; NAB: NGFI-A binding proteins; IF, intermediate filament.

Disorder

Gene

B. Axonal/Neuronal CMT

CMT4A CMT2

GDAP1

CMT4E

CMT1B

P0/MPZ

CMT1A

Point mutation: Gain of abnl fx

CMT1A
Dom/neg Functional null

Deletion

HNPP

Asymmetries axonal

< 38 m/s

/  dupl.

CMT1A

PMP22

NCV

Mutation/Effect

Disorder

Gene

A. Schwann Cell/Myelin Proteins Related

Table 4 Potential Pathogenic Mechanisms of Known Charcot-Marie-Tooth Disease

CHARCOT-MARIE-TOOTH NEUROPATHIES/JANI-ACSADI ET AL

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Figure 1 Distribution of median nerve conduction velocity (NCV) of Charcot-Marie-Tooth (CMT) patients at the Wayne State
University CMT Clinic in 2004.

This term is being used without consensus in research

publications and Medline to identify the group of
patients with conduction velocities between CMT1
and CMT2 despite the obvious overlaps with CMT1
and CMT2. At this point, however, no clear criteria or

definitions are available to clarify this entity or delineate

the pathophysiology. CMTX patients constitute the
majority of patients with intermediately slowed
NCV.21 Patients with CMTX and CMT1B may present
with NCVs in the intermediate range but also with

Figure 2 NCV, nerve conduction velocity; PMP22, peripheral myelin protein gene; MPZ, myelin protein zero gene; LITAF,
lipopolysaccharide-induced tumor necrosis factor-alpha factor gene; EGR2, early growth response gene 2; NFL, neurofilament
light chain gene; MFN2, mitofusin 2 gene; GDAP1, ganglioside-induced differentiation-associated protein 1 gene; GJB1, gap
junction protein, beta-1 gene. *It is important that the family history is taken in a careful manner and that all possibilities are
considered that fit a given pedigree. **NCV testing indicates velocity of impulses; amplitudes not included.

CHARCOT-MARIE-TOOTH NEUROPATHIES/JANI-ACSADI ET AL

electrodiagnostic features misleadingly suggestive of a

primarily axonal neuropathy (e.g., markedly reduced
sensory nerve action potential [SNAP] and compound
muscle action potential [CMAP] amplitudes [Fig. 1]).
In such cases, however, distal motor latencies and Fwave latencies are usually prolonged, consistent with the
underlying mutations in the Cx32 protein, a protein that
is expressed in the myelinating Schwann cell. Similar
issues occur in some patients with mutations in the MPZ
gene (Thr118Met).
Because all of these disorders may appear de novo,
one has to be careful in applying NCV parameters alone
to separate acquired from inherited demyelinating neuropathies or to use them as a guide to distinguish
between inherited neuropathies.38 Electrodiagnostic
assessment of inherited neuropathies is important,
however, because CMAPs are considered a measure
of axonal integrity, and it has been shown in clinical
studies41 that axonal loss correlates better with the
patients actual disability.

Table 5 Charcot-Marie-Tooth Disease Management:

Supportive Therapy
1. Musculoskeletal dysfunctions
Scoliosis, foot deformities, hand atrophy
Evaluation by physiatry, physical therapy (low impact),
occupational therapy, orthotics and assistive devices,
corrective surgery
2. Respiratory dysfunction
Pulmonary evaluation, CPAP, BiPAP, scoliosis correction
3. Sensory dysfunction
Pain control
Topical medications: lidocaine patch
Antidepressants: tricyclics (amitriptyline, nortriptyline,
desipramine) lowest cost, generic available
Anticonvulsants: gabapentin (generic available), pregabalin
($$$)
Lamotrigine, carbamazepine (second line due to higher
adverse effects)
4. Iatrogenic neurology
Medications to avoid: chemotherapeutic drugs (vincristine,
cis-platinum, mivacurium)

APPROACH TO DIAGNOSIS AND

MANAGEMENT
Marked variations in phenotypic presentations represent
a challenge in the diagnosis of CMT. It is well documented in patients with CMT that they may present
with variable age of onset and different speed of
symptom progression.2 The diagnosis and management
of the patient with CMT is best undertaken by a
multidisciplinary approach that involves a neurologist,
and, when appropriate, a genetic counselor, orthopedic
surgeon, physiatrist, pulmonary specialist, physical
therapist, occupational therapist, and/or social worker
to provide the maximum care for patients with chronic
disability.
It seems obvious that severe, early onset nerve
dysfunction, such as seen in DSD and some of the early
onset CMT1B patients,18 puts a different type of burden
on families and provides more challenges for healthcare
providers than a slower, progressive, adult-onset form of
the disorder that nonetheless may also lead to significant
reductions in quality of life over time.42 No clear
estimates are currently available that assess the financial
burden of this chronic disease on families and the
healthcare system. Early diagnosis and, if possible,
interventions impact the patients day-to-day life in a
positive way at multiple levels.4345
One of the most important issues is genetic testing and counseling.46 Despite the increasing availability
of commercial and research testing, CMT remains
principally a clinical diagnosis established by signs and
symptoms of examination, family history, and electrodiagnostic testing (Fig. 2).46,47 Genetic testing supports
the clinical and electrophysiological diagnosis, and at the
same time genetic counseling is important for the

Refer to CMTA Web site regarding updated lists of medication

(www.charcot-marie-tooth.org)
CPAP, continuous positive airway pressure; BiPAP, bilevel positive
airway pressure, CMT, Charcot-Marie-Tooth disease.

patients and their families to help with disease prognosis.

Decisions regarding genetic testing should be made in
consensus with the individual family members. Distinction should be made regarding testing in affected or atrisk individuals. Appropriate indications for genetic
testing may soon change as more genes causing neuropathy are identified and more is learned about the
phenotypic range produced by mutations in these genes.
For example, cases of CMT1B are now being reported
with normal NCV; these would have been missed if
genetic testing had not been performed.
Predictive testing of individuals at risk for CMT
should be approached with more circumspection. A
patient, along with a support person, should be seen by
both a neurologist and genetic counselor and be counseled about the possible implications of testing with
respect to their family relationships, insurance, and
employability. Every effort should be made to obtain
documentation of the disease in a relative. Testing is
not recommended for asymptomatic children who are
at risk for CMT, in agreement with the Statement of
the Practice Committee Genetics Testing Task Force
of the American Academy of Neurology (1996). When
a child is clearly showing symptoms of CMT, testing
may be appropriate.
Other than establishing an individuals risk for
the disease, genetic testing may also help delineate
more accurate genotype-phenotype interactions.46 Online resources are available and provide comprehensive

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information for both healthcare providers and patients

(see Addendum).

MANAGEMENT
Management of hereditary neuropathies is aimed at
complex supportive and, when available, curative treatment modalities. Table 5 provides a summary of current
supportive treatment options, addressing leading symptoms. Treating physicians need to also be aware of
potential dangers associated with iatrogenic complications associated with therapeutic interventions to be able
to assess risk-benefit ratios and provide appropriate
counseling for their patients.
There is currently no cure for CMT. Basic
research into therapeutic strategies is being done
using transgenic animal models to develop new human applications. Gene therapy approaches for gene
replacement are only possible in monogenic disorders
if the mutation leads to clear loss of function. The
gene dosage-dependent changes in CMT1A48 or
partial loss of function disease mechanism found in
certain CMT1B (Thr118Met) patients represent a
challenge to overcome despite advances in the
field.49,50 It has been shown that clinical disability is
related to axonal degeneration.41 Therefore, the attempt to provide trophic support by neurotrophic
factors is a promising approach. It is likely that
despite promising results in animal models51 more
research needs to be done before this can be extrapolated to human applications. Further studies need to
be performed regarding potential immunomodulatory
therapies in CMT despite recent indications of
improved myelination in immunodeficient transgenic
mice.52

THERAPY: NEW CLINICAL APPROACHES

Ascorbic acid treatment of the animal model of CMT1A
has improved myelination and reduced PMP22 levels in
affected rats. A multicenter international clinical trial is
already on the way that uses high-dose ascorbic acid for
treatment in patients with CMT1A.53 Another exciting
new approach is based on data obtained in the animal
model of CMT1A, which showed that a selective
progesterone antagonist, onapristone, reduced PMP22
overexpression in tissue culture and improved the CMT
phenotype in CMT1A rats.54

CONCLUSIONS
Inherited neuropathies are among the most prevalent
genetic neurological diseases. They affect the quality of
life of the patients by leading to marked disability due
to progressive weakness and social and psychological
burden. Treatment of this chronic disorder challenges

families and healthcare workers. Developing treatments

for patients will directly affect thousands of individuals.
In addition, the genes and their proteins that cause
inherited neuropathies serve as a source of molecules
that are important for peripheral nerve function. Identifying the molecular pathways involved in these disorders will also lead to a better understanding of
pathways involved in neurodegenerative disease in
general.

ADDENDUM: RESOURCES FOR PATIENTS

AND FAMILIES
Multiple resources exist for people with CMT to learn
more about their disease, genetic conditions in general,
where to find others in a similar situation, and
keep abreast of new therapies and/or clinical trials.
This addendum provides the path to some of these
resources.

Patient Support Organizations

Charcot-Marie-Tooth Association (CMTA)
Address: Charcot-Marie-Tooth Association,
2700 Chestnut Street, Chester, PA 190134867
Toll-Free: 8006062682 (U.S. only)
Phone: 6104999264
Fax: 6104999267
E-mail: info@charcot-marie-tooth.org
Web site: http://www.charcot-marie-tooth.org
Muscular Dystrophy Association (MDA)
Address: Muscular Dystrophy Association USA,
National Headquarters, 3300 E. Sunrise Drive, Tucson,
AZ 85718
Toll Free: 800-FIGHT-MD (3444863)
E-mail: mda@mdausa.org
Web site: http://www.mdausa.org
The Charcot-Marie-Tooth Foundation
Address: The Charcot-Marie-Tooth Foundation, 142
Gazebo Park, Johnstown, PA 15901
Toll-free: 8772962341
Phone: 8145392341-JD Griffith
E-mail: jdgriffith@atlanticbb.net
Web site: http://www.cmtfoundation.org
Hereditary Neuropathy Foundation (HNF)
Address: Hereditary Neuropathy Foundation Inc., PO
Box 287103, New York, NY 10128
Phone: 9176486971
E-mail: info@hnf-cure.org
Web site: http://www.hnf-cure.org
The Neuropathy Association
Address: The Neuropathy Association, Inc.1, PO Box
26226, New York, NY 101173422
Phone: 2126920662

CHARCOT-MARIE-TOOTH NEUROPATHIES/JANI-ACSADI ET AL

E-mail: info@neuropathy.org
Web site: http://www.neuropathy.org
National Organization of Rare Disorders
(NORD)
Address: National Organization for Rare Disorders,
55 Kenosia Avenue, PO Box 1968, Danbury, CT
068131968
Toll free: 8009996673 (voicemail only)
Phone: 2037440100
Fax: 2037982291
E-mail: orphan@rarediseases.org
Web site: http://www.rarediseases.org
Online Resources
Patients should be cautioned that information on
the Internet is not always accurate or reliable and issues
regarding a persons management or treatment should
always be discussed with the persons physician.
GeneTests (http://www.geneclinics.org)
This Web site offers detailed information about
the availability of genetic testing, information about
genetic conditions, and contact information for genetics
services providers such as laboratories performing preimplantation genetic diagnosis.
Online Mendelian Inheritance in Man
(OMIM) (http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM)
Thousands of entries on genetic disorders and
genes can be found on this Web site. The information
listed here tends to be more technical and contains
summaries of significant findings in the published literature.
PubMed (http://www.ncbi.nlm.nih.gov/entrez/
query.fcgi)
This Web site allows the user to find citations in
the biomedical literature.
National Coalition for Health Professional
Education in Genetics(http://www.nchpeg.org)
This Web site provides information on genetics
advances and genetics health information.
Genetic Alliance (http://www.geneticalliance.org)
The Genetic Alliance is an international coalition
comprised of millions of individuals with genetic conditions and more than 600 advocacy, research, and
healthcare organizations that represent their interests.
The Web site provides access to links for support groups
for many genetic conditions as well as to other geneticsrelated informational sites.
Inherited Peripheral Neuropathies Mutation
Database (http://www.molgen.ua.ac.be/CMTMutations/
default.cfm)
This database contains detailed information on all
of the published mutations that cause inherited peripheral neuropathies, including references.
HNPP Web site (www.hnpp.org)

This site is a place where people with HNPP, their

physicians, and therapists can learn about the disease,
where to find help, and how to manage their symptoms.
Clinical Trials (http://www.clinicialtrials.gov)
This Web site, supported by the U.S. National
Institutes of Health, contains regularly updated information about federally and privately supported clinical
research in human volunteers.
REFERENCES
1. Skre H. Genetic and clinical aspects of Charcot-MarieTooths disease. Clin Genet 1974;6:98118
2. Shy M, Lupski JR, Chance PF, Klein CJ, Dyck P. The
hereditary motor and sensory neuropathies: an overview of
the clinical, genetic, electrophysiologic and pathologic
features. In: Dyck PJ, ed. Peripheral Neuropathy. 4th ed.
Philadelphia: WB Saunders; 2005:16231658
3. Song SJ, Zhang YZ, Chen B, et al. No mutation was detected
in the LMNA gene among sporadic Charcot-Marie-Tooth
patients. Beijing Da Xue Xue Bao 2006;38:7879
4. Charcot J, Marie P. Sue une forme particulaire datrophie
musculaire progressive souvent familial debutant par les pieds
et les jamber et atteingnant plus tard les mains. Re Med
1886;6:97138
5. Tooth H. The Peroneal Type of Progressive Muscular
Atrophy. London: Lewis; 1886
6. Dejerine H, Sottas J. Sur la nevritte interstitielle, hypertrophique et progressive de lenfance. CR Soc Biol Paris
1893;45:6396
7. Roussy G, Levy G. A sept cas dune maladie familiale
particulaire. Rev Neurol 1926;33:427450
8. Dawidenkow S. Uber die neurotische Muskelatrophie
Charcot-Marie: Klinisch-genetische Studien. Z Ges Neurol
Psychiat 1927;107:259
9. Dawidenkow S. Uber dir neurotische Muskelatrophie
Charcot-Marie: Klinisch-genetische Studien. Z Neurol 1927;
108:344
10. Dyck PJ, Lambert EH. Lower motor and primary sensory
neuron diseases with peroneal muscular atrophy: II. Neurologic, genetic, and electrophysiologic findings in various
neuronal degenerations. Arch Neurol 1968;18:619625
11. Dyck PJ, Lambert EH. Lower motor and primary sensory
neuron diseases with peroneal muscular atrophy: I. Neurologic, genetic, and electrophysiologic findings in hereditary
polyneuropathies. Arch Neurol 1968;18:603618
12. Harding AE, Thomas PK. The clinical features of hereditary
motor and sensory neuropathy types I and II. Brain 1980;103:
259280
13. Harding AE, Thomas PK. Genetic aspects of hereditary
motor and sensory neuropathy (types I and II). J Med Genet
1980;17:329336
14. Aguayo AJ, Attiwell M, Trecarten J, Perkins S, Bray GM.
Abnormal myelination in transplanted Trembler mouse
Schwann cells. Nature 1977;265:7375
15. Aguayo AJ, Kasarjian J, Skamene E, Kongshavn P, Bray
GM. Myelination of mouse axons by Schwann cells transplanted from normal and abnormal human nerves. Nature
1977;268:753755
16. Lupski JR, de Oca-Luna RM, Slaugenhaupt S, et al. DNA
duplication associated with Charcot-Marie-Tooth disease
type 1A. Cell 1991;66:219232

193

194

SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2

2008

17. Raeymaekers P, Timmerman V, Nelis E, et al. Duplication in

chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy
type 1a (CMT1a). The HMSN Collaborative Research
Group. Neuromuscul Disord 1991;1:9397
18. Shy ME, Jani A, Krajewski KM, et al. Phenotypic clustering
in MPZ mutations. Brain 2004;127:371384
19. Bradley WG, Madrid R, Davis CJ. The peroneal muscular
atrophy syndrome. Clinical, genetic, electrophysiological
and nerve biopsy studies. Part 3: Clinical, electrophysiological and pathological correlations. J Neurol Sci 1977;32:
123136
20. Lovelace R. Hereditary induced peripheral neuropathies.
Clin Podiatr Med Surg 1990;7:3750
21. Nicholson G, Nash J. Intermediate nerve conduction
velocities define X-linked Charcot-Marie-Tooth neuropathy
families. Neurology 1993;43:25582564
22. Nelis E, Van Broeckhoven C, De Jonghe P, et al. Estimation
of the mutation frequencies in Charcot-Marie-Tooth disease
type 1 and hereditary neuropathy with liability to pressure
palsies: a European collaborative study. Eur J Hum Genet
1996;4:2533
23. Shy ME, Scavina MT, Clark A, et al. T118M PMP22
mutation causes partial loss of function and HNPP-like
neuropathy. Ann Neurol 2006;59:358364
24. Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of
unclassified neuropathies yields improved diagnosis. Ann
Neurol 1981;10:222226
25. Ionasescu VV, Burns TL, Searby C, Ionasescu R. X-linked
dominant Charcot-Marie-Tooth neuropathy with 15 cases in a
family genetic linkage study. Muscle Nerve 1988;11:1154
1156
26. Wise CA, Garcia CA, Davis SN, et al. Molecular analyses of
unrelated Charcot-Marie-Tooth (CMT) disease patients
suggest a high frequency of the CMTIA duplication. Am J
Hum Genet 1993;53:853863
27. Li J, Krajewski K, Lewis RA, Shy ME. Loss-of-function
phenotype of hereditary neuropathy with liability to pressure
palsies. Muscle Nerve 2004;29:205210
28. Nicholson GA. Mutation testing in Charcot-Marie-Tooth
neuropathy. Ann N Y Acad Sci 1999;883:383388
29. Ionasescu VV, Ionasescu R, Searby C. Screening of
dominantly inherited Charcot-Marie-Tooth neuropathies.
Muscle Nerve 1993;16:12321238
30. Shy ME. Therapeutic strategies for the inherited neuropathies. Neuromolecular Med 2006;8:255278
31. Suter U, Scherer SS. Disease mechanisms in inherited
neuropathies. Nat Rev Neurosci 2003;4:714726
32. Arroyo EJ, Scherer SS. On the molecular architecture
of myelinated fibers. Histochem Cell Biol 2000;113:1
18
33. Massicotte C, Scherer SS. Neuropathies: translating causes
into treatments. In: Waxman SG, ed. Neuroscience,
Molecular Medicine, and the Therapeutic Transformation
of Neurology. Philadelphia: Elsevier Science; 2004:405418
34. Kamholz J, Menichella D, Jani A, et al. Charcot-MarieTooth disease type 1: molecular pathogenesis to gene therapy.
Brain 2000;123:222233
35. Wrabetz L, Feltri ML, Kleopa K. Inherited neuropathies:
clinical, genetic, and biological features. In: Lazzarini RA, ed.
Myelin Biology and Disorders. London: Elsevier; 2004:
905952

36. Michailov GV, Sereda MW, Brinkmann BG, et al. Axonal

neuregulin-1 regulates myelin sheath thickness. Science
2004;304:700703
37. Taveggia C, Zanazzi G, Petrylak A, et al. Neuregulin-1
type III determines the ensheathment fate of axons. Neuron
2005;47:681694
38. Lewis RA, Sumner AJ, Shy ME. Electrophysiological
features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis. Muscle Nerve 2000;
23:14721487
39. Brust JC, Lovelace RE, Devi S. Clinical and electrodiagnostic features of Charcot-Marie-Tooth syndrome. Acta
Neurol Scand Suppl 1978;68:1142
40. Davis CJF, Bradley WG, Madrid R. The peroneal muscular
atrophy syndrome: clinical, genetic, electrophysiological and
nerve biopsy findings and classification. J Genet Hum 1978;
26:311349
41. Krajewski KM, Lewis RA, Fuerst DR, et al. Neurological
dysfunction and axonal degeneration in Charcot-MarieTooth disease type 1A. Brain 2000;123:15161527
42. Shy ME, Rose MR. Charcot-Marie-Tooth disease impairs
quality of life: why? And how do we improve it? Neurology
2005;65:790791
43. Arnold LD, Bachmann GA, Rosen R, Kelly S, Rhoads GG.
Vulvodynia: characteristics and associations with comorbidities and quality of life. Obstet Gynecol 2006;107:617624
44. Vinci P, Serrao M, Millul A, et al. Quality of life in patients
with Charcot-Marie-Tooth disease. Neurology 2005;65:922
924
45. Carter GT, Han JJ, Abresch RT, Jensen MP. The
importance of assessing quality of life in patients with
neuromuscular disorders. Am J Hosp Palliat Care 2006;23:
493497
46. Krajewski KM, Shy ME. Genetic testing in neuromuscular
disease. Neurol Clin 2004;22:481508
47. Bird TD. Risks and benefits of DNA testing for neurogenetic
disorders. Semin Neurol 1999;19:253259
48. Boerkoel CF, Takashima H, Garcia CA, et al. CharcotMarie-Tooth disease and related neuropathies: mutation
distribution and genotype-phenotype correlation. Ann Neurol 2002;51:190201
49. Sereda M, Griffiths I, Puhlhofer A, et al. A transgenic rat
model of Charcot-Marie-Tooth disease. Neuron 1996;16:
10491060
50. Guenard V, Schweitzer B, Flechsig E, et al. Effective gene
transfer of lacZ and P0 into Schwann cells of P0-deficient
mice. Glia 1999;25:165178
51. Ianokova E, Lewis R, Acsadi G, et al. AAV-GDNF
improves neuropathy in MPZ-/- mice. Neurology 2006;66
(suppl 2):A276
52. Maurer M, Kobsar I, Berghoff M, Schmid CD, Carenini S,
Martini R. Role of immune cells in animal models for
inherited neuropathies: facts and visions. J Anat 2002;200:
405414
53. Passage E, Norreel JC, Noack-Fraissignes P, et al. Ascorbic
acid treatment corrects the phenotype of a mouse model
of Charcot-Marie-Tooth disease. Nat Med 2004;10:396401
54. Sereda MW, Meyer Zu Horste G, Suter U, Uzma N, Nave
KA. Therapeutic administration of progesterone antagonist
in a model of Charcot-Marie-Tooth disease (CMT-1A).
Nat Med 2003;9:15331537