Copyright © 1993-2012, University of Washington, Seattle. All rights reserved.
NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.
Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
Summary
Disease characteristics. Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is an axonal (non-demyelinating) peripheral neuropathy characterized by distal muscle weakness and atrophy, mild sensory loss, and normal or near-normal nerve conduction velocities. CMT2 is clinically similar to CMT1, although typically less severe. Peripheral nerves are not enlarged or hypertrophic. The subtypes of CMT2 are similar clinically and distinguished only by molecular genetic findings.
Diagnosis/testing. The diagnosis is based on clinical findings and EMG/NCV characteristics. The 13 genes known to be associated with the CMT2 subtypes are KIF1B (CMT2A1), MFN2 (CMT2A2), RAB7A (formerly RAB7) (CMT2B), LMNA (CMT2B1), MED25 (CMT2B2), TRPV4 (CMTC), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/J), GDAP1 (CMT2H/K), HSPB8 (CMT2L), AARS (CMT2N), DYNC1H1 (CMT2O), and LRSAM1 (CMT2P). Molecular genetic testing is clinically available for CMT subtypes 2A1, 2A2, 2B, 2B1, 2B2, 2C, 2D, 2E, 2F, 2I, 2J, 2H/K, 2L and 2N.
Management. Treatment of manifestations: Treatment by a team including a neurologist, physiatrists, orthopedic surgeons, physical, and occupational therapist; special shoes and/or ankle/foot orthoses (AFO) to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated; symptomatic treatment of pain, depression, sleep apnea, restless legs syndrome.
Prevention of secondary complications: Daily heel cord stretching to prevent Achilles' tendon shortening.
Surveillance: Monitoring gait and condition of feet to determine need for bracing, special shoes, surgery.
Agents/circumstances to avoid: Obesity, which makes ambulation more difficult; medications known to cause nerve damage (e.g., vincristine, isoniazid, nitrofurantoin).
Other: Career and employment counseling.
Genetic counseling. CMT2B1, CMT2B2, and CMT2H/K are inherited in an autosomal recessive manner; all other subtypes of CMT2 are inherited in an autosomal dominant manner. Most probands with autosomal dominant subtypes of CMT2 have inherited the disease-causing mutation from an affected parent. The offspring of an affected individual with autosomal dominant CMT2 are at a 50% risk of inheriting the altered gene. Availability of prenatal diagnosis varies by subtype.
Diagnosis
Clinical Diagnosis
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is diagnosed clinically in individuals with the following:
A progressive peripheral motor and sensory neuropathy
Nerve conduction velocities (NCVs) that are usually within the normal range (>40-45 m/s), although occasionally in a mildly abnormal range (30-40 m/s)
EMG testing that shows evidence of an axonal neuropathy with such findings as positive waves, polyphasic potentials, or fibrillations and reduced amplitudes of evoked motor and sensory responses
Greatly reduced compound motor action potentials (CMAP)
A family history consistent with autosomal dominant inheritance
Testing
Nerve biopsy does not show the hypertrophy or onion bulb formation seen in Charcot-Marie-Tooth hereditary neuropathy type 1 (CMT1) but instead shows loss of myelinated fibers with signs of regeneration, axonal sprouting, and atrophic axons with neurofilaments.
Molecular Genetic Testing
Genes. Thirteen genes are known to be associated with subtypes of CMT2 [Züchner & Vance 2006b] (Table 1).
Table 1. Genes Associated with CMT2 Subtypes
| CMT2 Subtype | Gene Symbol | Reference |
|---|---|---|
| CMT2A1 | KIF1B 1 | Zhao et al [2001] |
| CMT2A2 | MFN2 2 | Verhoeven et al [2006] |
| CMT2B | RAB7A | Verhoeven et al [2003] |
| CMT2B1 | LMNA | De Sandre-Giovannoli et al [2002] |
| CMT2B2 | MED25 | Leal et al [2009] |
| CMTC | TRPV4 | Deng et al [2010], Auer-Grumbach et al [2010], Landouré et al [2010] |
| CMT2D | GARS | |
| CMT2E/1F | NEFL | |
| CMT2F | HSPB1 (HSP27) | Evgrafov et al [2004] |
| CMT2I/J | MPZ | Sowden et al [2005] |
| CMT2H/K | GDAP1 | Barhoumi et al [2001], Claramunt et al [2005] |
| CMT2L | HSPB8 (HSP22) | Tang et al [2005] |
| CMT2N | AARS | McLaughlin et al [2012] |
| CMT2O | DYNC1H1 | Weedon et al 2011 |
| CMT2P | LRSAM1 | Guersney et al [2010], Weterman et al [2012] |
1. Found in one family
2. Represents approximately 20%-30% of CMT2
Other loci. Another locus for CMT2 has been mapped; no gene has yet been identified (Table 2):
Table 2. CMT2: Other Locus
| CMT2 Subtype | Chromosomal Locus | Reference |
|---|---|---|
| CMT2G | 12q12-q13.3 | Nelis et al [2004] |
Clinical testing (CMT2A1, CMT2A2, CMT2B, CMT2B1, CMT2B2, CMT2C, CMT2D, CMT2E/1F, CMT2F, CMT2I/J, CMT2H/K, CMT2L, CMT2N)
Sequence analysis. Sequence analysis of KIFB1, MFN2, RAB7A, LMNA, MED25, TRPV4, GARS, NEFL, HSPB1, MPZ, GDAP1, HSPB8 and AARS is available on a clinical basis.
Mutation scanning of MFN2 and MPZ is available clinically.
Targeted mutation analysis for the p.Ala335Val mutation in MED25 is available on a clinical basis.
Table 3. Summary of Molecular Genetic Testing Used in CMT2
| Gene Symbol / Locus Name | Test Method | Mutations Detected | Proportion of CMT2 Attributed to Mutations in This Gene | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|---|---|
| KIF1B / CMT2A1 | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical![]() |
| MFN2 / CMT2A2 | Sequence analysis and mutation scanning 3 | Sequence variants 2 | 20% | Unknown | Clinical ![]() |
| RAB7A / CMT2B | Mutation scanning | Sequence variants 2 | Rare | Unknown | Clinical ![]() |
| LMNA / CMT2B1 | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical ![]() |
| Deletion / duplication analysis 4 | Deletions or duplications 5 | Unknown | |||
| MED25 / CMT2B2 | Mutation scanning of selected exons 3 | Sequence variants 2 | Rare | Unknown | Clinical ![]() |
| Targeted mutation analysis | p.Ala335Val | ||||
| TRPV4 / CMT2C | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical![]() |
| GARS / CMT2D | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical![]() |
| NEFL / CMT2E/1F | Sequence variants 2 | Rare | Unknown | Clinical![]() | |
| HSPB1 / CMT2F | Sequence variants 2 | Rare | Unknown | Clinical ![]() | |
| Unknown / CMT2G | Linkage analysis | Rare | Unknown | Research only | |
| MPZ / CMT2I/J | Sequence analysis, mutation scanning 6 | Sequence variants 2 | Rare | Unknown | Clinical ![]() |
| Deletion / duplication analysis 4 | Deletions or duplications 5 | Unknown | |||
| GDAP1 / CMT2H/K | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical ![]() |
| HSPB8 / CMT2L | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical![]() |
| AARS / CMT2N | Sequence analysis | Sequence variants 2 | Rare | Unknown | Clinical ![]() |
| DYNC1H1 / CMT2O | Sequence analysis | Sequence variants 2 | Rare | Research only | |
| LRSAM1 / CMT2P | Sequence analysis | Sequence variants 2 | Rare | Research only |
Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.
1. The ability of the test method used to detect a mutation that is present in the indicated gene
2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.
3. Selected exons for testing may vary among laboratories.
3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.
5. No deletions or duplications have been reported involving these genes as causative of CMT2. However, newly available deletion/duplication testing methods may define mutations in individuals where prior testing by sequence analysis of the entire coding region was negative.
6. Sequence analysis and mutation scanning of the entire gene can have similar detection frequencies, although mutation scanning detection rates may vary considerably among laboratories as that method is highly dependent on details of the methodology employed.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Testing Strategy
To establish the diagnosis of a CMT2 subtype the proband should first be tested for mutations in MFN2, MPZ, and GJB1 (encoding connexin 32) as these are the most common genes responsible for this syndrome, probably accounting for 20%-25% of cases [Züchner & Vance 2006b, Bienfait et al 2007, Saporta et al 2011].
Note: If there is male-to-male transmission in the family it is not necessary to check GJB1, an X-linked gene.
If no mutation is identified in these three genes, many neurologists do no further genetic tests because the other known genes are quite rare and many genetic causes remain to be discovered. Patients who wish to exhaust all possibilities may wish to proceed with the other clinically available tests relevant to CMT2 (e.g., NEFL, GDAP1, RAB7A, MED25, TRPV4, AARS). If the phenotype includes vocal cord paresis, molecular genetic testing of GDAP1 and TRPV4 is appropriate.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.
Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
Genetically Related (Allelic) Disorders
KIF1B. CMT2A is the only phenotype known to be associated with KIF1B.
MFN2. CMT2A is the only phenotype known to be associated with MFN2.
RAB7A. CMT2B is the only phenotype known to be associated with RAB7A.
LMNA. In addition to CMT2B1, the following phenotypes are associated with pathologic or normal variations in LMNA:
Hutchinson-Gilford progeria syndrome (HGPS or progeria)
Autosomal dominant Emery-Dreifuss muscular dystrophy type 2 (EMD2). See Emery-Dreifuss Muscular Dystrophy (EDMD).
Autosomal recessive Emery-Dreifuss muscular dystrophy type 2 (EMD2). See EDMD.
Autosomal dominant familial dilated cardiomyopathy and conduction system defects (CMD1A) (see Dilated Cardiomyopathy Overview)
Autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD)
Autosomal dominant limb-girdle muscular dystrophy 1B (LGMD1B). See Limb-Girdle Muscular Dystrophy Overview.
A normal allelic variant in LMNA (NM_170707.2:c.1908C>T) associated with obesity-related traits in Canadian Oji-Cree
Autosomal recessive mandibuloacral dysplasia (MAD). A compound heterozygous mutation p.[Arg471Cys]+ [Arg527Cys] in a 28-year-old woman with mandibuloacral dysplasia, previously diagnosed as "atypical progeria," was reported [Cao & Hegele 2003].
Atypical Werner syndrome [Chen et al 2003]
A single case report of a male heterozygous for the mutation p.Arg133Leu with lipoatrophy, disseminated white skin papules, hypertrophic cardiomyopathy, hepatic steatosis, and insulin resistance [Caux et al 2003]
Co-occurrence of myopathy and neuropathy [Benedetti et al 2005, Walter et al 2005]
See OMIM 150330 for additional references regarding other laminopathies.
TRPV4. In addition to CMT2C, TRPV4 has been associated with both brachyolmia and metaphyseal dysplasia [Rock et al 2008, Krakow et al 2009]
GARS. In addition to CMT2D, the other phenotype associated with mutations in GARS is hereditary motor neuropathy type 5 (HMN V) [Antonellis et al 2003].
NEFL. CMT2E/1F is the only phenotype known to be associated with mutations in NEFL.
HSPB1. CMT2F is the only phenotype known to be associated with mutations in HSPB1.
MPZ. In addition to CMT2I and CMT2J, mutations in MPZ are associated with CMT1B (see CMT1) [Senderek et al 2000].
GDAP1. In addition to CMT2H/K, autosomal recessive CMT4A is associated with mutations in GDAP1.
HSPB8. In addition to CMT2L, mutations in HSPB8 have been reported in distal hereditary motor neuropathy type 2 (dHMNII) [Irobi et al 2004b].
AARS. CMT2N is the only phenotype known to be associated with mutations in AARS.
DYNC1H1. CMT2O is the only phenotype known to be associated with mutations in DYNC1H1.
LRSAM1. CMT2P is the only phenotype known to be associated with mutations in LRSAM1.
Clinical Description
Natural History
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) is a disorder of peripheral nerves in which the motor system is more prominently involved than the sensory system, although both are involved [Pareyson & Marchesi 2009]. The affected individual typically has slowly progressive weakness and atrophy of distal muscles in the feet and/or hands usually associated with depressed tendon reflexes and mild or no sensory loss. The clinical syndrome overlaps extensively with CMT1. With the exception of CMT2B, CMT2 tends to be less disabling and to cause less sensory loss than CMT1 [Bienfait et al 2006, Pareyson et al 2006].
Affected individuals usually become symptomatic between ages five and 25 years [Bienfait et al 2006], though onset ranges from infancy with delayed walking to after the third decade. The typical presenting symptom is weakness of the feet and ankles. The initial physical findings are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle.
The adult with CMT2 typically has bilateral foot drop, symmetric atrophy of muscles below the knee (stork leg appearance) and absent tendon reflexes in the lower extremities. However, brisk tendon reflexes and extensor plantar responses have been reported as well as asymmetric muscle atrophy in up to 15% of affected individuals [Bienfait et al 2007].
Atrophy of intrinsic hand muscles is less frequently present and tendon reflexes may be intact in the upper limbs.
Proximal muscles usually remain strong. Brisk tendon reflexes and extensor plantar responses have been reported [Bienfait et al 2007].
Mild sensory deficits of position, vibration, and pain/temperature may occur in the feet or sensation may be intact. Pain, especially in the feet, is reported by about 20%-40% of affected individuals [Gemignani et al 2004]. Hearing impairment has been reported [Bienfait et al 2006].
Optic atrophy may occur in CMT2A [Züchner et al 2006].
A few individuals have vocal cord or phrenic nerve involvement resulting in difficulty with phonation or breathing [Dematteis et al 2001, Sulica et al 2001].
Restless legs and sleep apnea have been associated with CMT2 [Aboussouan et al 2007].
CMT2 is progressive over many years, but affected individuals experience long plateau periods without obvious deterioration. In some, the disease can be so mild as to go unrecognized by the affected individual and physician. The disease does not decrease life span.
CMT2 subtypes
CMT2A (comprising CMT2A1 and CMT2A2) has a typical CMT phenotype with onset in the second or third decade of distal muscle weakness and atrophy, less severe sensory loss, and depressed tendon reflexes. NCVs fall within the normal or near-normal range, compatible with an axonal neuropathy. Clinical features of families with MFN2 mutations are described by Züchner et al [2004a] and Kijima et al [2005]. Optic atrophy may occur in CMT2A [Züchner et al 2006].
CMT2B has prominent sensory loss with distal ulceration; controversy exists regarding its exact classification. Additional phenotype information is presented in Auer-Grumbach et al [2000], Verhoeven et al [2003], and Houlden et al [2004].
CMT2B1 is found primarily in Algeria. Mean age of onset is 14 years (range 6-27 years); functional disability ranges from mild to severe [Tazir et al 2004].
CMT2B2 occurred in a Costa Rican family with adult onset [Leal et al 2001, Berghoff et al 2004].
CMT2C is associated with frequent vocal cord and phrenic nerve paralysis sometimes requiring tracheotomy [Santoro et al 2002, McEntagart et al 2005]. Mild sensory loss was noted in the individuals reported by Dyck et al [1994].
CMT2D is characterized by predominately distal motor weakness with wasting of the hand muscles [Antonellis et al 2003].
CMT2E/1F has been reported in several families with a progressive sensory and motor neuropathy. The full range of phenotype may overlap with the CMT1 syndrome characterized by slow NCV [Georgiou et al 2002; Jordanova et al 2003; Züchner et al 2004a]. A Belgian family had NCVs ranging from 25 to 42 m/s, overlapping both axonal and demyelinating phenotypes [De Jonghe et al 2001]. A Russian family had relatively normal NCV and hyperkeratosis [Mersiyanova et al 2000]. It is unknown if the presence of hyperkeratosis is coincidental or represents variable expressivity of the CMT2E/1F phenotype.
CMT2F has been reported in a single Russian family with distal weakness, atrophy, and sensory loss beginning between ages 15 and 25 years. This disorder is similar to distal hereditary motor neuropathy (HMN), except that there is no sensory loss in HMN [Ismailov et al 2001, Evgrafov et al 2004, Irobi et al 2004a].
CMT2G has been reported in a single Spanish family [Nelis et al 2004].
CMT2H has associated pyramidal features [Barhoumi et al 2001] and CMT2K is associated with the p.Arg120Trp and Thr157Pro mutations in GDAP1 [Claramunt et al 2005]
CMT2I has only mild slowing of NCV [Li et al 2006].
CMT2J. The MPZ mutation p.Thr134Met is associated with an axonal neuropathy with deafness and Argyll Robertson pupils [Chapon et al 1999]. In addition, the pathologic allelic variants p.Thr134Met and p.Asp85Val have been associated with axonal neuropathy and marked sensory impairment, Adie's pupil, and deafness [Misu et al 2000].
CMT2L has been reported in a single Chinese family, with onset between ages 15 and 33 years and normal NCV [Tang et al 2004, Tang et al 2005].
CMT2N has been reported in two French families and in one Australian family. The recurrent loss-of-function AARS mutation p.Arg329His segregates with and results in the CMT phenotype in each of these families [Latour et al 2010, McLaughlin et al 2012].
CMT2O has been reported in a large family with childhood onset of delayed motor milestones associated with progressive distal lower limb weakness, pes cavus, variable sensory loss, and normal nerve conductions. Occasional proximal weakness and waddling gait were noted [Weedon et al 2011].
CMT2P has been reported in a large rural Canadian family with onset of progressive distal muscle weakness and atrophy usually starting in young adulthood [Guernsey et al 2010]. Nerve electrophysiology was consistent with an axonal neuropathy. The inheritance was autosomal recessive and associated with a homozygous single nucleotide change in an intronic consensus acceptor splicing site of LRSAM1. Weterman et al [2011] reported a three-generation Dutch family with onset in the second or third decade of slowly progressive distal weakness and atrophy with mild sensory loss and an axonal neuropathy. The disease was autosomal dominant and caused by a frameshift mutation (p.Leu708Arg fx28) in LRSAM1.
Neuropathology. The disease process is presumed to occur in the axon or cytoplasm of the anterior horn cell neuron. Anterior horn cell loss has been found in two autopsies [Schroder 2006].
In CMT2E, electron microscopy has shown giant axons with accumulation of disorganized neurofilaments [Fabrizi et al 2004].
Genotype-Phenotype Correlations
Few specific genotype-phenotype correlations are known. Considerable variability of phenotype has been observed within a family [Züchner et al 2004a].
Optic atrophy is associated with mutations in MFN2 [Verhoeven et al 2006, Züchner et al 2006].
Penetrance
Penetrance is usually nearly complete; however, some subtypes of CMT2 are associated with adult onset of symptoms.
Nomenclature
CMT2A. In addition to the pure CMT2A phenotype, optic atrophy has been reported in a number of individuals [Züchner et al 2006]; this disorder is also known as hereditary motor and sensory neuropathy VI (HMSN VI).
CMT2 with pyramidal signs, also known as hereditary motor and sensory neuropathy V (HMSN V), has been associated with MFN2 mutations [Zhu et al 2005] and with mutations in BSCL2 [Bienfait et al 2007] (see BSCL2-Related Neurologic Disorders).
CMT2C. Previously this has sometimes been called scapuloperoneal spinal muscular atrophy.
CMT2E/1F. Some individuals with mutations in NEFL, which typically cause CMT2E, may have slow NCVs, resulting in a diagnosis of CMT1F. To accommodate these two phenotypes associated with mutations in NEFL, the designation CMT2E/1F has been used.
Prevalence
The overall prevalence of hereditary neuropathies is estimated at approximately 3:10,000 population. About 30% of these individuals (1:10,000) may have CMT2. The prevalence of the various subtypes of CMT2 is unknown.
Differential Diagnosis
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
See CMT Overview, particularly to exclude potentially treatable causes of acquired neuropathy.
Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) can sometimes be difficult to distinguish from chronic idiopathic axonal neuropathy.
Bienfait et al [2006] found extensive clinical overlap between individuals with CMT1A and CMT2, while noting that people with CMT1A are more likely to have earlier-onset disease, foot deformity, and total areflexia.
A median motor NCV of 38 m/s is often used as a threshold for differentiating CMT1 from CMT2; however, the CMT2 phenotype can result from mutations in genes primarily associated with CMT1 and CMTX1 [Gutierrez et al 2000, Young et al 2001, Shy et al 2004].
CMT2C resembles two other disorders:
A similar, but pure motor syndrome without sensory loss, termed distal hereditary motor neuropathy VII (dHMV-VII) and linked to chromosome 2q14 [McEntagart et al 2001]
Autosomal dominant motor neuropathy with vocal paralysis associated with a missense mutation in the DCTN1, encoding the protein dynactin 1 [Puls et al 2003]
Several different types of autosomal dominant hereditary axonal neuropathy may cause predominantly sensory symptoms, including the "burning feet syndrome" [Stogbauer et al 1999, Auer-Grumbach et al 2003]. Families with hereditary sensory neuropathy (including hereditary sensory neuropathy type 1 caused by mutations in SPTLC1 [Bejaoui et al 2001]) usually do not have motor symptoms such as muscle weakness, but findings can sometimes overlap with CMT2B.
Bellone et al [2002] reported a family with autosomal dominant mutilating neuropathy that was not linked to the CMT2B locus or the HSN1 locus.
The CMT2 phenotype may sometimes be associated with signs of spasticity (e.g., hyperactive tendon reflexes and/or Babinski signs). This phenotype has sometimes been referred to as HMSN V. Two affected families have been reported by Vucic et al [2003]. One gene associated with this phenotype has been identified (see BSCL2-Related Neurologic Disorders).
Another form of autosomal dominant motor and sensory neuropathy from Okinawa has been mapped to 3q13 [Takashima et al 1999]. The relationship of this entity to CMT2B, which is linked to a similar region, is undetermined.
Females with CMTX1 (GJB1, encoding connexin 32) may have a CMT2 phenotype.
Boyer et al [2011] have reported heterozygous mutation in INF2 associated with childhood-onset CMT syndrome later complicated by renal glomerulosclerosis. Nerve conductions have varied from moderately slow to normal.
An intermediate form of CMT inherited in an autosomal dominant manner has been described; affected individuals have a relatively typical CMT phenotype with nerve conduction velocities that overlap those observed in CMT1 (demyelinating form) and CMT2 (axonal form). Motor NCVs in these families usually range between 25 and 50 m/sec.
At least three chromosomal loci (1p, 10q, and 19p) for this intermediate form have been identified by linkage analysis [Kennerson et al 2001, Verhoeven et al 2001]. Mutations in YARS and DNM2 may cause this syndrome.
Lopez-Bigas et al [2001] have described an autosomal dominant neuropathy associated with hearing impairment caused by a mutation in GJB3, encoding the protein connexin 31. Although the sural nerve pathology showed demyelination compatible with CMT1, the nerve condition velocities were not markedly slow and may suggest a clinical diagnosis of CMT2.
Weedon et al [2011] have described a large four-generation family with childhood-onset axonal CMT and a missense mutation (p.His306Arg) in DYNC1H1, the gene encoding cytoplasmic dynein 1 heavy chain 1.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2), the following evaluations are recommended:
Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
Nerve conduction velocity (NCV)
Complete family history
Treatment of Manifestations
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].
The following may be indicated:
Special shoes, including those with good ankle support
Ankle/foot orthoses (AFO) to correct foot drop and aid walking
Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2000]
Forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.
Treatment of sleep apnea or restless legs [Aboussouan et al 2007]
Exercise is encouraged within the individual's capability and many individuals remain physically active.
Pain and depression should be treated symptomatically [Gemignani et al 2004, Padua et al 2006].
Prevention of Secondary Complications
Daily heel cord-stretching exercises are helpful in preventing Achilles' tendon shortening.
Surveillance
Gait and condition of feet should be monitored to determine need for bracing, special shoes, or surgery.
Agents/Circumstances to Avoid
Obesity is to be avoided because it makes walking more difficult.
Medications which 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 4. For more information, click here (pdf).
Table 4. Medications 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 (pdf) 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].
Evaluation of Relatives at Risk
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Therapies Under Investigation
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Other
Career and employment choices may be influenced by persistent weakness of hands and/or feet.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Mode of Inheritance
CMT2B1, CMT2B2, CMT2H, and CMT2K are inherited in an autosomal recessive manner; all other subtypes of Charcot-Marie-Tooth hereditary neuropathy type 2 (CMT2) are inherited in an autosomal dominant manner.
CMT2P has been reported to be inherited in an autosomal recessive manner in one family and in an autosomal dominant manner in one family.
Risk to Family Members — Autosomal Dominant CMT2
Parents of a proband
Most individuals with autosomal dominant CMT2 have an affected parent.
A proband with autosomal dominant CMT2 may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown but likely very small.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include neurologic examination and molecular genetic testing if the mutation in the proband has been identified.
Note: Although most individuals diagnosed with autosomal dominant CMT2 have an affected parent, the family history 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.
Sibs of a proband. The risk to sibs depends on the genetic status of the proband's parents.
If a parent has a disease-causing mutation, the risk to the sibs is 50%.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. No instances of germline mosaicism have been reported, although it remains a possibility.
Offspring of a proband. Every child of an individual with autosomal dominant CMT2 has a 50% chance of inheriting the mutation.
Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected and/or has a disease-causing mutation, his or her family members are at risk.
Risk to Family Members — Autosomal Recessive CMT2
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
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.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with autosomal recessive CMT2 are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier Detection
Carrier testing for at-risk family members for CMT2B1 and CMT2K is possible if the disease-causing mutations have been identified in the family.
Related Genetic Counseling Issues
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal 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. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made 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.
Testing of at-risk asymptomatic adults. Asymptomatic adults at risk of having inherited a mutation associated with autosomal dominant CMT2 may wish to pursue further clinical evaluation and NCV testing. No treatment is available to individuals early in the course of the disease. Thus, such testing is for personal decision making only.
Testing of at-risk asymptomatic individuals during childhood. Testing of at-risk asymptomatic individuals who are younger than age 18 years is not appropriate. See also the National Society of Genetic Counselors resolution on genetic testing of children 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. See testing for a list of laboratories offering DNA banking.
Prenatal Testing
Prenatal diagnosis for pregnancies at increased risk for most subtypes of CMT2 is available by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele(s) must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
For some subtypes of CMT2, no laboratories offering prenatal testing are listed in the GeneTests™ Laboratory Directory. However, for these subtypes prenatal testing may be available for families in which a disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see testing.
Requests for prenatal testing for conditions which (like CMT2) do not affect intellect or life span are not common. Differences in perspectives 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 regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) of CMT2E has been reported [Sharapova et al 2004]. Preimplantation genetic diagnosis of other CMT2 subtypes may be available for families in which the disease-causing mutation(s) have been identified. For laboratories offering PGD, see testing.
Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
Table A. Charcot-Marie-Tooth Neuropathy Type 2: Genes and Databases
Table B. OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 2 (View All in OMIM)
| 118210 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A1; CMT2A1 |
| 150330 | LAMIN A/C; LMNA |
| 159440 | MYELIN PROTEIN ZERO; MPZ |
| 162280 | NEUROFILAMENT PROTEIN, LIGHT POLYPEPTIDE; NEFL |
| 600112 | DYNEIN, CYTOPLASMIC 1, HEAVY CHAIN 1; DYNC1H1 |
| 600287 | GLYCYL-tRNA SYNTHETASE; GARS |
| 600882 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B |
| 601065 | ALANYL-tRNA SYNTHETASE; AARS |
| 601472 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D; CMT2D |
| 602195 | HEAT-SHOCK 27-KD PROTEIN 1; HSPB1 |
| 602298 | RAS-ASSOCIATED PROTEIN RAB7; RAB7 |
| 605427 | TRANSIENT RECEPTOR POTENTIAL CATION CHANNEL, SUBFAMILY V, MEMBER 4; TRPV4 |
| 605588 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1; CMT2B1 |
| 605589 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2; CMT2B2 |
| 605995 | KINESIN FAMILY MEMBER 1B; KIF1B |
| 606071 | HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C |
| 606595 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F; CMT2F |
| 606598 | GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1 |
| 607677 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2I; CMT2I |
| 607684 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E; CMT2E |
| 607731 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2H; CMT2H |
| 607736 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2J; CMT2J |
| 607831 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2K; CMT2K |
| 608014 | HEAT-SHOCK 22-KD PROTEIN 8; HSPB8 |
| 608507 | MITOFUSIN 2; MFN2 |
| 608591 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2G; CMT2G |
| 608673 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2L; CMT2L |
| 609260 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2 |
| 610197 | MEDIATOR COMPLEX SUBUNIT 25; MED25 |
| 610933 | LEUCINE-RICH REPEAT- AND STERILE ALPHA MOTIF-CONTAINING 1; LRSAM1 |
| 613287 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2N; CMT2N |
| 614228 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2O; CMT2O |
| 614436 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2P; CMT2P |
Molecular Genetic Pathogenesis
The relationship of myelin and axon pathology to the pathogenesis of CMT is discussed in detail in several reviews [Krajewski et al 2000, Berger et al 2002, Maier et al 2002, Züchner & Vance 2006a, Züchner & Vance 2006b].
KIF1B
Normal allelic variants. KIF1B comprises 47 exons and 167.13 kb of DNA.
Pathologic allelic variants. A p.Gln98Leu mutation was reported in a single family [Zhao et al 2001]. See also Table A.
Table 5. Selected KIF1B Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.293A>T | p.Gln98Leu | NM_015074 NP_055889 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. Kinesin-like protein KIF1B is involved in axonal transport of synaptic vesicle precursors [Zhao et al 2001]. The kinesin superfamily of proteins is essential for intracellular transport along microtubules.
Abnormal gene product. There may be a defect in the transport of synaptic vesicles.
MFN2
Normal allelic variants. MFN2 has 19 exons with a 2274-bp open reading frame.
Pathologic allelic variants. Züchner et al [2004b] and Verhoeven et al [2006] have reported more than 25 missense mutations in MFN2. See also Table A.
Normal gene product. Mitofusin-2, encoded by MFN2, is involved in mitochondrial network architecture and mediates mitochondrial fusion.
Abnormal gene product. Mutations in MFN2 may disrupt the mitochondrial fusion-fission balance in peripheral nerve. Diminished axonal mitochondrial transport has been described [Baloh et al 2007].
RAB7A
Normal allelic variants. RAB7A has six exons and 87.9 kb of DNA.
Pathologic allelic variants. See Table A.
Normal gene product. Ras-related protein Rab-7a belongs to the RAB family of Ras-related GTPases essential for the regulation of intracellular membrane trafficking. Rab-7a is involved in transport between late endosomes and lysosomes. RAB-interacting lysosomal protein (RILP) induces the recruitment of dynein-dynactin motors and regulates transport toward the minus-end of microtubules [Verhoeven et al 2003].
Abnormal gene product. Abnormal Rab-7a may cause malfunction of lysosomes.
LMNA
Normal allelic variants. LMNA has 12 exons spread over 24 kb of genomic DNA.
Pathologic allelic variants. The most common mutation found in individuals with CMT2B1 is p.Arg298Cys. See also Table A.
Table 6. Selected LMNA Allelic Variants
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|---|
| Normal | c.1908C>T | p.= 1 | NM_170707 NP_733821 |
| Pathologic | c.398G>T | p.Arg133Leu | |
| c.892C>T | p.Arg298Cys | ||
| c.1411C>T | p.Arg471Cys | ||
| c.1579C>T | p.Arg527Cys |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org). 1. p.= designates that protein has not been analyzed, but no change is expected
Normal gene product. Lamins are the principal component of the nuclear lamina, a major portion of the nuclear envelope. Two A-type lamins exist: A and C. Lamins play a role in DNA replication, chromatin organization, spatial arrangement of nuclear pore complexes, nuclear growth, mechanical stabilization of the nucleus, and anchorage of the nuclear envelope protein.
Abnormal gene product. Position 29 is located in the lamin-A/C rod domain. The manner in which disruption of this domain adversely affects peripheral nerve function is unknown. Other LMNA mutations are associated with a wide variety of disorders (see Genetically Related Disorders).
MED25
Normal allelic variants. MED25 has 18 exons.
Pathologic allelic variants. One pathologic allelic variant has been described in an extended Costa Rican family with autosomal recessively inherited CMT neuropathy linked to the CMT2B2 locus in chromosome 19q13.3. Affected individuals were homozygous for p.Ala335Val [Leal et al 2009].
Table 7. Selected MED25 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.1004C>T | p.Ala335Val | NM_030973 NP_112235 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. MED25 encodes a 747-amino acid protein designated the mediator complex subunit 25 protein (reference sequence NM_030973.2). This protein is a subunit of the human activator-recruited cofactor (ARC), a family of large transcriptional coactivator complexes. Its precise function in transcriptional regulation is unknown.
Abnormal gene product. The p.Ala335Val substitution is located in a proline-rich region with high affinity for SH3 domains of the Abelson type. The mutation causes a decrease in binding specificity leading to the recognition of a broader range of SH3 domain proteins.
TRPV4
Normal allelic variants. TRPV4 has 16 exons; exon 1 of NM_021625.3 is non-coding.
Pathologic allelic variants. The mutations in Table 8 have been associated with CMT2C.
Table 8. Selected TRPV4 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.805C>T | p.Arg269Cys | NM_021625 NP_067638 |
| c.806G>A | p.Arg269His | |
| c.943C>T | p.Arg315Trp | |
| c.946C>T | p.Arg316Cys |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. TRPV is a vanilloid receptor-related transient receptor potential channel which plays an important role in neural signal. The protein is composed of a cytosolic N-terminal region and six transmembrane domains, including the pore region and an intracellular C-terminal tail. The N-terminal region contains the ankyrin repeat domain (ARD).
Abnormal gene product. Landouré et al [2010] demonstrated cellular toxicity and increased constitutive and activated channel currents in TRPV4-transected cells. Deng et al [2010] showed increased calcium channel activity resulting from the two mutations found in two families with CMT2C.
GARS
Normal allelic variants. GARS is a 40-kb gene with 17 exons.
Pathologic allelic variants. See Table A.
Normal gene product. Glycyl-tRNA synthetase ligates amino acids to their cognate tRNA.
Abnormal gene product. The missense mutations in this gene may produce a loss of function that allows the incorporation of the wrong amino acid in the place of glycine.
NEFL
Normal allelic variants. NEFL contains four coding exons; the 5' UTRs are highly conserved.
Pathologic allelic variants. One family with CMT2E/1F has a mutation in exon 1 of NEFL [Mersiyanova et al 2000] and another family has a deletion/insertion mutation in exon 1 (c.22_23delCCinsAG) [De Jonghe et al 2001]. See also Table A.
Table 9. Selected NEFL Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.22_23delCCinsAG | p.Pro8Arg | NM_006158 NP_006149 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. Neurofilament light polypeptide, the protein encoded by NEFL, contains 543 amino acids with a head, rod, and tail domain. Neurofilaments form the cytoskeletal component of myelinated axons.
Abnormal gene product. Knockout mice lacking neurofilaments have diminished axon caliber and delayed regeneration of myelinated axons following crush injury. A mouse mutation in Nefl has massive degeneration of spinal motor neurons and abnormal neurofilament accumulation with severe neurogenic skeletal muscle atrophy. Defects in transport and assembly of neurofilaments have been reported [Perez-Olle et al 2004].
HSPB1 (HSP27)
Normal allelic variants. HSPB1 contains three exons with a central HSP20-α-crystallin domain.
Pathologic allelic variants. See Table A.
Normal gene product. The heat shock protein beta-1 (also referred to as heat-shock protein 27) has many possible functions including antiapoptotic and cytoprotective properties, inhibition of caspase activation, prevention of aggresome formation, and involvement in the neurofilament network.
Abnormal gene product. Mutations in HSPB1 result in altered neurofilament assembly [Evgrafov et al 2004].
MPZ
Normal allelic variants. MPZ spans approximately seven kilobases and contains six exons.
Pathologic allelic variants. More than 56 point mutations in MPZ have been reported [Nelis et al 1999]. More than 70% of the mutations are localized in exons 2 and 3 of MPZ coding for the extracellular domain, indicating the functional importance of this domain (see also Table A).
Table 10. Selected MPZ Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change (Alias 1) | Reference Sequences |
|---|---|---|
| c.254A>T | p.Asp85Val (p.Asp75Val) | NM_000530 NP_000521 |
| c.401C>T | p.Thr134Met (p.Thr124Met) |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org). 1. Variant designation that does not conform to current naming conventions
Normal gene product. Myelin P0 protein is a major structural component of peripheral myelin representing about 50% of peripheral myelin protein by weight and about 7% of Schwann cell message. It is a homophilic adhesion molecule of the immunoglobulin family that plays an important role in myelin compaction. It has a single transmembrane domain, a large extracellular domain, and a smaller intracellular domain.
Abnormal gene product. Different mutations affect all portions of the protein and may alter myelin adhesion. Either demyelinating or axonal phenotypes can result.
GDAP1
Normal allelic variants. GDAP1 has six exons, 13.9 kb of DNA, and a 1007-nucleotide open reading frame.
Pathologic allelic variants. See also Table A.
Table 11. Selected GDAP1 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.358C>T | p.Arg120Trp | NM_018972 NP_061845 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. Ganglioside-induced differentiation-associated protein-1 [Baxter et al 2002]
Abnormal gene product. It is speculated that mutations may prevent the correct catalyzing S conjugation of reduced GCH, resulting in progressive attrition of both axons and Schwann cells.
HSPB8 (HSP22)
Normal allelic variants. HSPB8 has three exons and spans about 16 kb.
Pathologic allelic variants. Three mutations have been reported, see Table 12: [Irobi et al 2004b, Tang et al 2005].
Table 12. Selected HSPB8 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.423G>T | p.Lys141Asn | NM_014365 NP_055180 |
| c.423G>C | p.Lys141Asn | |
| c.421A>G | p.Lys141Glu |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. HSPB8 (also called HSP22) is a phosphor protein that interacts with HSPB1.
Abnormal gene product. Mutant HSPB8 proteins interact with HSPB1 and form aggregates that may lead to dysfunctional axonal transport and dysregulation of the cytoskeleton [Irobi et al 2004b].
AARS
Normal allelic variants. AARS has 21 exons and is located on chromosome 16.
Pathologic allelic variants. Two mutations have been associated with CMT (p.Arg329His and p.Glu778Ala). See Table 13. The mutation p.Asn71Tyr (c.211A>T) may also be pathologic.
Table 13. Selected AARS Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.986G>A | p.Arg329His | NM_001605 NP_001596 |
| c.2333A>C | p.Glu778Ala |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. Alanyl-tRNA synthetase attaches alanine to tRNA molecules in cytoplasm and mitochondria completing the first step in protein translation.
Abnormal gene product. Functional studies suggest these are loss of function mutations [McLaughlin et al 2012].
DYNC1H1
Pathologic allelic variants. One human mutation has been described (His306Arg) by Weedon et al [2011]. See Table 14.
Table 14. Selected DYNC1H1 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.917A>G | p.His306Arg | NM_001376 |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. 4,644-amino acid protein. DYNC1H1 is a subunit of cytoplasmic dynein, the primary motor protein producing retrograde axonal transport in neurons.
Abnormal gene product. Presumably the abnormal protein produces defective retrograde axonal transport in peripheral nerves.
LRSAM1
Pathologic allelic variants. A single autosomal dominant and a single autosomal recessive mutation have been described. See Table 15.
Table 15. Selected LRSAM1 Pathologic Allelic Variants
| DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequences |
|---|---|---|
| c.2121_2122 insGC | p.Leu708Arg fx28 | -- |
| AG>AA exon 24 | Intronic splice site |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www
.hgvs.org).
Normal gene product. A ubiquitin ligase (E3) involved with sorting ubiquitinylated cytoplasmic cargo (TSG101); 702-amino acid 70-kd protein
Abnormal gene product. Disturbs sorting of ubiquitinylated cargo in neuronal cytoplasm.
Resources
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
References
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page PubMed
Published Guidelines/Consensus Statements
- 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 at www.ashg.org. 1995. Accessed 2-6-12.
- National Society of Genetic Counselors. Resolution on prenatal and childhood testing for adult-onset disorders. Available at www.nsgc.org. 1995. Accessed 2-6-12.
Literature Cited
- Aboussouan LS, Lewis RA, Shy ME. Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease. Lung. 2007;185:1–7. [PubMed: 17294338]
- Antonellis A, Ellsworth RE, Sambuughin N, Puls I, Abel A, Lee-Lin SQ, Jordanova A, Kremensky I, Christodoulou K, Middleton LT, Sivakumar K, Ionasescu V, Funalot B, Vance JM, Goldfarb LG, Fischbeck KH, Green ED. Glycyl tRNA Synthetase Mutations in Charcot-Marie-Tooth Disease Type 2D and Distal Spinal Muscular Atrophy Type V. Am J Hum Genet. 2003;72:1293–9. [PMC free article: PMC1180282] [PubMed: 12690580]
- Auer-Grumbach M, De Jonghe P, Wagner K, Verhoeven K, Hartung HP, Timmerman V. Phenotype-genotype correlations in a CMT2B family with refined 3q13-q22 locus. Neurology. 2000;55:1552–7. [PubMed: 11094113]
- Auer-Grumbach M, De Jonghe P, Verhoeven K, Timmerman V, Wagner K, Hartung HP, Nicholson GA. Autosomal dominant inherited neuropathies with prominent sensory loss and mutilations: a review. Arch Neurol. 2003;60:329–34. [PubMed: 12633143]
- Auer-Grumbach M, Olschewski A, Papić L, Kremer H, McEntagart ME, Uhrig S, Fischer C, Fröhlich E, Bálint Z, Tang B, Strohmaier H, Lochmüller H, Schlotter-Weigel B, Senderek J, Krebs A, Dick KJ, Petty R, Longman C, Anderson NE, Padberg GW, Schelhaas HJ, van Ravenswaaij-Arts CM, Pieber TR, Crosby AH, Guelly C. Alterations in the ankyrin domain of TRPV4 cause congenital distal SMA, scapuloperoneal SMA and HMSN2C. Nat Genet. 2010;42:160–4. [PMC free article: PMC3272392] [PubMed: 20037588]
- Baloh RH, Schmidt RE, Pestronk A, Milbrandt J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. 2007;27:422–30. [PubMed: 17215403]
- Barhoumi C, Amouri R, Ben Hamida C, Ben Hamida M, Machghoul S, Gueddiche M, Hentati F. Linkage of a new locus for autosomal recessive axonal form of Charcot-Marie-Tooth disease to chromosome 8q21.3. Neuromuscul Disord. 2001;11:27–34. [PubMed: 11166163]
- Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet. 2002;30:21–2. [PubMed: 11743579]
- Bejaoui K, Wu C, Scheffler MD, Haan G, Ashby P, Wu L, de Jong P, Brown RH. SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nat Genet. 2001;27:261–2. [PubMed: 11242106]
- Bellone E, Rodolico C, Toscano A, Di Maria E, Cassandrini D, Pizzuti A, Pigullo S, Mazzeo A, Macaione V, Girlanda P, Vita G, Ajmar F, Mandich P. A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci. Neuromuscul Disord. 2002;12:286–91. [PubMed: 11801401]
- Benedetti S, Bertini E, Iannaccone S, Angelini C, Trisciani M, Toniolo D, Sferrazza B, Carrera P, Comi G, Ferrari M, Quattrini A, Previtali SC. Dominant LMNA mutations can cause combined muscular dystrophy and peripheral neuropathy. J Neurol Neurosurg Psychiatry. 2005;76:1019–21. [PMC free article: PMC1739728] [PubMed: 15965218]
- Berger P, Young P, Suter U. Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics. 2002;4:1–15. [PubMed: 12030326]
- Berghoff C, Berghoff M, Leal A, Morera B, Barrantes R, Reis A, Neundorfer B, Rautenstrauss B, Del Valle G, Heuss D. Clinical and electrophysiological characteristics of autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2B) that maps to chromosome 19q13.3. Neuromuscul Disord. 2004;14:301–6. [PubMed: 15099588]
- Bienfait HM, Baas F, Koelman JH, de Haan RJ, van Engelen BG, Gabreels-Festen AA, Ongerboer de Visser BW, Meggouh F, Weterman MA, De Jonghe P, Timmerman V, de Visser M. Phenotype of Charcot-Marie-Tooth disease Type 2. Neurology. 2007;68:1658–67. [PubMed: 17502546]
- Bienfait HM, Verhamme C, van Schaik IN, Koelman JH, de Visser BW, de Haan RJ, Baas F, van Engelen BG, de Visser M. Comparison of CMT1A and CMT2: similarities and differences. J Neurol. 2006;253:1572–80. [PubMed: 16941080]
- Boyer O, Nevo F, Plaisier E, Funalot B, Gribouval O, Benoit G, Cong EH, Arrondel C, Tête MJ, Montjean R, Richard L, Karras A, Pouteil-Noble C, Balafrej L, Bonnardeaux A, Canaud G, Charasse C, Dantal J, Deschenes G, Deteix P, Dubourg O, Petiot P, Pouthier D, Leguern E, Guiochon-Mantel A, Broutin I, Gubler MC, Saunier S, Ronco P, Vallat JM, Alonso MA, Antignac C, Mollet G. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. N Engl J Med. 2011;365:2377–88. [PubMed: 22187985]
- Cao H, Hegele RA. LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). J Hum Genet. 2003;48:271–4. [PubMed: 12768443]
- Caux F, Dubosclard E, Lascols O, Buendia B, Chazouilleres O, Cohen A, Courvalin JC, Laroche L, Capeau J, Vigouroux C, Christin-Maitre S. A new clinical condition linked to a novel mutation in lamins A and C with generalized lipoatrophy, insulin-resistant diabetes, disseminated leukomelanodermic papules, liver steatosis, and cardiomyopathy. J Clin Endocrinol Metab. 2003;88:1006–13. [PubMed: 12629077]
- Chapon F, Latour P, Diraison P, Schaeffer S, Vandenberghe A. Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J Neurol Neurosurg Psychiatry. 1999;66:779–82. [PMC free article: PMC1736388] [PubMed: 10329755]
- Chen L, Lee L, Kudlow BA, Dos Santos HG, Sletvold O, Shafeghati Y, Botha EG, Garg A, Hanson NB, Martin GM, Mian IS, Kennedy BK, Oshima J. LMNA mutations in atypical Werner's syndrome. Lancet. 2003;362:440–5. [PubMed: 12927431]
- Claramunt R, Pedrola L, Sevilla T, Lopez de Munain A, Berciano J, Cuesta A, Sanchez-Navarro B, Millan JM, Saifi GM, Lupski JR, Vilchez JJ, Espinos C, Palau F. Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet. 2005;42:358–65. [PMC free article: PMC1736030] [PubMed: 15805163]
- De Jonghe P, Mersivanova I, Nelis E, Del Favero J, Martin JJ, Van Broeckhoven C, Evgrafov O, Timmerman V. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol. 2001;49:245–9. [PubMed: 11220745]
- De Sandre-Giovannoli A, Chaouch M, Kozlov S, Vallat JM, Tazir M, Kassouri N, Szepetowski P, Hammadouche T, Vandenberghe A, Stewart CL, Grid D, Levy N. Homozygous defects in LMNA, encoding lamin A/C nuclear-envelope proteins, cause autosomal recessive axonal neuropathy in human (Charcot- Marie-Tooth disorder type 2) and mouse. Am J Hum Genet. 2002;70:726–36. [PMC free article: PMC384949] [PubMed: 11799477]
- Dematteis M, Pepin JL, Jeanmart M, Deschaux C, Labarre-Vila A, Levy P. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet. 2001;357:267–72. [PubMed: 11214130]
- Deng H-X, Klein CJ, Yan J, Shi Y, Wu Y, Fecto F, Yau H-J, Yang Y, Zhai H, Siddique N, Hedley-Whyte ET, DeLong R, Martina M, Dyck PJ, Siddique T. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42:165–169. [PubMed: 20037587]
- Dyck PJ, Litchy WJ, Minnerath S, Bird TD, Chance PF, Schaid DJ, Aronson AE. Hereditary motor and sensory neuropathy with diaphragm and vocal cord paresis. Ann Neurol. 1994;35:608–15. [PubMed: 8179305]
- Evgrafov OV, Mersiyanova I, Irobi J, Van Den Bosch L, Dierick I, Leung CL, Schagina O, Verpoorten N, Van Impe K, Fedotov V, Dadali E, Auer-Grumbach M, Windpassinger C, Wagner K, Mitrovic Z, Hilton-Jones D, Talbot K, Martin JJ, Vasserman N, Tverskaya S, Polyakov A, Liem RK, Gettemans J, Robberecht W, De Jonghe P, Timmerman V. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet. 2004;36:602–6. [PubMed: 15122254]
- Fabrizi GM, Cavallaro T, Angiari C, Bertolasi L, Cabrini I, Ferrarini M, Rizzuto N. Giant axon and neurofilament accumulation in Charcot-Marie-Tooth disease type 2E. Neurology. 2004;62:1429–31. [PubMed: 15111691]
- Gemignani F, Melli G, Alfieri S, Inglese C, Marbini A. Sensory manifestations in Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2004;9:7–14. [PubMed: 14871449]
- Georgiou DM, Zidar J, Korosec M, Middleton LT, Kyriakides T, Christodoulou K. A novel NF-L mutation Pro22Ser is associated with CMT2 in a large Slovenian family. Neurogenetics. 2002;4:93–6. [PubMed: 12481988]
- Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77(7):1356–62. [PubMed: 8608515]
- Grandis M, Shy ME. Current therapy for Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2005;7:23–31. [PubMed: 15610704]
- Guernsey DL, Jiang H, Bedard K, Evans SC, Ferguson M, Matsuoka M, Macgillivray C, Nightingale M, Perry S, Rideout AL, Orr A, Ludman M, Skidmore DL, Benstead T, Samuels ME (2010) Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease. PLoS Genet. 2010 Aug 26;6(8). pii: e1001081.
- Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, Garcia CA. Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease. Muscle Nerve. 2000;23:182–8. [PubMed: 10639608]
- Guyton GP, Mann RA. The pathogenesis and surgical management of foot deformity in Charcot-Marie-Tooth disease. Foot Ankle Clin. 2000;5:317–26. [PubMed: 11232233]
- Houlden H, King RH, Muddle JR, Warner TT, Reilly MM, Orrell RW, Ginsberg L. A novel RAB7 mutation associated with ulcero-mutilating neuropathy. Ann Neurol. 2004;56:586–90. [PubMed: 15455439]
- Irobi J, De Jonghe P, Timmerman V. Molecular genetics of distal hereditary motor neuropathies. Hum Mol Genet. 2004a;13(Spec No 2):R195–202. [PubMed: 15358725]
- Irobi J, Van Impe K, Seeman P, Jordanova A, Dierick I, Verpoorten N, Michalik A, De Vriendt E, Jacobs A, Van Gerwen V, Vennekens K, Mazanec R, Tournev I, Hilton-Jones D, Talbot K, Kremensky I, Van Den Bosch L, Robberecht W, Van Vandekerckhove J, Van Broeckhoven C, Gettemans J, De Jonghe P, Timmerman V. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004b;36:597–601. [PubMed: 15122253]
- Ismailov SM, Fedotov VP, Dadali EL, Polyakov AV, Van Broeckhoven C, Ivanov VI, De Jonghe P, Timmerman V, Evgrafov OV. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2F) maps to chromosome 7q11-q21. Eur J Hum Genet. 2001;9:646–50. [PubMed: 11528513]
- Jordanova A, De Jonghe P, Boerkoel CF, Takashima H, De Vriendt E, Ceuterick C, Martin JJ, Butler IJ, Mancias P, Papasozomenos SCh, Terespolsky D, Potocki L, Brown CW, Shy M, Rita DA, Tournev I, Kremensky I, Lupski JR, Timmerman V. Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease. Brain. 2003;126:590–7. [PubMed: 12566280]
- Kennerson ML, Zhu D, Gardner RJ, Storey E, Merory J, Robertson SP, Nicholson GA. Dominant intermediate charcot-marie-tooth neuropathy maps to chromosome 19p12-p13.2. Am J Hum Genet. 2001;69:883–8. [PMC free article: PMC1226074] [PubMed: 11533912]
- Kijima K, Numakura C, Izumino H, Umetsu K, Nezu A, Shiiki T, Ogawa M, Ishizaki Y, Kitamura T, Shozawa Y, Hayasaka K. Mitochondrial GTPase mitofusin 2 mutation in Charcot-Marie-Tooth neuropathy type 2A. Hum Genet. 2005;116:23–7. [PubMed: 15549395]
- Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, Kamholz J, Shy ME. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000;123(Pt 7):1516–27. [PubMed: 10869062]
- Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009;84:307–15. [PMC free article: PMC2667978] [PubMed: 19232556]
- Landouré G, Zdebik AA, Martinez TL, Burnett BG, Stanescu HC, Inada H, Shi Y, Taye AA, Kong L, Munns CH, Choo SS, Phelps CB, Paudel R, Houlden H, Ludlow CL, Caterina MJ, Gaudet R, Kleta R, Fischbeck KH, Sumner CJ. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42:170–4. [PMC free article: PMC2812627] [PubMed: 20037586]
- Latour P, Thauvin-Robinet C, Baudelet-Méry C, Soichot P, Cusin V, Faivre L, Locatelli MC, Mayençon M, Sarcey A, Broussolle E, Camu W, David A, Rousson R. A major determinant for binding and aminoacylation of tRNA(Ala) in cytoplasmic Alanyl-tRNA synthetase is mutated in dominant axonal Charcot-Marie-Tooth disease. Am J Hum Genet. 2010;86:77–82. [PMC free article: PMC2801750] [PubMed: 20045102]
- Leal A, Morera B, Del Valle G, Heuss D, Kayser C, Berghoff M, Villegas R, Hernandez E, Mendez M, Hennies HC, Neundorfer B, Barrantes R, Reis A, Rautenstrauss B. A second locus for an axonal form of autosomal recessive Charcot-Marie-Tooth disease maps to chromosome 19q13.3. Am J Hum Genet. 2001;68:269–74. [PMC free article: PMC1234926] [PubMed: 11112660]
- Leal A, Huehne K, Bauer F, Sticht H, Berger P, Suter U, Morera B, Del Valle G, Lupski JR, Ekici A, Pasutto F, Endele S, Barrantes R, Berghoff C, Berghoff M, Neundörfer B, Heuss D, Dorn T, Young P, Santolin L, Uhlmann T, Meisterernst M, Sereda MW, Stassart RM, Zu Horste GM, Nave KA, Reis A, Rautenstrauss B. Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models. Neurogenetics. 2009;10:275–87. [PMC free article: PMC2847151] [PubMed: 19290556]
- Li J, Bai Y, Ianakova E, Grandis M, Uchwat F, Trostinskaia A, Krajewski KM, Garbern J, Kupsky WJ, Shy ME. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol. 2006;498:252–65. [PubMed: 16856127]
- Lopez-Bigas N, Olive M, Rabionet R, Ben-David O, Martinez-Matos JA, Bravo O, Banchs I, Volpini V, Gasparini P, Avraham KB, Ferrer I, Arbones ML, Estivill X. Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment. Hum Mol Genet. 2001;10:947–52. [PubMed: 11309368]
- Maier M, Berger P, Suter U. Understanding Schwann cell-neurone interactions: the key to Charcot- Marie-Tooth disease? J Anat. 2002;200:357–66. [PMC free article: PMC1570699] [PubMed: 12090402]
- McEntagart M, Norton N, Williams H, Teare MD, Dunstan M, Baker P, Houlden H, Reilly M, Wood N, Harper PS, Futreal PA, Williams N, Rahman N. Localization of the gene for distal hereditary motor neuronopathy VII (dHMN-VII) to chromosome 2q14. Am J Hum Genet. 2001;68:1270–6. [PMC free article: PMC1226107] [PubMed: 11294660]
- McEntagart ME, Reid SL, Irtthum A, Douglas JB, Eyre KE, Donaghy MJ, Anderson NE, Rahman N. Confirmation of a hereditary motor and sensory neuropathy IIC locus at chromosome 12q23-q24. Ann Neurol. 2005;57:293–7. [PubMed: 15668982]
- McLaughlin HM, Sakaguchi R, Giblin W. A Recurrent loss-of-function alanyl-tRNA synthetase (AARS) mutation in patients with charcot-marie-tooth disease type 2N (CMT2N). Hum Mutat. 2012;33:244–53. [PMC free article: PMC3240693] [PubMed: 22009580]
- Mersiyanova IV, Perepelov AV, Polyakov AV, Sitnikov VF, Dadali EL, Oparin RB, Petrin AN, Evgrafov OV. A new variant of Charcot-Marie-Tooth disease type 2 is probably the result of a mutation in the neurofilament-light gene. Am J Hum Genet. 2000;67:37–46. [PMC free article: PMC1287099] [PubMed: 10841809]
- Misu K, Yoshihara T, Shikama Y, Awaki E, Yamamoto M, Hattori N, Hirayama M, Takegami T, Nakashima K, Sobue G. An axonal form of Charcot-Marie-Tooth disease showing distinctive features in association with mutations in the peripheral myelin protein zero gene (Thr124Met or Asp75Val). J Neurol Neurosurg Psychiatry. 2000;69:806–11. [PMC free article: PMC1737183] [PubMed: 11080237]
- Nelis E, Berciano J, Verpoorten N, Coen K, Dierick I, Van Gerwen V, Combarros O, De Jonghe P, Timmerman V. Autosomal dominant axonal Charcot-Marie-Tooth disease type 2 (CMT2G) maps to chromosome 12q12-q13.3. J Med Genet. 2004;41:193–7. [PMC free article: PMC1735709] [PubMed: 14985381]
- Nelis E, Haites N, Van Broeckhoven C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat. 1999;13:11–28. [PubMed: 9888385]
- Nishikawa T, Kawakami K, Kumamoto T, Tonooka S, Abe A, Hayasaka K, Okamoto Y, Kawano Y. Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30:519–21. [PubMed: 18797198]
- Padua L, Aprile I, Cavallaro T, Commodari I, La Torre G, Pareyson D, Quattrone A, Rizzuto N, Vita G, Tonali P, Schenone A, Italian CMT. Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study. Neurol Sci. 2006;27:417–23. [PubMed: 17205227]
- Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009;8:654–67. [PubMed: 19539237]
- Pareyson D, Scaioli V, Laura M. Clinical and electrophysiological aspects of Charcot-Marie-Tooth disease. Neuromolecular Med. 2006;8:3–22. [PubMed: 16775364]
- Perez-Olle R, Jones ST, Liem RK. Phenotypic analysis of neurofilament light gene mutations linked to Charcot-Marie-Tooth disease in cell culture models. Hum Mol Genet. 2004;13:2207–20. [PubMed: 15282209]
- Porter CC, Carver AE, Albano EA. Vincristine induced peripheral neuropathy potentiated by voriconazole in a patient with previously undiagnosed CMT1X. Pediatr Blood Cancer. 2009;52:298–300. [PubMed: 18837430]
- Rock MJ, Prenen J, Funari TL, Merriman B, Nelson SF, Lachman RS, Wilcox WR, Reyno S, Quadrelli R, Vaglio A, Owsianik G, Janssens A, Voets T, Ikegawa S, Nagai T, Rimoin DL, Nilius B, Cohn DH. Gain-of-function mutations in TRPV4 cause autosomal dominant brachyolmia. Nat Genet. 2008;40:999–1003. [PubMed: 18587396]
- Puls I, Jonnakuty C, LaMonte BH, Holzbaur EL, Tokito M, Mann E, Floeter MK, Bidus K, Drayna D, Oh SJ, Brown RH, Ludlow CL, Fischbeck KH. Mutant dynactin in motor neuron disease. Nat Genet. 2003;33:455–6. [PubMed: 12627231]
- Santoro L, Manganelli F, Di Maio L, Barbieri F, Carella M, D'Adamo P, Casari G. Charcot-Marie-Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European family. Neuromuscul Disord. 2002;12:399–404. [PubMed: 12062259]
- Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011;69:22–33. [PMC free article: PMC3058597] [PubMed: 21280073]
- Schroder JM. Neuropathology of Charcot-Marie-Tooth and related disorders. Neuromolecular Med. 2006;8:23–42. [PubMed: 16775365]
- Senderek J, Hermanns B, Lehmann U, Bergmann C, Marx G, Kabus C, Timmerman V, Stoltenburg-Didinger G, Schroder JM. Charcot-Marie-Tooth neuropathy type 2 and P0 point mutations: two novel amino acid substitutions (Asp61Gly; Tyr119Cys) and a possible "hotspot" on Thr124Met. Brain Pathol. 2000;10:235–48. [PubMed: 10764043]
- Sharapova T, Rechitsky S, Verlinsky Y. Preimplantation genetic diagnosis (PGD) for three types of Charcot-Marie-Tooth (CMT) disease. Am J Hum Genet. 2004;S75:A2806.
- Shy ME, Jani A, Krajewski K, Grandis M, Lewis RA, Li J, Shy RR, Balsamo J, Lilien J, Garbern JY, Kamholz J. Phenotypic clustering in MPZ mutations. Brain. 2004;127:371–84. [PubMed: 14711881]
- Stogbauer F, Young P, Kuhlenbaumer G, Kiefer R, Timmerman V, Ringelstein EB, Wang JF, Schroder JM, Van Broeckhoven C, Weis J. Autosomal dominant burning feet syndrome. J Neurol Neurosurg Psychiatry. 1999;67:78–81. [PMC free article: PMC1736450] [PubMed: 10369826]
- Sowden JE, Logigian EL, Malik K, Herrmann DN. Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation. J Neurol Neurosurg Psychiatry. 2005;76:442–4. [PMC free article: PMC1739547] [PubMed: 15716547]
- Sulica L, Blitzer A, Lovelace RE, Kaufmann P. Vocal fold paresis of Charcot-Marie-Tooth disease. Ann Otol Rhinol Laryngol. 2001;110:1072–6. [PubMed: 11713921]
- Takashima H, Nakagawa M, Suehara M, Saito M, Saito A, Kanzato N, Matsuzaki T, Hirata K, Terwilliger JD, Osame M. Gene for hereditary motor and sensory neuropathy (proximal dominant form) mapped to 3q13.1. Neuromuscul Disord. 1999;9:368–71. [PubMed: 10545038]
- Tang BS, Luo W, Xia K, Xiao JF, Jiang H, Shen L, Tang JG, Zhao GH, Cai F, Pan Q, Dai HP, Yang QD, Xia JH, Evgrafov OV. A new locus for autosomal dominant Charcot-Marie-Tooth disease type 2 (CMT2L) maps to chromosome 12q24. Hum Genet. 2004;114:527–33. [PubMed: 15021985]
- Tang BS, Zhao GH, Luo W, Xia K, Cai F, Pan Q, Zhang RX, Zhang FF, Liu XM, Chen B, Zhang C, Shen L, Jiang H, Long ZG, Dai HP. Small heat-shock protein 22 mutated in autosomal dominant Charcot-Marie-Tooth disease type 2L. Hum Genet. 2005;116:222–4. [PubMed: 15565283]
- Tazir M, Azzedine H, Assami S, Sindou P, Nouioua S, Zemmouri R, Hamadouche T, Chaouch M, Feingold J, Vallat JM, Leguern E, Grid D. Phenotypic variability in autosomal recessive axonal Charcot-Marie-Tooth disease due to the R298C mutation in lamin A/C. Brain. 2004;127:154–63. [PubMed: 14607793]
- Verhoeven K, Claeys KG, Züchner S, Schroder JM, Weis J, Ceuterick C, Jordanova A, Nelis E, De Vriendt E, Van Hul M, Seeman P, Mazanec R, Saifi GM, Szigeti K, Mancias P, Butler IJ, Kochanski A, Ryniewicz B, De Bleecker J, Van den Bergh P, Verellen C, Van Coster R, Goemans N, Auer-Grumbach M, Robberecht W, Milic Rasic V, Nevo Y, Tournev I, Guergueltcheva V, Roelens F, Vieregge P, Vinci P, Moreno MT, Christen HJ, Shy ME, Lupski JR, Vance JM, De Jonghe P, Timmerman V. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129:2093–102. [PubMed: 16714318]
- Verhoeven K, De Jonghe P, Coen K, Verpoorten N, Auer-Grumbach M, Kwon JM, FitzPatrick D, Schmedding E, De Vriendt E, Jacobs A, Van Gerwen V, Wagner K, Hartung HP, Timmerman V. Mutations in the small GTP-ase late endosomal protein RAB7 cause Charcot-Marie-Tooth type 2B neuropathy. Am J Hum Genet. 2003;72:722–7. [PMC free article: PMC1180247] [PubMed: 12545426]
- Verhoeven K, Villanova M, Rossi A, Malandrini A, De Jonghe P, Timmerman V. Localization of the gene for the intermediate form of charcot-marie- tooth to chromosome 10q24.1-q25.1. Am J Hum Genet. 2001;69:889–94. [PMC free article: PMC1226075] [PubMed: 11533914]
- Vucic S, Kennerson M, Zhu D, Miedema E, Kok C, Nicholson GA. CMT with pyramidal features. Neurology. 2003;60:696–9. [PubMed: 12601114]
- Walter MC, Witt TN, Weigel BS, Reilich P, Richard P, Pongratz D, Bonne G, Wehnert MS, Lochmuller H. Deletion of the LMNA initiator codon leading to a neurogenic variant of autosomal dominant Emery-Dreifuss muscular dystrophy. Neuromuscul Disord. 2005;15:40–4. [PubMed: 15639119]
- 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]
- Weimer LM, Podwall D. Medication-induced exacerbation of neuropathy in Charcot-Marie-Tooth Disease. J Neurol Sci. 2006;242:47–54. [PubMed: 16386273]
- 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(2):358–70. [PMC free article: PMC3276280] [PubMed: 22012984]
- Young P, Grote K, Kuhlenbaumer G, Debus O, Kurlemann H, Halfter H, Funke H, Ringelstein EB, Stogbauer F. Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity. J Neurol. 2001;248:410–5. [PubMed: 11437164]
- Zhao C, Takita J, Tanaka Y, Setou M, Nakagawa T, Takeda S, Yang HW, Terada S, Nakata T, Takei Y, Saito M, Tsuji S, Hayashi Y, Hirokawa N. Charcot-Marie-Tooth disease type 2a caused by mutation in a microtubule motor KIF1Bbeta. Cell. 2001;105:587–97. [PubMed: 11389829]
- Zhu D, Kennerson ML, Walizada G, Züchner S, Vance JM, Nicholson GA. Charcot-Marie-Tooth with pyramidal signs is genetically heterogeneous: families with and without MFN2 mutations. Neurology. 2005;65:496–7. [PubMed: 16087932]
- Züchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V, Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J, Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T, Timmerman V, Shy M, Vance JM. Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2. Ann Neurol. 2006;59:276–81. [PubMed: 16437557]
- Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y, Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battologlu E, Polyakov AV, Timmerman V, Schroder JM, Vance JM. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. 2004a;36:449–51. [PubMed: 15064763]
- Züchner S, Vance JM. Mechanisms of disease: a molecular genetic update on hereditary axonal neuropathies. Nat Clin Pract Neurol. 2006a;2:45–53. [PubMed: 16932520]
- Züchner S, Vance JM. Molecular genetics of autosomal-dominant axonal Charcot-Marie-Tooth disease. Neuromolecular Med. 2006b;8:63–74. [PubMed: 16775367]
- Züchner S, Vorgerd M, Sindern E, Schroder JM. The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy. Neuromuscul Disord. 2004b;14:147–57. [PubMed: 14733962]
Chapter Notes
Revision History
9 February 2012 (tb) Revision: mutations in DYNC1H1 reported to be associated with CMT2O; mutation in LRSAM1 associated with CMT2P
22 December 2011 (tb) Revision: mutations in AARS cause CMT2N.
15 September 2011 (tb) Revision: Differential Diagnosis — intermediate form of CMT
18 August 2011 (cd) Revision: targeted mutation analysis for p.Ala335Val in MED25 associated with CMT2B2
1 March 2011 (cd) Revision: edits to Testing Strategy
27 January 2011 (cd) Revision: testing available clinically for CMT2C
27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
11 March 2010 (me) Comprehensive update posted live
7 January 2008 (cd) Revision: prenatal diagnosis for CMT2D available
16 August 2007 (me) Comprehensive update posted to live Web site
30 January 2007 (tb) Revision: sequence analysis clinically available on a limited basis for CMT2D
30 December 2005 (cd) Revision: testing and prenatal diagnosis for CMT2B clinically available; prenatal diagnosis for CMT2A clinically available
21 December 2005 (tb) Revision: Differential Diagnosis — HMSN-V
14 June 2005 (tb) Revision: CMT2K added
4 May 2005 (me) Comprehensive update posted to live Web site
6 December 2004 (tb) Revision: testing
9 September 2004 (tb,cd) Revision: MFN2 added; sequence analysis clinically available
9 August 2004 (tb,cd) Revision: CMT2B1
21 June 2004 (tb) Revision: CMT2F
10 May 2004 (tb) Author revisions
1 April 2004 (tb) Revision: prenatal diagnosis available for CMT2E
7 April 2003 (me) Comprehensive update posted to live Web site
12 September 2001 (tb) Author revisions
24 July 2001 (tb) Author revisions
27 June 2001 (tb) Author revisions
19 June 2001 (tb) Revision: CMT2A gene found
23 March 2001 (tb) Author revisions
16 January 2001 (tb) Author revisions
25 August 2000 (me) Comprehensive update posted to live Web site
15 June 2000 (tb) Author revisions
15 May 2000 (tb) Author revisions
3 February 2000 (tb) Author revisions
12 October 1998 (tb) Author revisions
24 September 1998 (pb) Review posted to live Web site
April 1996 (tb) Original submission
-
Charcot-Marie-Tooth Neuropathy Type 2E/1F
[GeneReviews™. 1993]
Charcot-Marie-Tooth Neuropathy Type 2E/1FDe Jonghe P, Jordanova AK. GeneReviews™. 1993
-
Charcot-Marie-Tooth Neuropathy Type 1
[GeneReviews™. 1993]
Charcot-Marie-Tooth Neuropathy Type 1Bird TD. GeneReviews™. 1993
-
Charcot-Marie-Tooth Neuropathy Type 4
[GeneReviews™. 1993]
Charcot-Marie-Tooth Neuropathy Type 4Bird TD. GeneReviews™. 1993
-
Review [Molecular genetics of inherited neuropathies].
[Rinsho Shinkeigaku. 2006]
Review [Molecular genetics of inherited neuropathies].Takashima H. Rinsho Shinkeigaku. 2006 Jan; 46(1):1-18.
-
Review Genetic evaluation of inherited motor/sensory neuropathy.
[Suppl Clin Neurophysiol. 2004]
Review Genetic evaluation of inherited motor/sensory neuropathy.Chance PF. Suppl Clin Neurophysiol. 2004; 57:228-42.
-
Charcot-Marie-Tooth Neuropathy Type 2 - GeneReviews™
Charcot-Marie-Tooth Neuropathy Type 2 - GeneReviews™Bookshelf
-
Charcot-Marie-Tooth Hereditary Neuropathy Overview - GeneReviews™
Charcot-Marie-Tooth Hereditary Neuropathy Overview - GeneReviews™Bookshelf
-
DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy - GeneReviews™
DNM2-Related Intermediate Charcot-Marie-Tooth Neuropathy - GeneReviews™Bookshelf
-
Charcot-Marie-Tooth Neuropathy Type 4A - GeneReviews™
Charcot-Marie-Tooth Neuropathy Type 4A - GeneReviews™Bookshelf
-
Congenital Myasthenic Syndromes - GeneReviews™
Congenital Myasthenic Syndromes - GeneReviews™Bookshelf
Your browsing activity is empty.
Activity recording is turned off.
See more...