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 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) (CMT2) 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 4, 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 an individual's findings can be described in terms of mode of inheritance, neuropathy type, and gene (see 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.
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
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Gene 1 | MOI | Disorder | Other | GeneReview / OMIM |
---|
ABCD1
| XL | Adrenomyeloneuropathy | Progressive stiffness & weakness of legs, sphincter disturbances, sexual dysfunction, & often, impaired adrenocortical function |
X-Linked Adrenoleukodystrophy
|
ABHD12
| AR | Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, & cataract (PHARC) | | OMIM 612674 |
FXN
| AR | Friedreich ataxia | May present w/sensory loss, depressed tendon reflexes, & high-arched feet |
Friedreich Ataxia
|
MT-ATP6
| mt | NARP | Neurogenic muscle weakness, ataxia, & retinitis pigmentosa |
Mitochondrial DNA-Associated Leigh Syndrome and NARP
|
PEX7 (PHYH) | AR | Refsum disease | Anosmia & early-onset retinitis pigmentosa ± neuropathy, deafness, ataxia, &/or ichthyosis |
Refsum Disease
|
PMP22
| AD | Hereditary neuropathy with liability to pressure palsies | Acute onset of recurrent, painless, focal sensorimotor neuropathy in a single nerve |
Hereditary Neuropathy with Liability to Pressure Palsies
|
SCN9A
| AD | SCN9A-related inherited erythromelalgia | Recurrent attacks of bilateral & symmetric intense pain, redness, warmth, & swelling involving feet & (less frequently) hands |
SCN9A-Related Inherited Erythromelalgia
|
SEPTIN9
| AD | Hereditary neuralgic amyotrophy | Recurrent sudden onset of shoulder or upper arm pain & weakness ± sensory loss; later atrophy of the upper extremity | OMIM 162100 |
SPART
| AR | Troyer syndrome | Progressive spastic paraparesis, dysarthria, & pseudobulbar palsy; distal amyotrophy; motor & cognitive delays |
Troyer Syndrome
|
TTR
| AD | Transthyretin-associated amyloidosis | Sensorimotor & autonomic neuropathy; cardiomyopathy; nephropathy; CNS amyloidosis |
Familial Transthyretin Amyloidosis
|
TYMP
| AR | MNGIE | Progressive gastrointestinal dysmotility; cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; demyelinating peripheral neuropathy |
Mitochondrial Neurogastrointestinal Encephalopathy Disease
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; XL = X-linked
- 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.
View in own window
Gene 1 | MOI | Disorder | Clinical Manifestations | GeneReview / OMIM |
---|
Mean Age of Onset | Initial Muscle Group Involved |
---|
ANO5
| AR | Miyoshi dystrophy type 3 | | |
ANO5-Related Muscle Diseases
|
CAV3
| AD AR | Distal myopathy | | | OMIM PS601419 |
CRYAB
| AD | Distal myofibrillar myopathy | Adult | Distal leg & hands + cardiomyopathy |
DES
| AD AR | Mesminopathy myofibrillar myopathy | 15-40 yrs | Distal leg & forearm + cardiomyopathy |
DNAJB6
| AD | Myofibrillar myopathy | Teens-adult | Distal leg |
DYSF
| AR | Miyoshi early-adult-onset myopathy | 15-20 yrs | Posterior compartment in legs |
Dysferlinopathy
|
FLNC
| AD | Distal myopathy 4 | | | OMIM 614065 |
GNE
| AR | Nonaka early-adult-onset distal myopathy | 15-20 yrs | Anterior compartment in legs |
GNE-Related Myopathy
|
LDB3
| AD | Zaspopathy (Markesbery-Griggs late-onset distal myopathy) | >40 yrs | Anterior compartment in legs | OMIM PS601419 |
MATR3
| AD | Amyotrophic lateral sclerosis 21 (Formerly MPD2) | 35-60 yrs | Asymmetric lower leg & hands, dysphonia | Amyotrophic Lateral Sclerosis Overview, OMIM 606070 |
MYH7
| AD | Laing early-onset distal myopathy | <20 yrs | Anterior compartment in legs & neck flexors |
Laing Distal Myopathy
|
MYOT
| AD | Distal myotilinopathy | >40 yrs | Posterior > anterior in legs | OMIM PS601419 |
NEB
| AR | Distal nebulin myopathy | 2-15 yrs | Anterior lower leg | OMIM 256030 |
TIA1
| AD AR | Welander distal myopathy | >40 yrs | Distal upper limbs (finger & wrist extensors) | OMIM 604454 |
TCAP
| AR | Distal onset in telethoninopathy | Early | Lower leg | OMIM 601954 |
TTN
| AD | Udd distal myopathy | >35 yrs | Anterior compartment in legs |
Udd Distal Myopathy
|
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
- 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)
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HSAN = hereditary sensory and autonomic neuropathy; HSN = hereditary sensory 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 74 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
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Gene 1 | MOI | Neuropathy Type | Other Phenotypic Features / Comments | GeneReview / OMIM / Reference | Other Designations 2 |
---|
Ax | De | In |
---|
Most commonly involved genes 3
|
GDAP1
| AR | ● | | | Vocal cord paresis 4 |
GDAP1-Related Hereditary Motor and Sensory Neuropathy
| CMT2K |
AR | ● | ● | ● | | CMT4A CMT2H CMT2K CMTRIA |
AD, AR | ● | | | | OMIM 607831 | |
GJB1
| XL | ● | ● | ● | Family history may appear to be AD as females can be as severely affected as males; CNS myelin may be affected. |
Charcot-Marie-Tooth Neuropathy X Type 1
| CMT1X |
HINT1
| AR | ● | | | Neuromyotonia | OMIM 601314 | |
MFN2
| AD, AR | ● | | | Optic atrophy |
Charcot-Marie-Tooth Neuropathy Type 2A
| CMT2A2A/B |
MPZ
| AD | ● | ● | ● | | OMIM 118200 | CMT1B CMT2I/J DI-CMTD |
PMP22
| AD | | ● | | | OMIM 601097 | CMT1A CMT1E |
SH3TC2
| AR | ● | | | |
SH3TC2-Related Hereditary Motor and Sensory Neuropathy
| CMT4C |
SORD
| AR | ● | | ● | Distal muscle atrophy & weakness |
Cortese et al [2020]
| |
Other genes
|
AARS1
| AD | ● | | | |
Setlere et al [2022]
| CMT2N |
ABHD12
| AR | | ● | | Deafness, cataract, retinitis pigmentosa | OMIM 613599 | PHARC |
AIFM1
| XL | ● | | | Deafness, intellectual disability | OMIM 300169 | CMTX4 |
ARHGEF10
| AD | | ● | | | OMIM 608136 | |
ATP1A1
| AD | ● | | | |
Lassuthova et al [2018]
| |
ATP7A 5 | XL | ● | | | Distal lower extremities | ATP7A-Related Copper Transport Disorders, OMIM 300011 | |
BAG3
| AD | ● | | | Myofibrillar myopathy, cardiomyopathy | OMIM 603883 | |
BSCL2
| AD | ● | | | Distal lower extremities; UMN involvement can cause spastic paraplegia |
BSCL2-Related Neurologic Disorders / Seipinopathy
| dHMN5A |
CADM3
| AD | ● | | | Forearm & hand atrophy as well as lower limb |
Rebelo et al [2021]
| |
CNTNAP1
| AR | ● | ● | | Arthrogryposis, leukodystrophy | OMIM 602346 | |
COA7
| AR | ● | | | |
Higuchi et al [2018]
| |
DCTN1
| AD | | | | Distal lower extremities | OMIM 601143 | dHMN7B |
DCTN2
| AD | ● | | | Vocal cord paresis 4 | OMIM 607376 | |
DGAT2
| AD | ● | | | | OMIM 606983 | |
DHTKD1
| AD | ● | | | | OMIM 614984 | CMT2Q |
DNAJB2
| AR | ● | | | Distal motor neuropathy | Frasquet et al [2016], Lupo et al [2016] | DSMA5 |
DNMT1
| AD | ● | | | Hearing loss, dementia |
DNMT1-Related Dementia, Deafness, and Sensory Neuropathy
| DMNT1 |
DNM2
| AD | | | ● | | OMIM 606482 | CMT2M DI-CMTB |
DRP2
| XL | | | ● | Autism | OMIM 300052 | |
DYNC1H1
| AD | ● | | | SMA |
DYNC1H1-Related Disorders
| CMT2O |
EGR2
| AD | | ● | | | OMIM 129010 | CMT1D |
AR | | ● | | | CMT4E |
FGD4
| AR | | ● | | | OMIM 609311 | CMT4H |
FIG4
| AR | | ● | | | OMIM 611228 | CMT4J |
GARS1
| AD | ● | | | Onset in hands |
GARS1-Associated Axonal Neuropathy
| CMT2D dHMN5A |
GNB4
| AD | | | ● | | OMIM 610863 | DI-CMTF |
HARS1
| AD | ● | ● | | | OMIM 142810 | CMT2W |
HSPB1
| AD | ● | | | | OMIM 602195 | CMT2F dHMN2B |
HSPB3
| AD | | | | | OMIM 604624 | dHMN2C |
HSPB8
| AD | ● | | | Adult onset | OMIM 608014 | CMT2L dHMN2A |
IGHMBP2
| AR | ● | | | | OMIM 600502 | CMT2S DSMA1 |
INF2
| AD | | | ● | Glomerulosclerosis | OMIM 610982 | |
ITPR3
| AD | | ● | | Marked variability in onset age & severity |
Beijer et al [2024]
| |
KIF1B
| AD | ● | | | | OMIM 605995 | CMT2A1 |
KIF5A
| AD | ● | | | Spasticity | OMIM 602821 | |
LITAF
| AD | | ● | | | OMIM 603795 | CMT1C |
LMNA
| AR | ● | | | | OMIM 150330 | CMT2B1 |
LRSAM1
| AD, AR | ● | | | | OMIM 610933 | CMT2G CMT2P |
MARS1
| AD | ● | | | | OMIM 156560 | CMT2U |
MCM3AP
| AR | ● | ● | | Childhood onset, severe | OMIM 603294 | |
MME
| AR, AD | ● | | | | OMIM 120520 | CMT2T |
MORC2
| AD | ● | | | | OMIM 616661 | CMT2Z |
MPV17
| AR | ● | | | Navaho neurohepatopathy | OMIM 137960 | |
MPZ
| AD | ● | ● | ● | | OMIM 118200 | CMT1B CMT2I/J DI-CMTD |
MTMR2
| AR | | ● | | Vocal cord paresis 4 | OMIM 603557 | CMT4B1 |
NAGLU
| AD | ● | | | | OMIM 609701 | CMT2V |
NDRG1
| AR | | ● | | | OMIM 605262 | CMT4D |
NEFH
| AD | ● | | | | OMIM 162230 | |
NEFL
| AD, AR | ● | ● | | | OMIM 162280 | CMT1F/2E |
PDK3
| XL | ● | | | | OMIM 300906 | CMTX6 |
PLEKHG5
| AR | | | ● | Distal predominant | OMIM 611101 | DSMA4 |
PMP2
| AD | | ● | | | OMIM 618279 | CMT1G |
PNKP
| AR | ● | | | | OMIM 605610 | CMT2B2 |
PRPS1
| XL | | | | Retinopathy, deafness | Charcot-Marie-Tooth Neuropathy X Type 5 (See Phosphoribosylpyrophosphate Synthetase Deficiency.) | CMTX5 |
PRX
| AR | ● | | | | OMIM 605725 | CMT4F |
PTRH2
| AR | | | | Hearing loss | OMIM 608625 | |
RAB7A | AD | ● | | | Prominent sensory loss | OMIM 602298 | CMT2B |
SARS1
| AD | | | ● | Sensorimotor neuropathy, distal muscle atrophy |
He et al [2023]
| |
SBF1
| AR | ● | | | | OMIM 603560 | CMT4B3 |
SBF2
| AR | | ● | | | OMIM 607697 | CMT4B2 |
SCO2
| AR | ● | | | Motor neuropathy |
Rebelo et al [2018]
| |
SETX
| AD | | | | Distal lower extremities | OMIM 608465 | FALS |
SIGMAR1
| AR | ● | | | Motor neuropathy | OMIM 601978 | |
SGPL1
| AR | ● | | | Recurrent mononeuropathy |
Sphingosine Phosphate Lyase Insufficiency Syndrome
| |
SPG11
| AR | ● | | | Spasticity, cognitive decline | OMIM 610844 | CMT2X ALS5 |
SPTLC1
| AD | ● | | | May be assoc w/a juvenile ALS syndrome 6 | OMIM 605712 | HSAN1A |
TRIM2
| AR | ● | | | Vocal cord paresis 4 | OMIM 614141 | CMT2R |
TRPV4
| AD | ● | | | Vocal cord paresis, 4 skeletal dysplasia |
Autosomal Dominant TRPV4 Disorders
| CMT2C |
VCP
| AD | ● | | | Inclusion body myopathy, dementia |
Inclusion Body Myopathy with Paget Disease of Bone and/or Frontotemporal Dementia
| CMT2Y |
VWA1
| AR | ● | | | Motor neuropathy, pes cavus, & proximal muscle weakness | OMIM 619216 | |
WARS
| AD | ● | | | Motor neuropathy | OMIM 191050 | dHMN9 |
YARS1
| AD | | | ● | | OMIM 603623 | DI-CMTC |
Unknown 7 | XL | | ● | | Rapid progression, severe hand weakness | OMIM 302802 | CMTX3 |
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; Ax = axonal; De = demyelinating; dHMN = distal hereditary motor neuropathy; DI-CMT = dominant intermediate CMT; DSMA = distal spinal muscular atrophy; HSAN = hereditary sensory and autonomic neuropathy; In = intermediate; UMN = upper motor neuron; XL = X-linked
- 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.
- 6.
- 7.
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, 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 an individual 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 eight most commonly involved genes (i.e., GDAP1, GJB1, HINT1, MFN2, MPZ, PMP22, SH3CT2, and SORD) 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 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.
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).
4. Genetic Counseling of Family Members of an Individual with Charcot-Marie-Tooth (CMT) Hereditary Neuropathy
Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
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).
Autosomal Dominant Inheritance – Risk to Family Members
Parents of a proband
Most individuals diagnosed with autosomal dominant CMT have an affected parent.
Some individuals diagnosed with autosomal dominant CMT have the disorder as the result of a
de novo pathogenic variant. The proportion of cases caused by a
de novo pathogenic variant varies depending on the involved gene. In a study of 1,206 index cases,
Rudnik-Schöneborn et al [2016] identified
de novo variants in 1.3% of individuals with a
PMP duplication and 25% of those with
MPZ variants.
Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a
de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported [
Fabrizi et al 2001].
The family history of some individuals diagnosed with autosomal dominant CMT may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
If the proband has a known CMT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CMT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
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, the parent's family members may be at risk.
Autosomal Recessive Inheritance – Risk to Family Members
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 detection. Carrier testing for at-risk relatives requires prior identification of the CMT-related pathogenic variants in the family.
X-Linked Inheritance – Risk to Family Members
Parents of a male proband
The father of an affected male will not have the disorder nor will he be hemizygous for the pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
If a male is the only affected family member (i.e., represents a simplex case), the mother may be a heterozygote or the affected male may have a de novo pathogenic variant, in which case the mother is not heterozygous. The frequency of males with a de novo pathogenic variant is not known.
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, the parent's female family members may be at risk of being heterozygotes (asymptomatic or symptomatic) and the parent's 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.
Prenatal Testing and Preimplantation Genetic Testing
Once the CMT-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
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, Sivera Mascaró et al 2024] are available. Guidelines for the management of the pediatric population with CMT have been published [Yiu et al 2022].
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]. Clinical assessment and management approaches to foot deformities that may be associated with CMT are reviewed in Laurá et al [2024]. Management regarding surgery referral and intervention ideally involves multidisciplinary input (i.e., neurology, physical therapy, and orthopedics). 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].
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].
In a study of five individuals with CMT-associated sensorineural hearing loss and auditory neuropathy spectrum disorder, Farber et al [2024] found that cochlear implants were safe and reliable and improved both hearing and speech. Note: Four of the described individuals were from a family with the PMP22 pathogenic variant c.199G>C (p.Ala67Pro) [Kovach et al 1999].
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. See the Charcot-Marie-Tooth Association website (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].
Pregnancy Management
CMT appears to be an independent risk factor for maternal complications during pregnancy and delivery [Pisciotta et al 2020]. In a study of 157 deliveries in 193 pregnancies Pisciotta et al found that:
In 9.3% of pregnancies, new manifestations of CMT can appear and existing manifestations (including reduced strength and sensitivity, cramps, and pain) can worsen, and may persist following pregnancy;
Placenta previa (1.6%) abnormal nonvertex presentation (8.4%), and preterm delivery (20.3%) occurred more frequently in the pregnancies of mothers with CMT.