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Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview

Synonyms: Distal Hereditary Motor Neuropathy (dHMN), Hereditary Motor/Sensory Neuropathy (HMSN)

, MD.

Author Information

Initial Posting: ; Last Update: June 28, 2018.

Summary

The purpose of this overview is to increase the awareness of clinicians regarding Charcot-Marie-Tooth (CMT) hereditary neuropathy, its causes, and its management.

The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of CMT hereditary neuropathy.

Goal 2.

Review the causes of CMT hereditary neuropathy.

Goal 3.

Provide an evaluation strategy to identify the cause of CMT hereditary neuropathy in a proband (when possible).

Goal 4.

Inform genetic counseling of family members of an individual with CMT hereditary neuropathy.

Goal 5.

Review management of CMT hereditary neuropathy.

1. Clinical Characteristics of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy

Charcot-Marie-Tooth (CMT) hereditary neuropathy refers to a group of disorders characterized by a chronic motor and sensory polyneuropathy, also known as hereditary motor and sensory neuropathy (HMSN).

Clinical Findings

Individuals with CMT manifest 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. The affected individual typically has distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed tendon reflexes, and pes cavus foot deformity (i.e., high-arched feet).

Muscle weakness is often associated with mild to moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful [Azevedo et al 2018]. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration, but can also include impaired sensation of pain/pinprick, temperature, and joint position.

Sensorineural hearing loss can occur.

The clinical diagnosis of CMT in a symptomatic person is based on characteristic findings of peripheral neuropathy on medical history and physical examination.

Classification of CMT Type

Traditional classification of CMT (e.g., CMT1, CMT2, and DI-CMT [dominant intermediate]) was based on peripheral neuropathy type as determined by nerve conduction velocity (NCV) and mode of inheritance as determined by family history. As understanding of the genetic basis of CMT gradually evolved, letters in alphabetic order were assigned to the CMT type to represent the gene involved (e.g., CMT1A).

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

  • Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
  • Axonal (non-demyelinating) (CMT 2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
  • Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

Newly proposed CMT naming system. As more genes causing CMT were identified and as the overlap of neuropathy phenotypes and modes of inheritance became apparent, the above alphanumeric classification system proved unwieldy and inadequate. In 2018, Magy et al [2018] proposed a gene-based classification of inherited neuropathies (see Table 3, which includes a comprehensive list of CMT-associated genes and correlation with the alphanumeric classification). An additional advantage of the Magy et al [2018] classification system is that a patient's findings can be described in terms of mode of inheritance, neuropathy type, and gene (see 3. Evaluation Strategies).

Nomenclature

Distal hereditary motor neuropathy (dHMN) and distal spinal muscular atrophy (DSMA) = CMT. In their study of distal hereditary motor neuropathies (the clinically and genetically heterogeneous group of disorders characterized by lower motor neuron dysfunction), Bansagi et al [2017] reported that pathogenic variants in the same genes can cause the phenotypes known as dHMN and DSMA, leading them to conclude that dHMN and motor CMT should not be classified differently.

Dejerine-Sottas syndrome (DSS) originally referred to 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. 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].

Differential Diagnosis of CMT

CMT – the subject of this overview – needs to be distinguished from the following entities: systemic disorders with neuropathy, other types of hereditary neuropathy (Table1), distal myopathies (Table 2), hereditary sensory neuropathies (HSN), and acquired disorders. Note: These entities are not discussed elsewhere in this overview.

Systemic Disorders with Neuropathy

Blindness, seizures, dementia, and intellectual disability are not part of the CMT hereditary neuropathy phenotype discussed in this overview and suggest a different diagnosis, including childhood-onset disorders with significant CNS involvement such as metachromatic leukodystrophy, Krabbe disease, Pelizaeus-Merzbacher disease, and Lowe syndrome.

Other Hereditary Neuropathies

Table 1 includes multisystem disorders in which peripheral motor neuropathy may be a presenting feature (i.e., before multisystem involvement is appreciated) and/or one manifestation in a complex neurologic disorder.

Table 1.

Other Hereditary Neuropathies

Gene 1MOIDisorderOtherGeneReview/OMIM
ABCD1XLAdrenomyeloneuropathyProgressive stiffness & weakness of legs, sphincter disturbances, sexual dysfunction, & often, impaired adrenocortical functionX-Linked Adrenoleukodystrophy
ABHD12ARPolyneuropathy, hearing loss, ataxia, retinitis pigmentosa, & cataract (PHARC)OMIM 612674
FXNARFriedreich ataxiaMay present w/sensory loss, depressed tendon reflexes, & high-arched feetFriedreich Ataxia
MT-ATP6mitNARPNeurogenic muscle weakness, ataxia, & retinitis pigmentosaMitochondrial DNA-Associated Leigh Syndrome and NARP
PEX7
(PHYH)
ARRefsum diseaseAnosmia & early-onset retinitis pigmentosa ± neuropathy, deafness, ataxia, &/or ichthyosisRefsum Disease
PMP22ADHereditary neuropathy with liability to pressure palsiesAcute onset of recurrent, painless, focal sensorimotor neuropathy in a single nerveHereditary Neuropathy with Liability to Pressure Palsies
SCN9AADSCN9A-related inherited erythromelalgiaRecurrent attacks of bilateral & symmetric intense pain, redness, warmth, & swelling involving feet & (less frequently) handsSCN9A-Related Inherited Erythromelalgia
SEPT9ADHereditary neuralgic amyotrophyRecurrent sudden onset of shoulder or upper arm pain & weakness ± sensory loss; later atrophy of the upper extremityHereditary Neuralgic Amyotrophy
SPARTARTroyer syndromeProgressive spastic paraparesis, dysarthria, & pseudobulbar palsy; distal amyotrophy; motor & cognitive delaysTroyer Syndrome
TTRADTransthyretin-associated amyloidosisSensorimotor & autonomic neuropathy; cardiomyopathy; nephropathy; CNS amyloidosisFamilial Transthyretin Amyloidosis
TYMPARMNGIEProgressive gastrointestinal dysmotility; cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; demyelinating peripheral neuropathyMitochondrial Neurogastrointestinal Encephalopathy Disease

mit =mitochondrial

1.

Genes are listed in alphabetic order.

Distal Myopathies

Some genetic myopathies that present with weakness in the distal lower and/or upper limbs can be confused with CMT (Table 2). In these so-called distal myopathies peripheral nerve electrophysiology is normal and EMG and muscle biopsy are myopathic.

Table 2.

Distal Myopathies

Gene 1MOIDisorderClinical ManifestationsGeneReview/OMIM
Mean Age of Onset (Years)Initial Muscle Group Involved
ANO5ARMiyoshi dystrophy type 3ANO5-Related Muscle Diseases
CAV3AD
AR
Distal myopathyMyofibrillar Myopathy
CRYABADDistal myofibrillar myopathyAdultDistal leg & hands + cardiomyopathy
DESAD
AR
Mesminopathy myofibrillar myopathy15-40Distal leg & forearm + cardiomyopathy
DNAJB6ADMyofibrillar myopathyTeens-adultDistal leg
DYSFARMiyoshi early-adult-onset myopathy15-20Posterior compartment in legsDysferlinopathy
FLNCADDistal myopathy 4OMIM 614065
GNEARNonaka early-adult-onset distal myopathy15-20Anterior compartment in legsGNE-Related Myopathy
LDB3ADZaspopathy (Markesbery-Griggs late-onset distal myopathy)>40Anterior compartment in legsMyofibrillar Myopathy
MATR3ADAmyotrophic lateral sclerosis 21 (Formerly MPD2)35-60Asymmetric lower leg & hands, dysphoniaAmyotrophic Lateral Sclerosis Overview, OMIM 606070
MYH7ADLaing early-onset distal myopathy<20Anterior compartment in legs & neck flexorsLaing Distal Myopathy
MYOTADDistal myotilinopathy>40Posterior > anterior in legsMyofibrillar Myopathy
NEBARDistal nebulin myopathy2-15Anterior lower legNemaline Myopathy
TIA1AD
AR
Welander distal myopathy>40Distal upper limbs (finger & wrist extensors)OMIM 604454
TCAPARDistal onset in telethoninopathyEarlyLower legOMIM 601954
TTNADUdd distal myopathy>35Anterior compartment in legsUdd Distal Myopathy
1.

Genes are listed in alphabetic order.

Hereditary Sensory Neuropathy and Hereditary Sensory and Autonomic Neuropathy

Hereditary sensory neuropathy (HSN) and hereditary sensory and autonomic neuropathy (HSAN) can produce mild, moderate, or severe sensory loss without muscle weakness or atrophy. Rotthier et al [2012] have reviewed the clinical and genetic factors associated with six autosomal dominant and seven autosomal recessive types.

Table 3.

Hereditary Sensory Neuropathy (HSN) and Hereditary Sensory and Autonomic Neuropathy (HSAN)

Gene 1MOIDisorderOtherGeneReview/OMIM
ATL1ADHSN1DOMIM 613708
ATL3ADHSN1FOMIM 615632
DNMT1ADHSN1EDeafness, dementiaDNMT1-Related Dementia, Deafness, and Sensory Neuropathy
DSTARHSAN6OMIM 614653
RETREG1ARHSAN2BHyperhidrosis, urinary incontinenceHereditary Sensory and Autonomic Neuropathy Type II
ELP1ARHSAN3Episodic hypertension, hyperhidrosis, cyclic vomitingFamilial Dysautonomia
KIF1AARHSN2CHereditary Sensory and Autonomic Neuropathy Type II
NGFARHSAN5Congenital Insensitivity to Pain Overview
NTRK1ARHSAN4Congenital Insensitivity to Pain with Anhidrosis
PRDM12ARHSAN8Congenital Insensitivity to Pain Overview
SCN11AADHSAN7Gastrointestinal dysfunction
SCN9AARHSAN2DInsensitivity to pain (also erythromelalgia)Hereditary Sensory and Autonomic Neuropathy Type II
SPTLC1ADHSAN1APerforating ulcersHereditary Sensory Neuropathy Type IA
SPTLC2ADHSAN1COMIM 613640
WNK1ARHSAN2AHereditary Sensory and Autonomic Neuropathy Type II

HSN = hereditary sensory neuropathy

HSAN = hereditary sensory and autonomic neuropathy

1.

Genes are listed in alphabetic order.

Acquired Neuropathies

Acquired (non-genetic) neuropathies include alcoholism, vitamin B12 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).

2. Causes of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy

More than 80 different genes are associated with CMT [Stojkovic 2016].

Table 4 presents information on 73 of the known CMT-associated genes including mode of inheritance and neuropathy type (axonal, demyelinating, and dominant intermediate). Organization of this table is modeled on the newly proposed classification system of Magy et al [2018]. Note that the column titled Other Designations includes designations used in other classification systems which include dominant intermediate CMT (DI-CMT), distal spinal muscular atrophy (DSMA), hereditary sensory and autonomic neuropathy (HSAN), and distal hereditary motor neuropathy (dHMN).

Table 4.

CMT: Genes, Mode of Inheritance, Neuropathy Phenotype

Gene 1MOINeuropathy TypeOther Phenotypic Features / CommentsGeneReview / OMIM / ReferenceOther Designations 2
AxDeIn
Most commonly involved genes 3
GDAP1ARVocal cord paresis 4GDAP1-Related Hereditary Motor and Sensory NeuropathyCMT2K
ARCMT4A
CMT2H
CMT2K
CMTRIA
AD, AROMIM 607831
GJB1XLFamily history may appear to be AD as females can be as severely affected as males.CMT Neuropathy X Type 1CMTX1
HINT1ARNeuromyotoniaOMIM 601314
MFN2AD, AROptic atrophyCMT Neuropathy Type 2ACMT2A2
CMT2I/2J
MPZADOMIM 118200CMT1B
CMT2I/J
DI-CMTD
PMP22ADOMIM 601097CMT1A
CMT1E
SH3TC2ARCMT Neuropathy Type 4CCMT4C
Other genes
AARSADOMIM 601065CMT2N
ABHD12ARDeafness, cataract, retinitis pigmentosaOMIM 613599PHARC
AIFM1XLDeafness, intellectual disabilityOMIM 300169CMTX4
ARHGEF10ADOMIM 608136
ATP1A1ADLassuthova et al [2018]
ATP7A 5XLDistal lower extremitiesATP7A-Related Copper Transport Disorders, OMIM 300011
BAG3ADMyofibrillar myopathy, cardiomyopathyOMIM 603883
BSCL2ADDistal lower extremities;
UMN involvement can cause spastic paraplegia
BSCL2-Related Neurologic Disorders/SeipinopathydHMN5A
CNTNAP1ARArthrogryposis, leukodystrophyOMIM 602346
COA7ARHiguchi et al [2018]
DCTN1ADDistal lower extremitiesOMIM 601143dHMN7B
DCTN2ADVocal cord paresis 4OMIM 607376
DGAT2ADOMIM 606983
DHTKD1ADOMIM 614984CMT2Q
DNAJB2ARDistal motor neuropathyFrasquet et al [2016], Lupo et al [2016]DSMA5
DNMT1ADHearing loss, dementiaDNMT1-Related Dementia, Deafness, and Sensory NeuropathyDNMT1
DNM2ADDNM2-Related Intermediate CMT NeuropathyCMT2M
DI-CMTB
DRP2XLAutismOMIM 300052
DYNC1H1ADSMAOMIM 600112CMT2O
EGR2ADOMIM 129010CMT1D
ARCMT4E
FGD4ARCMT Neuropathy Type 4HCMT4H
FIG4ARCMT Neuropathy Type 4JCMT4J
GARSADOnset in handsGARS-Associated Axonal NeuropathyCMT2D
dHMN5A
GNB4ADOMIM 610863DI-CMTF
HARSADOMIM 142810CMT2W
HSPB1ADOMIM 602195CMT2F
dHMN2B
HSPB3ADOMIM 604624dHMN2C
HSPB8ADAdult onsetOMIM 608014CMT2L
dHMN2A
IGHMBP2AROMIM 600502CMT2S
DSMA1
INF2ADGlomerulosclerosisOMIM 610982
KIF1BADOMIM 605995CMT2A1
KIF5AADSpasticityOMIM 602821
LITAFADOMIM 603795CMT1C
LMNAAROMIM 150330CMT2B1
LRSAM1ADOMIM 610933CMT2G
CMT2P
AR
MARSADOMIM 156560CMT2U
MCM3APARChildhood onset, severeOMIM 603294
MED25AROMIM 610197CMT2B2
MMEAROMIM 120520CMT2T
AD
MORC2ADOMIM 616661CMT2Z
MPV17ARNavaho neurohepatopathyOMIM 137960
MPZADOMIM 118200CMT1B
CMT2I/J
DI-CMTD
MTMR2ARVocal cord paresis 4OMIM 603557CMT4B1
NAGLUADOMIM 609701CMT2V
NDRG1AROMIM 605262CMT4D
NEFHADOMIM 162230
NEFLAD, ARCMT Neuropathy Type 2E/1FCMT1F/2E
PDK3XLOMIM 300906CMTX6
PLEKHG5ARDistal predominantOMIM 611101DSMA4
PRPS1XLRetinopathy, deafnessCMT Neuropathy X Type 5CMTX5
PRXAROMIM 605725CMT4F
PTRH2ARHearing lossOMIM 608625
RAB7AADProminent sensory lossOMIM 602298CMT2B
SBF1AROMIM 603560CMT4B3
SBF2AROMIM 607697CMT4B2
SCO2ARMotor neuropathyRebelo et al [2018]
SETXADDistal lower extremitiesOMIM 608465FALS
SIGMAR1ARMotor neuropathyOMIM 601978
SGPL1ARRecurrent mononeuropathyOMIM 603729
SPG11ARSpasticity, cognitive declineOMIM 610844CMT2X
ALS5
SPTLC1ADOMIM 605712HSAN1A
TRIM2ARVocal cord paresis 4OMIM 614141CMT2R
TRPV4ADVocal cord paresis 4, skeletal dysplasiaTRPV4-Associated DisordersCMT2C
VCPADInclusion body myopathy, dementiaInclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal DementiaCMT2Y
WARSADMotor neuropathyOMIM 191050dHMN9
YARSADOMIM 603623DI-CMTC
Unknown 6XLRapid progression, severe hand weaknessOMIM 302802CMTX3

Ax = axonal

De = demyelinating

In = intermediate

UMN = upper motor neuron

DI-CMT = dominant intermediate CMT

DSMA = distal spinal muscular atrophy

ALS = amyotrophic lateral sclerosis

HSAN = hereditary sensory and autonomic neuropathy

dHMN = distal hereditary motor neuropathy

1.

Genes are listed in alphabetic order.

2.

Designations used in other classification systems

3.
4.

Can be the first manifestation of CMT. Typically presents as hoarse voice and stridor associated with use of accessory inspiratory muscles [Zambon et al 2017].

5.

ATP7A-CMT shares none of the clinical or biochemical abnormalities characteristic of the allelic disorders Menkes disease and occipital horn syndrome.

6.

A 78-kb interchromosomal insertion into the CMTX3 locus at Xq26.3-q27.3 requiring a custom-targeted assay [Brewer et al 2016, Kanhangad et al 2018]

3. Evaluation Strategies to Identify the Genetic Cause of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy in a Proband

Establishing a specific genetic cause of CMT hereditary neuropathy can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling.

Establishing the specific cause of CMT hereditary neuropathy for a given individual involves obtaining a medical history and performing a physical examination to exclude disorders that differ from CMT as defined in this overview; these include systemic disorders with neuropathy, other hereditary neuropathies (Table1), distal myopathies (Table 2), hereditary sensory neuropathies (HSN) and hereditary sensory and autonomic neuropathies (HSAN) (Table 3), and acquired disorders.

For those individuals with CMT (as defined in this overview) a detailed family history and the use of molecular genetic testing are essential to establishing a specific genetic cause.

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 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 a de novo heterozygous pathogenic variant in a gene associated with autosomal dominant inheritance [Rudnik-Schöneborn et al 2016] or X-linked inheritance.

Molecular Genetic Testing

Health care providers ordering genetic testing should be familiar with the genetics of CMT. Given the complexity of interpreting genetic test results and their implications for genetic counseling, health care providers should consider referral to a neurogenetics center or a genetic counselor specializing in neurogenetics (see NSGC – Find a Genetic Counselor).

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, exome array). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

Step 1

Single-gene testing for PMP22 duplication/deletion is recommended as the first test in all probands with CMT as defined in this GeneReview. PMP22 duplication (a 1.5-Mb duplication at 17p11.2 that includes PMP22) accounts for as much as 50% of all CMT and, thus, PMP22 deletion/duplication analysis is recommended as the first test for all probands with CMT. Note: (1) Because the methodology to detect PMP22 duplication differs from that used in many multigene panels, this test needs to be ordered separately unless a laboratory explicitly states that PMP22 deletion/duplication analysis is included in its multigene panel. (2) Conversely, if PMP22 deletion/duplication analysis has already been performed and is normal, and if the next step in testing a patient is use of a multigene panel, it is appropriate to request that the laboratory not include PMP22 deletion/duplication analysis.

Step 2

A multigene panel that includes the seven most commonly involved genes (i.e., GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, and SH3CT2) as well as some or all of the other genes listed in Table 4 is most likely to identify the genetic cause of the neuropathy at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with CMT as defined in this GeneReview. Of note, given the rarity of some of the genes associated with CMT some panels may not include all the genes in Table 4. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Step 3

Comprehensive genomic testing – which does not require the clinician to determine which gene(s) are likely involved – may be considered if a genetic cause has not been identified in Step 1 and Step 2. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is nondiagnostic.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Expressing the particular type of CMT in a given individual based on the results of molecular genetic testing in the context of inheritance, neurologic examination, and gene involved as proposed by Magy et al [2018] is illustrated for GDAP1-related hereditary motor and sensory neuropathy (Table 5).

Table 5.

GDAP1-Related CMT Classification

Historical CMT
Classification
MOIType Based on NCVMagy et al [2018] Classification
CMT2HARAxAR-CMTAx-GDAP1
CMT2KADAxAD-CMTAx-GDAP1
CMT4AARDeAR-CMTDe-GDAP1
CMTRIAARInAR-CMTIn-GDAP1

NCV = nerve conduction velocity

Ax = axonal

De = demyelinating

In = intermediate

4. Genetic Counseling of Family Members of an Individual with Charcot-Marie-Tooth (CMT) Hereditary Neuropathy

Mode of Inheritance

CMT hereditary neuropathy 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. Given the complexity of the genetics of CMT, health care providers should consider referring at-risk relatives to a neurogenetics center or genetic counselor specializing in neurogenetics (see NSGC – Find a Genetic Counselor search tool).

Risk to Family Members – Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with autosomal dominant CMT has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an individual diagnosed with autosomal recessive CMT are obligate heterozygotes (i.e., carriers of one pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual 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.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive CMT are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier (heterozygote) detection. Carrier testing for at-risk relatives requires prior identification of the CMT-related pathogenic variants in the family.

Risk to Family Members – X-Linked Inheritance

Parents of a male proband

Parents of a female proband

  • A female proband may have inherited the pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
  • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother.

  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not be affected.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents.

  • If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and may or may not be affected.
  • If the father of the proband has a pathogenic variant, he will transmit it to all of his daughters and none of his sons.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.

Offspring of a proband

  • Affected males transmit the pathogenic variant to all of their daughters and none of their sons.
  • Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters may or may not be affected.

Other family members. If a parent of the proband also has a pathogenic variant, his or her female family members may be at risk of being heterozygotes (asymptomatic or symptomatic) and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose, information that could help determine genetic risk status of the extended family.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

  • Predictive testing for at-risk relatives is possible once the CMT-related pathogenic variant has been identified in an affected family member.
  • Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

  • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
  • For more information, see 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.

In a family with an established diagnosis of CMT it is appropriate to consider testing of symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant or X-linked condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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.

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 and Preimplantation Genetic Diagnosis

Once the CMT-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

5. Management of Charcot-Marie-Tooth (CMT) Hereditary Neuropathy

Treatment of Manifestations

Reviews of treatment approaches to CMT [Carter et al 2008, Young et al 2008, Reilly & Shy 2009, Corrado et al 2016] as well as reviews of the diagnosis, natural history, and management of CMT [Pareyson & Marchesi 2009a, Pareyson & Marchesi 2009b, Cornett et al 2017] are available.

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 [Grandis & Shy 2005, McCorquodale et al 2016].

Quality of life and defining disability have been measured and compared among various groups of individuals with CMT [Burns et al 2010, Ramchandren et al 2015]. 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. Night splints have not improved ankle range of motion [Refshauge et al 2006, Kenis-Coskun & Matthews 2016].

Some individuals require forearm crutches or canes for gait stability; fewer than 5% of individuals need wheelchairs.

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

Exercise is encouraged within the individual's capability and many individuals remain physically active [Sman et al 2015].

Orthopedic surgery may be required to correct severe pes cavus deformity [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 anti-inflammatory 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].

Those at increased risk for vocal cord paralysis (see Table 4) warrant consultation with specialists in otolaryngology at the time of diagnosis; evidence of vocal cord paralysis (hoarseness and/or stridor) at any time warrants periodic monitoring by specialists in otolaryngology to detect vocal cord hypomotility and quantify the degree of airway obstruction, a potentially lethal complication [Zambon et al 2017].

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].

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
  • 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
  • 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
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • 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
  • 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
  • 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
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

References

Published Guidelines / Consensus Statements

  • 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 6-20-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2017. Accessed 6-20-18.

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Suggested Reading

  • 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: McGraw-Hill.

Chapter Notes

Revision History

  • 28 June 2018 (bp) Comprehensive update posted live
  • 1 September 2016 (tb) Revision: CMTX3
  • 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 live
  • 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 live
  • 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 live
  • 10 May 2002 (tb) Author revisions
  • 12 September 2001 (tb) Author revisions
  • 20 June 2001 (me) Comprehensive update posted live
  • 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 live
  • April 1996 (tb) Original submission
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