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Charcot-Marie-Tooth Hereditary Neuropathy Overview

Synonym: CMT
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: March 6, 2014.

Summary

Disease 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 under-recognized 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 [Schroder 2006].

Differential Diagnosis of CMT

Causes of acquired peripheral neuropathy 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).

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]. Mutations in SEPT9 are causative [Kuhlenbaumer 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

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 mutations in BSCL2 (see BSCL2-Related Neurologic Disorders) and another with mutations 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" [Stogbauer 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 mutations 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

NameMean Age at Onset (Years)Initial Muscle Group InvolvedInheritanceGene
Welander distal myopathy >40Distal upper limbs (finger and wrist extensors)Autosomal dominantTIA1
Udd distal myopathy >35Anterior compartment in legsTTN
Markesbery-Griggs late-onset distal myopathy >40LDB3
Distal myotilinopathy >40Posterior > anterior in legsMYOT
Laing early-onset distal myopathy (MPD1) <20Anterior compartment in legs and neck flexorsMYH7
Nonaka early-adult-onset distal myopathy 15-20Anterior compartment in legsAutosomal recessiveGNE
Miyoshi early-adult-onset myopathy Posterior compartment in legsDYSF
Distal myopathy with vocal cord and pharyngeal signs (MPD2)35-60Asymmetric lower leg and hands, dysphoniaAutosomal dominantUnknown
Distal myopathy with pes cavus and areflexia 15-50Anterior and posterior lower leg; dysphonia and dysphagia
New Finnish distal myopathy (MPD3)>30Hands or anterior lower leg

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.

Figure 1

Figure

Figure 1. Genetic diagnoses in CMT and related disorders

Rossor et al [2013]; reprinted with permission

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 mutations 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 PathologyMode of InheritanceProportion of all CMT 2
CMT1 Abnormal myelin AD40%-50%
CMT2 AxonopathyAD10%-15%
Intermediate formCombination of myelinopathy and axonopathy in individualADRare
CMT4 Either myelinopathy or axonopathyARRare
CMTX Axonopathy with secondary myelin changesXLD10%-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 Zuchner & 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.

Figure 2

Figure

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 (more...)

Figure 3

Figure

Figure 3. Known disease genes for CMT and related disorders, and their proposed pathomechanism

Rossor et al [2013]; reprinted with permission

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 NameProportion of CMT1 (excluding CMTX) 1Gene Protein Product
CMT1A70%-80%PMP22 Peripheral myelin protein 22
CMT1B10%-12%MPZ Myelin P0 protein
CMT1C~1%LITAF Lipopolysaccharide-induced tumor necrosis factor-alpha factor
CMT1DUnknownEGR2 Early growth response protein 2
CMT1E~1%PMP22 Peripheral myelin protein 22
(sequence changes)
CMT1F/2EUnknownNEFL Neurofilament light polypeptide

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 mutations in MFN2 (reviewed in Chung et al [2006]). Known MFN2 mutations and related pathophysiology are reviewed in Cartoni & Martinou [2009].

CMT2B, caused by mutations in RAB7A, is associated with prominent sensory loss [Cogli et al 2009].

Table 4. CMT2: Molecular Genetics

Locus NameProportion of CMT2 1Gene / Chromosomal Locus 2Protein Product
CMT2A1 UnknownKIF1B Kinesin-like protein KIF1B
CMT2A220%MFN2 Mitofusin-2
CMT2BUnknownRAB7ARas-related protein Rab-7
CMT2B1UnknownLMNA Lamin A/C
CMT2B2UnknownMED25Mediator of RNA polymerase II transcription subunit 25
CMT2CUnknownTRPV4Transient receptor potential cation channel subfamily V member 4
CMT2D3%GARS Glycyl-tRNA synthetase
CMT2E/1F 4%NEFL Neurofilament light polypeptide
CMT2FUnknownHSPB1 Heat-shock protein beta-1
CMT2GUnknown12q12-q13Unknown
CMT2H/2K5%GDAP1Ganglioside-induced differentiation-associated protein-1
CMT2I/2JUnknownMPZMyelin P0 protein
CMT2LUnknownHSPB8 Heat-shock protein beta-8
CMT2NUnknownAARSAlanyl-tRNA synthetase, cytoplasmic
CMT2OUnknownDYNC1H1Cytoplasmic dynein 1 heavy chain 1
CMT2PUnknownLRSAM1E3 ubiquitin-protein ligase LRSAM1

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 NameProportion of Intermediate CMT Gene / Chromosomal Locus 1Protein ProductReference
DI-CMTAUnknown10q24.1-q25.1UnknownVerhoeven et al [2001]
DNM2-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTB) DNM2 Dynamin 2Kennerson et al [2001], Zuchner et al [2005]
YARS-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTC)YARS Tyrosyl-tRNA synthetaseJordanova et al [2003], Jordanova et al [2006]
MPZ-related intermediate Charcot-Marie-Tooth neuropathy (DI-CMTD) MPZMyelin P0 protein
GNB4-related intermediate Charcot-Marie-Tooth neuropathyGNB4Guanine nucleotide-binding protein subunit beta-4Soong et al [2013]

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 NameProportion of CMT4Gene Protein Product
CMT4AUnknownGDAP1 Ganglioside-induced differentiation-associated protein 1
CMT4B1MTMR2 Myotubularin-related protein 2
CMT4B2SBF2 Myotubularin-related protein 13
CMT4CSH3TC2 SH3 domain and tetratricopeptide repeats-containing protein 2
CMT4DNDRG1 Protein NDRG1
CMT4EEGR2 Early growth response protein 2
CMT4FPRX Periaxin
CMT4HFGD4FYVE, RhoGEF and PH domain-containing protein 4
CMT4JFIG4Phosphatidylinositol 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]:

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 NameProportion of X-Linked CMTGene / Chromosomal Locus 1Protein Product
CMTX1 90%GJB1 Gap junction beta-1 protein (connexin 32)
CMTX2UnknownXp22.2
CMTX3Xq26
CMTX4/Cowchock syndromeAIFM1 Apoptosis-inducing factor 1
CMTX5PRPS1Ribose-phosphate pyrophosphokinase 1
CMTX6PDK3Pyruvate dehydrogenase kinase isoform 3

1. Chromosomal locus given when gene is unknown

Mitochondrial CMT

Mitochondrial abnormalities are known to sometimes be associated with peripheral neuropathy. Mutations in the nuclear gene MFN2 produce 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 m.9185T>C mutation in MT-ATP6.

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 a de novo (new) mutation for 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 as de novo mutations 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 mutations in numerous genes associated with similar phenotypes. Note: Failure to identify a disease-causing mutation in a proband does not rule out a diagnosis of CMT since undetected mutations 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

Early childhood onset. Based on the study of 77 unrelated subjects with onset of neuropathy in the first year of life by Baets et al [2011], mutations 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 mutation (causing CMTX1) may be asymptomatic.
  • If no mutation 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 mutations in PMP22 (CMT1A or 1E), GDAP1 (CMT4A), EGR2 (CMT4E), PRX (CMT4F), SH3TC2 (CMT4C), FDG4 (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.

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 dominant 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

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 disease-causing mutation with each pregnancy. Sons who inherit the mutation will be affected; daughters who inherit the mutation 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 mutation 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 an apparent de novo mutation. When neither parent of a proband with an autosomal or X-linked dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. 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 Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

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, mutations, 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 is possible by analysis of DNA extracted from cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). Such testing may be available through laboratories that offer either testing for the gene of interest or custom testing.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 disease-causing mutation(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
    13 allée de Grèce
    35140 Saint Aubin du Cormier
    France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.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.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • 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 8605
    Fax: 44 0 191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry 91002
    France
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

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 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].

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 range of risks including:

  • Definite high risk. Vinca alkaloids (Vincristine)
    • This category should be avoided by all persons with CMT, including those who are asymptomatic
  • Other potential risk levels. See Table 8 or for more information click here (pdf).

Table 8. Medications that are Potentially Toxic to Persons with CMT

Moderate to Significant Risk 1
- Amiodarone (Cordarone)
- Bortezomib (Velcade)
- Cisplatin & Oxaliplatin
- Colchicine (extended use)
- Dapsone
- Didanosine (ddI, Videx)
- Dichloroacetate
- Disulfiram (Antabuse)
- Gold salts
- Leflunomide (Arava)
- Metronidazole/Misonidazole (extended use)
- Nitrofurantoin (Macrodantin, Furadantin, Macrobid)
- Nitrous oxide (inhalation abuse or Vitamin B12 deficiency)
- Perhexiline (not used in US)
- Pyridoxine (mega dose of Vitamin B6)
- Stavudine (d4T, Zerit)
- Suramin
- Taxols (paclitaxel, docetaxel)
- Thalidomide
- Zalcitabine (ddC, Hivid)

Click here for additional medications in lesser-risk categories.

The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.

1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996]; Nishikawa et al [2008], and Porter et al [2009].

Therapies Under Investigation

Patel & Pleasure [2013] 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 mutation (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. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 5-5-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  2. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 5-5-14.

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Suggested Reading

  1. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 227. Available online. 2013. Accessed 5-5-14.
  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]
  3. Weedon MN, Hastings R, Caswell R, Xie W, Paszkiewicz K, Antoniadi T, Williams M, King C, Greenhalgh L, Newbury-Ecob R, Ellard S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2011;89:308–12. [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, Nürnberg G, Nürnberg P, Zelcer N, Schelhaas HJ, Baas F. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy. Hum Mol Genet. 2012;21:358–70. [PMC free article: PMC3276280] [PubMed: 22012984]

Chapter Notes

Revision History

  • 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
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