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Charcot-Marie-Tooth Hereditary Neuropathy Overview

Synonym: CMT
Thomas D Bird, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington
ude.notgnihsaw.u@zornmot
Initial Posting: September 28, 1998; Last Revision: May 7, 2015.

Summary
Clinical characteristics.

Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders

characterized by a chronic motor and sensory polyneuropathy. The affected individual
typically has distal muscle weakness and atrophy often associated with mild to
moderate sensory loss, depressed tendon reflexes, and high-arched feet.
Diagnosis/testing.

The genetic neuropathies need to be distinguished from the many causes of acquired
(non-genetic) neuropathies. Clinical diagnosis is based on family history and
characteristic findings on physical examination, EMG/NCV testing, and occasionally
sural nerve biopsy. More than 40 different genes/loci are associated with CMT.
Molecular genetic testing is possible for some types of CMT.
Genetic counseling.

CMT hereditary neuropathy syndrome can be inherited in an autosomal dominant,

autosomal recessive, or X-linked manner. Genetic counseling regarding risk to family
members depends on accurate diagnosis, determination of the mode of inheritance in
each family, and results of molecular genetic testing. Prenatal testing for pregnancies
at increased risk is possible for some types of CMT if the pathogenic variant(s) in the
family are known.
Management.

Treatment of manifestations: Management by a multidisciplinary team of neurologists,

physiatrists, orthopedic surgeons, and physical and occupational therapists; special
shoes and/or ankle/foot orthoses (AFOs) to correct foot drop and aid walking; gripping
exercises for hand weakness; orthopedic surgery as needed for severe pes cavus
deformity and hip dysplasia; acetaminophen or nonsteroidal anti-inflammatory agents
for musculoskeletal pain; tricyclic antidepressants, carbamazepine or gabapentin for
neuropathic pain.

Prevention of secondary complications: Daily heel cord stretching exercises.

Agents/circumstances to avoid: Drugs and medications such as vincristine, taxol,
cisplatin, isoniazid, and nitrofurantoin that are known to cause nerve damage; obesity
as it makes walking more difficult.
Definition
Clinical Manifestations

Charcot-Marie-Tooth (CMT) hereditary neuropathy (also called hereditary

motor/sensory neuropathy [HMSN]) results from involvement of peripheral nerves
that can affect the motor system and/or the sensory system. Individuals with CMT
experience symmetric, slowly progressive distal motor neuropathy of the arms and
legs usually beginning in the first to third decade and resulting in weakness and
atrophy of the muscles in the feet and/or hands. Pes cavus foot deformity is common.
Although usually described as "painless," the neuropathy of CMT can be painful
[Carter et al 1998].
Other findings can include hearing loss and hip dysplasia, which may be underrecognized manifestations of CMT [McGann & Gurd 2002].
Establishing the Diagnosis of CMT

Reviews on diagnosis include Pareyson & Marchesi [2009a], Pareyson & Marchesi
[2009b], and Reilly & Shy [2009].
Progressive weakness of the distal muscles in the feet and/or hands is evident on
medical history.
Individuals with typical CMT have high-arched feet, weak ankle dorsiflexion, thin
distal muscles, depressed tendon reflexes, and distal sensory loss.
Electrophysiologic studies (electromyography [EMG] and nerve conduction velocity
[NCV]), when carefully done, are almost always abnormal [Carter et al
2004, Pareyson et al 2006].
Sural nerve biopsy is not routinely performed, but is occasionally helpful in
establishing the diagnosis of CMT hereditary neuropathy because relatively
characteristic lesions are found in CMT1, leprosy, vasculitis, and amyloid neuropathy
[Schrder 2006].
Differential Diagnosis of CMT

Causes of acquired peripheral neuropathy include alcoholism, vitamin B 12 deficiency,

thyroid disease, diabetes mellitus, HIV infection, vasculitis, leprosy, neurosyphilis,
amyloid deposition associated with chronic inflammation, occult neoplasm, heavy
metal intoxication, and inflammatory and immune-mediated neuropathies such as
chronic inflammatory demyelinating polyneuropathy (CIDP).

Blindness (with the exception of optic atrophy in CMT2A and CMTX5), seizures,
dementia, and intellectual disability are not part of the CMT hereditary neuropathy
phenotype and suggest a different diagnosis.
Autosomal dominant disorders with neuropathy
Familial brachial plexus neuropathy (hereditary neuralgic amyotrophy).
Affected individuals have sudden onset of pain and weakness in the shoulder or
upper arm associated with distal and/or proximal weakness and atrophy of the
upper extremity. Associated sensory loss may occur. Onset frequently occurs in
childhood but can occur at any age. Partial or full recovery is typical. The
syndrome may recur in the same or opposite limb and occasionally in the lower
extremity. In some families, associated clinical features include short stature,
ocular hypotelorism, cleft palate, epicanthal folds, facial asymmetry, and partial
syndactyly [Jeannet et al 2001]. Pathogenic variants in SEPT9 are causative
[Kuhlenbumer et al 2005].
Hereditary neuropathy with liability to pressure palsies (HNPP) is
characterized by the acute onset of recurrent, painless, focal sensorimotor
neuropathy in a single nerve [Kumar et al 2002]. Deletion of one copy
of PMP22 is causative.
Amyloid neuropathies, including transthyretin-associated amyloidosis, result in
progressive accumulation of amyloid protein in peripheral nerves [Lynch &
Chance 1997].
Autosomal recessive disorders with neuropathy
Refsum disease
Metachromatic leukodystrophy
Krabbe disease
Friedreich ataxia may present with sensory loss, depressed tendon reflexes, and
high-arched feet.
Other hereditary ataxias sometimes have an associated peripheral neuropathy
(see Ataxia Overview).
X-linked disorders with neuropathy
o Adrenomyeloneuropathy
o Pelizaeus-Merzbacher disease
o Lowe syndrome

Hereditary motor neuropathies (HMN) are associated with distal weakness without
sensory loss [Irobi et al 2004, Auer-Grumbach et al 2005]. The key distinction
between typical CMT and HMN is that the latter has no sensory loss.
CMT syndrome with spasticity. Some individuals with distal muscle atrophy and
weakness may have signs of spasticity with brisk tendon reflexes and/or Babinski
responses. This set of findings has been called HMSN V and sometimes overlaps with
hereditary motor neuropathy (HMN).
One type is associated with pathogenic variants in BSCL2 (see BSCL2-Related
Neurologic Disorders) and another with pathogenic variants in SPG20, the gene
encoding spartin (see Troyer Syndrome).
See also Hereditary Spastic Paraplegia Overview.
Hereditary sensory neuropathies (HSN). Several autosomal dominant axonal
neuropathies have primarily sensory symptoms (one family is described as having
"burning feet syndrome" [Stgbauer et al 1999]), and are classified as hereditary
sensory neuropathies (HSNs) [Auer-Grumbach et al 2003]. Distal weakness may also
occur. The most common form is HSAN-1 resulting from pathogenic variants
in SPTLC1. Rotthier et al [2012] have reviewed the clinical and genetic factors
associated with six autosomal dominant and seven autosomal recessive types. Kornak
et al [2014] have reported two autosomal dominant families with a missense mutation
in ATL3, a paralogue of ATL1, which is associated with spastic paraplegia and another
form of sensory neuropathy [Guelly et al 2011].
See also Hereditary Sensory Neuropathy Type I and Hereditary Sensory and
Autonomic Neuropathy Type II.
Distal myopathies. See Table 1.
Table 1.

Distal Myopathies
Name

Mean Age at
Initial Muscle Group
Onset
Involved
(Years)

Welander distal myopathy

>40

Udd distal myopathy

>35

Zaspopathy (Markesbery-Griggs
late-onset distal myopathy)

>40

Distal myotilinopathy

>40

Inheritance

Distal upper limbs (finger Autosomal

and wrist extensors)
dominant

Gene

TIA1
TTN

Anterior compartment in
legs

Posterior > anterior in legs

LDB3
MYOT

Name

Mean Age at
Initial Muscle Group
Onset
Involved
(Years)

Laing early-onset distal

myopathy (MPD1)

<20

Nonaka early-adult-onset distal

myopathy

Gene

Anterior compartment in
legs and neck flexors

MYH7

Anterior compartment in
legs

GNE

15-20
Miyoshi early-adult-onset myopathy

Posterior compartment in
legs

Distal myopathy with vocal cord and

35-60
pharyngeal signs (MPD2)

Asymmetric lower leg and

hands, dysphonia

Distal myopathy with pes cavus and

15-50
areflexia

Anterior and posterior

lower leg; dysphonia and
dysphagia

New Finnish distal myopathy

(MPD3)

Hands or anterior lower

leg

>30

Inheritance

Autosomal
recessive
DYSF

Autosomal
dominant

Unknow
n

From Udd & Griggs [2001]

Mitochondrial disorders associated with peripheral neuropathy

NARP (neuropathy, ataxia, and retinitis pigmentosa). A mitochondrial disorder
caused by mutations in mitochondrial DNA (mtDNA)
MNGIE (mitochondrial neurogastrointestinal encephalomyopathy) [Said et al
2005]
See also Mitochondrial Disorders Overview.
Prevalence

Charcot-Marie-Tooth (CMT) hereditary neuropathy is the most common genetic cause

of neuropathy. Prevalence is about 1:3,300.
Approximately 20% of all individuals presenting to neuromuscular clinics with an
unclassified chronic peripheral neuropathy have CMT1A.
The prevalence of genetic subtypes differs in Japan, where there are fewer cases of
CMT1A (23% of CMT1) and more cases with an unknown genetic cause [Abe et al
2011].
In a large study of German individuals with a CMT1 phenotype (776), Gess et al
[2013] found the following percentages: CMT1A (51%), CMTX1 (9%), and CMT1B

(5%). Sixty-six percent of subjects with a CMT1 phenotype had a genetic diagnosis.
Of those with a CMT2 phenotype, 11% had CMTX1, 8% had CMT2A, and 6% had
the rare giant axonal neuropathy. Thirty-five percent of individuals with CMT2 had a
genetic diagnosis.
Rossor et al [2013] show the prevalence of CMT subtypes relative to all CMT, CMT1,
CMT2, or intermediate CMT; see Figure 1.
Causes
Single-Gene Causes

The classification used in this GeneReview is based on inheritance patterns and

molecular genetics (see Table 2). However, classification is especially difficult when
different pathogenic variants in a single gene are associated with both autosomal
dominant and autosomal recessive inheritance, and/or both axonal and demyelinating
neuropathy. Reviews of the diagnosis and natural history include Pareyson & Marchesi
[2009a],Pareyson & Marchesi [2009b], and Reilly & Shy [2009].
Table 2.

Single-Gene Causes of CMT Hereditary Neuropathy

Disease Name 1 Pathology

Mode of
Inheritance

Proportion of all
CMT 2

CMT1

Abnormal myelin

AD

40%-50%

CMT2

Axonopathy

AD

10%-15%

Intermediate
form

Combination of myelinopathy and axonopathy

AD
in individual

Rare

CMT4

Either myelinopathy or axonopathy

AR

Rare

CMTX

Axonopathy with secondary myelin changes

XLD

10%-15%

See Charcot-Marie-Tooth Disease: OMIM Phenotypic Series to view genes associated with
this phenotype in OMIM.
1.
Each of the CMT subtypes (CMT1, CMT2, CMT4, and CMTX) is further subdivided
primarily on molecular genetic findings [De Jonghe et al 1997, Keller & Chance 1999, Nelis
et al 1999].
2.
Saporta et al [2011]

Vance [2000] suggested a similar classification system that differs slightly, with CMT3
referring to axonal presentations that are autosomal recessive and CMT4 referring to
demyelinating presentations that are autosomal recessive.
Other valid classification systems may emphasize electrophysiologic characteristics
such as nerve conduction velocities or pathologic findings.
The molecular genetics of CMT has been reviewed by Carter et al [2004], Houlden &
Reilly [2006], Kleopa & Scherer [2006], Nicholson [2006], Reilly & Shy [2009],
and Pareyson & Marchesi [2009a], and the molecular pathogenesis has been reviewed
by Bernard et al [2006] and Zchner & Vance [2006]. The various genetic subtypes
and their associated genes are shown in Figure 2 [Pareyson & Marchesi
2009a]. Rossor et al [2013] have illustrated the molecular and anatomic relationships
of all the genes and proteins reported thus far to cause various subtypes of CMT;
see Figure 3.
Charcot Marie Tooth Type 1 (CMT1) is a demyelinating peripheral neuropathy
characterized by distal muscle weakness and atrophy, sensory loss, and slow nerve
conduction velocity (typically 5-30 m/sec; normal: >40-45 m/sec). It is usually slowly
progressive and often associated with pes cavus foot deformity and bilateral foot drop.
Affected individuals usually become symptomatic between ages five and 25 years.
Fewer than 5% of individuals become wheelchair dependent. Life span is not
shortened.
The six subtypes of CMT1 are clinically indistinguishable and are designated solely on
molecular findings [Saifi et al 2003] (Table 3).
Table 3.

CMT1: Molecular Genetics

Locus
Name

Proportion of CMT1 (excluding

Gene
CMTX) 1

CMT1A

70%-80%

PMP2
Peripheral myelin protein 22
2

CMT1B

10%-12%

MPZ

Myelin P0 protein

CMT1C

~1%

LITAF

Lipopolysaccharide-induced tumor necrosis

factor-alpha factor

CMT1D

Unknown

EGR2 Early growth response protein 2

CMT1E

~1%

PMP2 Peripheral myelin protein 22

2
(sequence changes)

Protein Product

Locus
Name

Proportion of CMT1 (excluding

Gene
CMTX) 1

CMT1F/2E Unknown

Protein Product

NEFL Neurofilament light polypeptide

1.
Saporta et al [2011]

Charcot Marie Tooth Type 2 (CMT2) is an axonal (non-demyelinating) peripheral

neuropathy characterized by distal muscle weakness and atrophy. Nerve conduction
velocities are usually within the normal range; however, occasionally they fall in the
low-normal or mildly abnormal range (35-48 m/sec). Peripheral nerves are not
enlarged or hypertrophic.
CMT2 shows extensive clinical overlap with CMT1; however, in general, individuals
with CMT2 tend to be less disabled and have less sensory loss than individuals with
CMT1. A threshold of 38 m/sec for median motor nerve conduction is often used
clinically to distinguish CMT1 from CMT2.
CMTX1 may present with a relatively axonal form of CMT that may be confused with
CMT2.
CMT2A2, the most common type of CMT2, is caused by mutation
of MFN2 (reviewed in Chung et al [2006]). Known MFN2 pathogenic variants and
related pathophysiology are reviewed in Cartoni & Martinou [2009].
CMT2B, caused by mutation of RAB7A, is associated with prominent sensory loss
[Cogli et al 2009].
Table 4.

CMT2: Molecular Genetics

Locus
Name

Proportion of
CMT2 1

Gene / Chromosomal
Locus 2

Protein Product

CMT2A1

Unknown

KIF1B

Kinesin-like protein KIF1B

CMT2A2

20%

MFN2

Mitofusin-2

CMT2B

Unknown

RAB7A

Ras-related protein Rab-7

CMT2B1

Unknown

LMNA

Lamin A/C

CMT2B2

Unknown

MED25

Mediator of RNA polymerase II transcription

subunit 25

Locus
Name

Proportion of
CMT2 1

Gene / Chromosomal
Locus 2

Protein Product

CMT2C

Unknown

TRPV4

Transient receptor potential cation channel

subfamily V member 4

CMT2D

3%

GARS

Glycyl-tRNA synthetase

CMT2E/1F 4%

NEFL

Neurofilament light polypeptide

CMT2F

Unknown

HSPB1

Heat-shock protein beta-1

CMT2G

Unknown

12q12-q13

Unknown

CMT2H/2K 5%

GDAP1

Ganglioside-induced differentiation-associated
protein-1

CMT2I/2J

Unknown

MPZ

Myelin P0 protein

CMT2L

Unknown

HSPB8

Heat-shock protein beta-8

CMT2N

Unknown

AARS

Alanyl-tRNA synthetase, cytoplasmic

CMT2O

Unknown

DYNC1H1

Cytoplasmic dynein 1 heavy chain 1

CMT2P

Unknown

LRSAM1

E3 ubiquitin-protein ligase LRSAM1

CMT2S

Unknown

IGHMBP2

DNA-binding protein SMUBP-2

CMT2T

Unknown

DNAJB2

DnaJ homolog subfamily B member 2

CMT2U

Unknown

MARS

Methionine--tRNA ligase, cytoplasmic

1.
Saporta et al [2011]
2.
Chromosomal locus given only when gene is unknown
Autosomal Dominant Intermediate CMT

Autosomal dominant intermediate CMT (DI-CMT) (Table 5) is characterized by a

relatively typical CMT phenotype with clinical and pathologic evidence of both
abnormal myelin and axonopathy. Nerve conduction velocities (NCVs) overlap those

observed in CMT1 and CMT2 [Nicholson & Myers 2006]. Motor NCVs usually range
between 25 and 50 m/sec. In the two families reported by Soong et al [2013] median
motor nerve conduction velocities (MNCV) ranged from clearly slow/demyelinating
(16.5-28 m/s) to normal (44-45 m/s). The family members with slow MNCV would
have been classified as having CMT1.
Table 5.

Autosomal Dominant Intermediate CMT: Molecular Genetics

Locus Name

Proportion of
Intermediate
CMT

DI-CMTA

Gene /
Chromosomal
Locus 1

Protein Product

Reference

10q24.1-q25.1

Unknown

Verhoeven et al [2001]

DNM2-related
intermediate CharcotMarie-Tooth neuropathy
(DI-CMTB)

DNM2

Dynamin 2

Kennerson et al
[2001], Zchner et al
[2005]

YARS-related
intermediate CharcotMarie-Tooth neuropathy
(DI-CMTC)
Unknown

YARS

Tyrosyl-tRNA
synthetase

Jordanova et al
[2003], Jordanova et al
[2006]

MPZ-related
intermediate CharcotMarie-Tooth neuropathy
(DI-CMTD)

MPZ

Myelin P0 protein

GNB4

Guanine
nucleotide-binding
Soong et al [2013]
protein subunit
beta-4

GNB4-related
intermediate CharcotMarie-Tooth neuropathy
(DI-CMTF)

1.
Chromosomal locus given only when gene is unknown

Charcot-Marie-Tooth type 4 (CMT4) is a group of progressive motor and sensory

axonal and demyelinating neuropathies. It is distinguished from other forms of CMT
by autosomal recessive inheritance (see Table 6). Affected individuals have the typical
CMT phenotype of distal muscle weakness and atrophy associated with sensory loss
and, frequently, pes cavus foot deformity. The autosomal recessive forms of CMT are
reviewed by Bernard et al [2006] and Kabzinska et al [2008].
Note: The term Dejerine-Sottas syndrome (DSS) was originally used to describe a
severe demyelinating neuropathy of infancy and childhood associated with very slow
NCVs, elevated CSF protein, marked clinical weakness, and hypertrophic nerves with

onion bulb formation. Inheritance of DSS was assumed to be autosomal recessive.

Subsequently, individuals with this clinical diagnosis have had various types of
autosomal recessive CMT (CMT4) and have been heterozygous for point mutations in
genes associated with CMT1 including: PMP22 (CMT1A), MPZ (CMT1B),
and EGR2 (CMT1D) [Boerkoel et al 2001a, Boerkoel et al 2001b].
Although the term DSS is still sometimes used to indicate a clinical phenotype, it does
not imply an inheritance pattern or a specific genetic defect [Parman et al 2004].
Table 6.

CMT 4: Molecular Genetics

Locus
Name

Proportion of
CMT4

Gene

Protein Product

CMT4A

GDAP1 Ganglioside-induced differentiation-associated protein 1

CMT4B1

MTMR
Myotubularin-related protein 2
2

CMT4B2

SBF2

CMT4C

SH3TC SH3 domain and tetratricopeptide repeats-containing protein

2
2

Myotubularin-related protein 13

Unknown
CMT4D

NDRG1 Protein NDRG1

CMT4E

EGR2

Early growth response protein 2

CMT4F

PRX

Periaxin

CMT4H

FGD4

FYVE, RhoGEF and PH domain-containing protein 4

CMT4J

FIG4

Phosphatidylinositol 3, 5 biphosphate

X-Linked CMT

Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a

moderate to severe motor and sensory neuropathy in affected males and usually mild
to no symptoms in carrier females. Sensorineural deafness and central nervous system
symptoms also occur in some families (see Table 7).
Five other forms of hereditary neuropathy have been linked to the X chromosome. The
genes associated with CMTX5 and CMTX6 have been identified. Associated findings
are [Huttner et al 2006]:
CMTX2. Intellectual disability [Ionasescu et al 1991, Ionasescu et al 1992]
CMTX3. Spasticity and pyramidal tract signs [Ionasescu et al 1991, Ionasescu et
al 1992, Huttner et al 2006]
CMTX4 (Cowchock syndrome). Deafness and intellectual disability [Cowchock
et al 1985, Priest et al 1995]. Rinaldi et al [2012] identified a missense mutation
(p.Glu493Val) in AIFM1 (encoding apoptosis-inducing factor 1) in a member of
the original family.
CMTX5. Deafness and optic neuropathy. CMTX5 maps to Xq22-q24 [Kim et al
2005]. Pathogenic variants in PRPS1 (p.Glu43Asp, p.Met115Thr) have been
found in two American/European and Korean families. The gene encodes ribosephosphate pyrophosphokinase 1, an enzyme critical for nucleotide biosynthesis
[Kim et al 2007].
CMTX6. Males have childhood onset of a slowly progressive motor and sensory
neuropathy that is largely axonal (variable mild conduction slowing) with
steppage gait and absent tendon reflexes. Carrier females may have a mild
sensory motor axonal neuropathy [Kennerson et al 2013].
Kennerson et al [2010] described two families with an X-linked distal motor
neuropathy similar to CMT with missense mutations in ATP7A, the same gene
involved in Menkes disease.
A retrospective review of X-linked CMT in childhood has been reported [Yiu et al
2011].
Table 7.

CMTX: Molecular Genetics

Disease Name

Proportion of XLinked CMT

Gene / Chromosomal
Protein Product
Locus 1

CMTX1

90%

GJB1

Gap junction beta-1 protein

(connexin 32)

Disease Name

Proportion of XLinked CMT

Gene / Chromosomal
Protein Product
Locus 1

CMTX2

Xp22.2

CMTX3

Xq26

CMTX4/Cowchock
syndrome

AIFM1

Apoptosis-inducing factor 1

CMTX5

PRPS1

Ribose-phosphate
pyrophosphokinase 1

CMTX6

PDK3

Pyruvate dehydrogenase kinase

isoform 3

Unknown

1.
Chromosomal locus given when gene is unknown
Mitochondrial CMT

Mitochondrial abnormalities are known to sometimes be associated with peripheral

neuropathy. Mutation of the nuclear gene MFN2 produces abnormal mitochondrial
fusion/fission and resultant neuropathy (CMT2A). Mutations in the mitochondrial
genome may also be associated with neuropathy, for example in NARP. Pitceathly et al
[2012] have reported an axonal predominantly motor neuropathy associated with
the MT-ATP6variant m.9185T>C.
Evaluation Strategy
Establishing the specific cause of Charcot-Marie-Tooth (CMT) hereditary neuropathy
for a given individual involves a medical history, physical examination, neurologic
examination, and nerve conduction and EMG testing, as well as a detailed family
history and the use of molecular genetic testing when available.
Family History

A three-generation family history with attention to other relatives with neurologic

signs and symptoms should be obtained. Documentation of relevant findings in
relatives can be accomplished either through direct examination of those individuals or
through review of their medical records, including the results of molecular genetic
testing and EMG and NCV studies.
Individuals with CMT may have a negative family history for many reasons, including
mild subclinical expression in other family members, autosomal recessive inheritance,
or de novo (new) mutation of a dominant gene.

 About one third of individuals with identifiable point mutations

in PMP22, GJB1, or MPZ causing the CMT hereditary neuropathy phenotype
have de novo mutations, and thus present as simplex cases (i.e., a single
occurrence in a family) [Boerkoel et al 2002].
PMP22 duplications (which are much more common than point mutations)
occur de novo in about 10%-20% of people with CMT1 [Blair et al 1996, Bort et
al 1997].
Physical Examination

In individuals who have no family history of neuropathy, the first step is to exclude
acquired causes of neuropathy by standard neurologic evaluation (see Differential
Diagnosis of CMT).
Distal weakness, sensory loss, depressed tendon reflexes, and foot deformity are
commonly (but not always) present.
In CMT1, the most common CMT subtype, NCVs are very slow and peripheral nerves
may be palpably enlarged. This is not true of CMT2.
Molecular Genetic Testing

Testing is possible for pathogenic variants in numerous genes associated with similar
phenotypes. Note: Failure to identify a pathogenic variant in a proband does not rule
out a diagnosis of CMT since undetected variants in other genes may be causative.
One genetic testing strategy is serial single gene molecular genetic testing based on
family history and neurophysiologic data [England et al 2009, Saporta et al 2011].
The relative frequencies of various CMT subtypes are shown in Figure 1.
Positive family history
In families with at least two-generation involvement, known male-to-male
transmission, and very slow NCVs (<15 m/sec):
o First, obtain testing for the PMP22 duplication (CMT1A).
o If normal, follow with testing of MPZ (CMT1B) and point mutations
in PMP22 (CMT1E).
o If both are normal, test for LITAF (CMT1C) and EGR2 (CMT1D)
[England et al 2009 (full text; see figure), Saporta et al 2011 (full text; see
Figure 2)].
In families with at least two-generation involvement and slow NCVs (15-35
m/sec), but without male-to-male transmission, molecular genetic testing
of PMP22 (CMT1A), GJB1 (CMTX), MPZ (CMT1B), and LITAF (CMT1C)
should be performed sequentially [Saporta et al 2011 (full text; see Figure 1)]

Note: In more than 90% of individuals with a CMT1 phenotype a pathogenic

variant is found in one of three genes (PMP22, MPZ, GJB1) [Szigeti et al
2006, Saporta et al 2011].
In families with probable X-linked inheritance of the CMT phenotype, molecular
genetic testing of GJB1 (CMTX) is appropriate to confirm the diagnosis.
In individuals with the CMT2 phenotype, MFN2 (CMT2A2) can be tested first
followed by testing of MPZ (CMT2I/2J) and GJB1 (CMTX1). Other rarer causes
include GDAP1 (CMT2H/2K), NEFL(CMT2E/1F), and EGR2 (CMT1D)
[Saporta et al 2011 (full text; see Figure 4)].
Early childhood onset. Based on the Baets et al [2011] study of 77 unrelated subjects
with onset of neuropathy in the first year of life, pathogenic variants in MPZ, PMP22,
and EGR2 should be evaluated first as they were most frequent in those individuals
with hypotonia and breathing difficulties. Testing
of FGD4, PRX, MTMR2, SBF2, SH3TC2, and GDAP1 is indicated in individuals with
early foot deformities and delay in motor milestones after an uneventful neonatal
period.
Negative family history (i.e., a single occurrence in a family)
Molecular genetic testing of PMP22dup (CMT1A), MPZ (CMT1B),
and GJB1 (CMTX) should be performed on males and females who have no
family history of neuropathy because de novo duplications of the 17p11 region
(causing CMT1A) are common and because females who have
a GJB1 pathogenic variant (causing CMTX1) may be asymptomatic.
If no pathogenic variant is identified in any of these three genes testing for rarer
subtypes can be considered [England et al 2009 (full text; see Figure)].
Early-onset severe CMT may be caused by mutation of PMP22 (CMT1A or
1E), GDAP1 (CMT4A), EGR2 (CMT4E), PRX (CMT4F), SH3TC2 (CMT4C), F
DG4 (CMT4H), or MTMR2 (CMT4B1).
An alternative genetic testing strategy is use of a multi-gene panel that includes
genes associated with CMT and other genes of interest (see Differential Diagnosis of
CMT) [Rossor et al 2013]. Panels exist for dominantly and recessively inherited CMTs
as well as demyelination and axonal forms. Larger (all-inclusive) panels may also be
available. Note: The genes included and the methods used in multi-gene panels vary
by laboratory and over time.
A reasonable testing approach is to first test for pathogenic variant(s) in the single
most likely gene that best fits the phenotype (e.g., CMT1A or CMT2A). If such testing
does not identify the pathogenic variant(s), then proceed to a genetic neuropathy panel
followed by whole-exome sequencing if appropriate [Rossor et al 2015].
DiVincenzo et al [2014] have reported the results of genetic testing of more than
17,000 samples submitted to the largest commercial laboratory providing CMT testing

in the USA. The cases were not screened for family history or phenotype, but
represented individuals with peripheral neuropathy whose physicians suspected
possible CMT. In 18% of those tested, a causative allelic variant was identified in a
CMT-related gene. Importantly, 95% of the positive results involved one of four genes
(PMP22, GJB1, MPZ, MFN2). The authors conclude that these four genes should be
screened first before proceeding with further genetic testing.
Manganelli et al [2014], in a large Italian cohort with CMT, essentially confirm the
findings of DiVincenzo et al [2014] except for finding a larger number
of GDAP1 pathogenic variants (4%).
Test characteristics. See Clinical Utility Gene Card [Aretz et al 2010] for information
on test characteristics including sensitivity and specificity.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help
them make informed medical and personal decisions. The following section deals with
genetic risk assessment and the use of family history and genetic testing to clarify
genetic status for family members. This section is not meant to address all personal,
cultural, or ethical issues that individuals may face or to substitute for consultation
with a genetics professional. ED.
Mode of Inheritance

Charcot-Marie-Tooth (CMT) hereditary neuropathy may be transmitted in an

autosomal dominant, autosomal recessive, or X-linked manner depending on the
genetic subtype in a family.
Risk to Family Members Autosomal Dominant

Parents of a proband
Most individuals diagnosed as having autosomal dominant CMT have an
affected parent, although occasionally the family history is negative.
Family history may appear to be negative because of failure to recognize CMT
in family members, early death of the parent before the onset of symptoms, late
onset in an affected parent, or reduced penetrance of the mutant allele in an
asymptomatic parent.
Sibs of a proband
The risk to sibs depends on the genetic status of the proband's parents.
If one of the proband's parents has a mutant allele, the risk to the sibs of
inheriting the mutant allele is 50%.

Offspring of a proband. Individuals with autosomal dominant CMT have a 50%

chance of transmitting the mutant allele to each child.
Risk to Family Members Autosomal Recessive

Parents of a proband
The parents are obligate heterozygotes and therefore carry a single copy of a
pathogenic variant.
Heterozygotes are asymptomatic.
Sibs of a proband
At conception, each sib of a proband has a 25% chance of being affected, a 50%
chance of being an asymptomatic carrier, and a 25% chance of being unaffected
and not a carrier.
Once an at-risk sib is known to be unaffected, the chance of his/her being a
carrier is 2/3.
Heterozygotes are asymptomatic.
Offspring of a proband. All of the offspring are obligate carriers.
Risk to Family Members X-Linked

Parents of a proband
Women who have an affected son and another affected male relative are obligate
heterozygotes.
If pedigree analysis reveals that an affected male represents a simplex case (a
male with no family history of CMT), several possibilities regarding his mother's
carrier status need to be considered:
o He has a de novo disease-causing mutation, in which case his mother is not
a carrier;
o His mother has a de novo disease-causing mutation either (a) as a
"germline mutation" (i.e., occurring at the time of her conception and thus
present in every cell of her body; or (b) as "germline mosaicism" (i.e.,
present in some of her germ cells only);
o His maternal grandmother has a de novo disease-causing mutation.
Sibs of a proband
The risk to sibs depends on the genetic status of the proband's mother.

 A female who is a carrier has a 50% chance of transmitting the pathogenic

variant with each pregnancy. Sons who inherit the pathogenic variant will be
affected; daughters who inherit the variant may or may not be affected.
If the mother is not a carrier, the risk to sibs is low but greater than that of the
general population because of the possibility of germline mosaicism.
Offspring of a proband. All the daughters of an affected male inherit the pathogenic
variant and may or may not have symptoms; none of his sons will be affected.
Other family members of proband. The proband's maternal aunts and their offspring
may be at risk of being carriers.
Empiric Risks to Family Members

Empiric data regarding recurrence risk are not available for genetic counseling of
individuals who represent simplex cases (i.e., single occurrences in a family) in which
no pathogenic variant is identified.
Related Genetic Counseling Issues

Considerations in families with apparent de novo mutation. When neither parent of

a proband with an autosomal or X-linked condition has the pathogenic variant or
clinical evidence of the disorder, it is likely that mutation occurred de novo in the
proband. However, possible non-medical explanations including alternate paternity or
maternity (e.g., with assisted reproduction) or undisclosed adoption could also be
explored.
Family planning
The optimal time for determination of genetic risk and discussion of the
availability of prenatal testing is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential
risks to offspring and reproductive options) to young adults who are affected or
at risk of being affected.
Similarly, decisions about testing to determine the genetic status of at-risk
asymptomatic family members are best made before pregnancy. One study found
that many individuals with CMT give themselves high disability ratings and
36% would choose not to have children [Pfeiffer et al 2001].
Testing of asymptomatic adult relatives who are at risk of developing CMT is
possible after direct DNA testing has identified the specific pathogenic variant in an
affected relative. Such testing should be performed in the context of formal genetic
counseling.
Testing of asymptomatic at-risk children is discouraged. See also the National
Society of Genetic Counselors position statement on genetic testing of minors for
adult-onset conditions and the American Academy of Pediatrics and American College

of Medical Genetics and Genomics policy statement: ethical and policy issues in
genetic testing and screening of children.
DNA banking is the storage of DNA (typically extracted from white blood cells) for
possible future use. Because it is likely that testing methodology and our
understanding of genes, allelic variants, and diseases will improve in the future,
consideration should be given to banking DNA of affected individuals.
Prenatal Testing

If the pathogenic variant(s) have been identified in the family, prenatal diagnosis for
pregnancies at increased risk may be available from a laboratory offering testing for
the gene of interest or custom testing.
Requests for prenatal diagnosis of (typically) adult-onset diseases are uncommon.
Differences in perspective may exist among medical professionals and within families
regarding the use of prenatal testing, particularly if the testing is being considered for
the purpose of pregnancy termination rather than early diagnosis. Although most
centers would consider decisions about prenatal testing to be the choice of the parents,
discussion of these issues is appropriate [Bernard et al 2002].
Preimplantation genetic diagnosis (PGD) for some forms of CMT has been reported
[Sharapova et al 2004, Lee et al 2013] and may be available for some families in
which the pathogenic variant(s) have been identified.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support
organizations and/or registries for the benefit of individuals with this disorder and
their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.
Association CMT France
France
Phone: 820 077 540; 2 47 27 96 41
www.cmt-france.org
Charcot-Marie-Tooth Association (CMTA)
PO Box 105
Glenolden PA 19036
Phone: 800-606-2682 (toll-free); 610-499-9264
Fax: 610-499-9267
Email: info@cmtausa.org
www.cmtausa.org

 European Charcot-Marie-Tooth Consortium

Department of Molecular Genetics
University of Antwerp
Antwerp Antwerpen B-2610
Belgium
Fax: 03 2651002
Email: gisele.smeyers@ua.ac.be
Hereditary Neuropathy Foundation, Inc.
432 Park Avenue South
4th Floor
New York NY 10016
Phone: 855-435-7268 (toll-free); 212-722-8396
Fax: 917-591-2758
Email: info@hnf-cure.org
www.hnf-cure.org
My46 Trait Profile
Charcot Marie Tooth disease
National Library of Medicine Genetics Home Reference
Charcot-Marie-Tooth disease
NCBI Genes and Disease
Charcot-Marie-Tooth syndrome
TREAT-NMD
Institute of Genetic Medicine
University of Newcastle upon Tyne
International Centre for Life
Newcastle upon Tyne NE1 3BZ
United Kingdom
Phone: 44 (0)191 241 8617
Fax: 44 (0)191 241 8770

Email: info@treat-nmd.eu
Charcot-Marie-Tooth Disease
Association Francaise contre les Myopathies (AFM)
1 Rue de l'International
BP59
Evry cedex 91002
France
Phone: +33 01 69 47 28 28
Email: dmc@afm.genethon.fr
www.afm-telethon.fr
European Neuromuscular Centre (ENMC)
Lt Gen van Heutszlaan 6
3743 JN Baarn
Netherlands
Phone: 31 35 5480481
Fax: 31 35 5480499
Email: enmc@enmc.org
www.enmc.org
Muscular Dystrophy Association - USA (MDA)
222 South Riverside Plaza
Suite 1500
Chicago IL 60606
Phone: 800-572-1717
Email: mda@mdausa.org
www.mda.org
Muscular Dystrophy Campaign
61A Great Suffolk Street
London SE1 0BU
United Kingdom
Phone: 0800 652 6352 (toll-free); 020 7803 4800

Email: info@muscular-dystrophy.org
www.muscular-dystrophy.org
RDCRN Patient Contact Registry: Inherited Neuropathies Consortium
Patient Contact Registry
Management
Treatment of Manifestations

Reviews of treatment approaches to CMT are available [Carter et al 2008, Young et al

2008, Reilly & Shy 2009]. Reviews of the diagnosis, natural history and management
are available [Pareyson & Marchesi 2009a, Pareyson & Marchesi 2009b].
Treatment is symptomatic. Affected individuals are often evaluated and managed by a
multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons,
and physical and occupational therapists [Carter et al 2004, Grandis & Shy 2005].
Quality of life has been measured and compared among various groups of individuals
with Charcot-Marie-Tooth (CMT) [Vinci et al 2005a, Burns et al 2010]. Persistent
weakness of the hands and/or feet has important career and employment implications;
anticipatory counseling is appropriate.
Special shoes, including those with good ankle support, may be needed. Affected
individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid
walking.
Some individuals require forearm crutches or canes for gait stability; fewer than 5% of
individuals need wheelchairs.
Exercise is encouraged within the individual's capability and many individuals remain
physically active.
Orthopedic surgery may be required to correct severe pes cavus deformity [Guyton &
Mann 2000, Guyton 2006, Casasnovas et al 2008, Ward et al 2008]. Surgery is
sometimes required for hip dysplasia [Chan et al 2006].
The cause of any pain should be identified as accurately as possible [Padua et al 2006].
Musculoskeletal pain may respond to acetaminophen or nonsteroidal antiinflammatory agents [Carter et al 1998].
Neuropathic pain may respond to tricyclic antidepressants or drugs such as
carbamazepine or gabapentin.
Modafinil has been used to treat fatigue [Carter et al 2006].
Prevention of Secondary Complications

Daily heel cord stretching exercises to prevent Achilles' tendon shortening are
desirable, as well as gripping exercises for hand weakness [Vinci et al 2005b].

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications that are toxic or potentially toxic to persons with CMT comprise a
spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for
an up-to-date list.
Chemotherapy for cancer that includes vincristine may be especially damaging to
peripheral nerves and severely worsen CMT [Graf et al 1996, Nishikawa et al 2008].
Therapies Under Investigation

Patel & Pleasure [2013] and Ekins et al [2015] have summarized the potential
treatment approaches to CMT1.
Dyck et al [1982], Ginsberg et al [2004], and Carvalho et al [2005] have described a
few individuals with CMT1 and sudden deterioration in whom treatment with steroids
(prednisone) or IVIg has produced variable levels of improvement. Nerve biopsy has
shown lymphocytic infiltration. One such family had a specific MPZ pathogenic
variant (p.Ile99Thr) [Donaghy et al 2000]. A young child with CMT1A and an
inflammatory neuropathy has been reported [Marques et al 2010].
Sahenk et al [2003] are studying the effects of neurotrophin-3 on individuals with
CMT1A.
Passage et al [2004] reported benefit from ascorbic acid (vitamin C) in a mouse model
of CMT1. However, a study of 277 persons with CMT1A found no significant effect of
a daily 1.5-g dose of ascorbic acid after two years [Pareyson et al 2011]. Similar
studies of smaller numbers of patients have also shown no benefit of such treatment
[Micallef et al 2009, Verhamme et al 2009]. Lewis et al [2013] also found no positive
treatment response to ascorbic acid vs. placebo in 110 subjects with CMT1A.
Sereda et al [2003] and Meyer zu Horste et al [2007] used a progesterone antagonist to
improve neuropathy in a transgenic rat model of CMT1A.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range
of diseases and conditions.
Other

Night splints have not improved ankle range of motion [Refshauge et al 2006].
References
Published Guidelines/Consensus Statements

1. Committee on Bioethics, Committee on Genetics, and American College of

Medical Genetics and Genomics Social, Ethical, Legal Issues Committee.
Ethical and policy issues in genetic testing and screening of children.
Available online. 2013. Accessed 5-1-15. [PubMed: 23428972]

2. National Society of Genetic Counselors. Position statement on genetic testing of

minors for adult-onset conditions. Available online. 2012. Accessed 5-1-15.
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Suggested Reading

1. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related

disorders. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE,
Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular
Bases of Inherited Disease (OMMBID). Chap 227. New York, NY: McGrawHill. Available online. 2015. Accessed 5-1-15.
2. Nicholson G, Kennerson M, Brewer M, Gardern J, Shy M. Genotypes & sensory
phenotypes in 2 new X-linked neruopathies (CMTX3 and dSMAX) and
dominant CMT/HMN overlap syndromes. Adv Exp Med Biol. 2009;652:201
6. [PubMed: 20225027]
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sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant
axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2011;89:30812. [PMC
free article: PMC3155164] [PubMed: 21820100]
4. Weterman MA, Sorrentino V, Kasher PR, Jakobs ME, van Engelen BG, Fluiter
K, de Wissel MB, Sizarov A, Nrnberg G, Nrnberg P, Zelcer N, Schelhaas HJ,
Baas F. A frameshift mutation in LRSAM1 is responsible for a dominant
hereditary polyneuropathy. Hum Mol Genet. 2012;21:35870. [PMC free article:
PMC3276280] [PubMed: 22012984]
Chapter Notes
Revision History

7 May 2015 (cd) Revision: heterozygous mutation of IGHMBP2 as causative of

CMT2S, of DNAJB2 as causative of CMT2T, and of MARS as causative of
CMT2U

 12 February 2015 (tb) Revision: additions to alternative genetic testing strategy

6 March 2014 (tb) Revision: SPTLC1 and ATL3 added
20 February 2014 (tb) Revision: Lee et al 2013 added to Preimplantation genetic
diagnosis; OMIM Phenotypic Series link added
30 January 2014 (tb) Revision: edits to Evaluation Strategy
14 November 2013 (tb) Revision: figures added to Prevalence and Single-Gene
Causes [Rossor et al 2013]
11 July 2013 (tb) Revision: TIA1 mutations causative of Welander distal
myopathy; added information on: prevalence, ascorbic acid treatment
28 March 2013 (tb) Revision: to include GNB4 mutations as causative of
dominant intermediate Charcot-Marie-Tooth disease [Soong et al 2013]
7 March 2013 (tb) Revision: to include mutations in AIFM1 as causative of
CMTX4
14 February 2013 (tb) Revision: to include mutation in PDK3 as causative of
CMTX6
27 September 2012 (tb) Revision: report of CMT resulting from mutation in a
mitochondrial gene [Pitceathly et al 2012]
9 February 2012 (tb) Revision: mutations in DYNC1H1 reported to be associated
with CMT2O; mutation in LRSAM1 associated with CMT2P
31 May 2011 (me) Comprehensive update posted live
16 April 2009 (tb) Revision: sequence analysis available clinically for CMT4H;
CMT4J added
24 July 2008 (tb) Revision: gene (PRPS1) for CMTX5 identified
31 August 2007 (me) Comprehensive update posted to live Web site
19 June 2006 (cd) Revision: family history evaluation strategy
3 February 2006 (tb) Revision: mutations in YARS cause DI-CMTC
30 December 2005 (cd) Revision: testing for CMT2B clinically available
20 December 2005 (tb) Revision: SEPT9 mutations identified in individuals with
familial brachial plexus neuropathy; changes to Differential Diagnosis
27 April 2005 (me) Comprehensive update posted to live Web site
9 September 2004 (tb) Revision: test availability

 21 June 2004 (tb,cd) Revision: LITAF and MFN2 added

11 May 2004 (me) Author revisions
24 March 2004 (cd) Revision: CMT4A
22 December 2003 (tb,bp) Revision
23 October 2003 (cd) Revision: change in test availability
12 August 2003 (tb) Revision: CMT4 molecular genetics
29 May 2003 (td) Author revisions
24 April 2003 (tb) Author revisions
28 March 2003 (me) Comprehensive update posted to live Web site
10 May 2002 (tb) Author revisions
12 September 2001 (tb) Author revisions
20 June 2001 (me) Comprehensive update posted to live Web site
15 May 2000 (tb) Author revisions
14 January 2000 (tb) Author revisions
31 August 1999 (tb) Author revisions
18 June 1999 (tb) Author revisions
8 April 1999 (tb) Author revisions
5 March 1999 (tb) Author revisions
12 October 1998 (tb) Author revisions
28 September 1998 (pb) Overview posted to live Web site
April 1996 (tb) Original submission
Figures

Figure 1.

Genetic diagnoses in CMT and related disorders

Rossor et al [2013]; reprinted with permission

Figure 2.

Different forms of Charcot-Marie-Tooth disease and associated genes

There are areas of overlap between different types of CMT. Red shading indicates the
most commonly involved genes.
dHMN = distal hereditary motor neuropathy
DI = dominant intermediate
HMSN = hereditary motor and sensory neuropathy
HSN = hereditary sensory neuropathy
Pareyson & Marchesi [2009a]; reprinted from The Lancet Neurology with permission
from Elsevier

Figure 3.

Known disease genes for CMT and related disorders, and their proposed
pathomechanism
Rossor et al [2013]; reprinted with permission
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