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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.—ED.
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.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
Diagnosis/testing. The diagnosis is based on clinical findings and EMG/NCV characteristics. The nine genes known to be associated with the CMT2 subtypes are KIF1B (CMT2A1), MFN2 (CMT2A2), RAB7A (formerly RAB7) (CMT2B), LMNA (CMT2B1), GARS (CMT2D), NEFL (CMT2E/1F), HSPB1 (CMT2F), MPZ (CMT2I/CMT2J), GDAP1 (CMT2K), and HSPB8 (CMT2L). Molecular genetic testing is clinically available for CMT subtypes 2A1, 2A2, 2B, 2B1, 2D, 2E, 2F, 2I, 2J, and 2K.
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, CMT2H, and CMT2K 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.
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) [Saito et al 1997]
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
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.
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.—ED.
| 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 |
| CMT2D | GARS | |
| CMT2E/1F | NEFL | |
| CMT2F | HSPB1 | Evgrafov et al 2004 |
| CMT2I/J | MPZ | |
| CMT2K | GDAP1 | |
| CMT2L | HSPB8 | Tang et al 2005 |
1. Found in one family
2. Represents approximately 20%-30% of CMT2
| CMT2 Subtype | Chromosomal Locus | Reference |
|---|---|---|
| CMT2B2 | 19q13.3 | Berghoff et al 2004 |
| CMT2C | 12q23-q24 | Klein et al 2003, McEntagart et al 2005 |
| CMT2G | 12q12-q13.3 | Nelis et al 2004 |
| CMT2H | 8q21 | Barhoumi et al 2001 |
| CMT2L | 12q24 | Tang et al 2004 |
Clinical testing
CMT2A1, CMT2A2, CMT2B, CMT2B1, CMT2D, CMT2E/1F, CMT2F, CMT2I, CMT2J, CMT2K, CMT2L
Sequence analysis. Sequence analysis of the KIFB1, MFN2, LMNA, GARS, NEFL, HSPB1, MPZ, and GDAP1 genes is available on a clinical basis. One family with CMT2E/1F has a mutation in exon 1 of the NEFL gene [Mersiyanova et al 2000] and another family has a double missense mutation, also in exon 1 [De Jonghe et al 2001].
Mutation scanning. Mutation scanning of the RAB7A gene is available clinically.
| Locus Name | Test Method | Mutations Detected | Proportion of CMT2 Attributed to Mutations in This Gene | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|---|---|
| CMT2A1 | Sequence analysis | Sequence variants in KIF1B | Rare | Unknown | Clinical
 |
| CMT2A2 | Sequence variants in MFN2 | 20% | Clinical
| ||
| CMT2B | Mutation scanning | Sequence variants in RAB7A | Rare | Clinical
| |
| CMT2B1 | Sequence analysis | Sequence variants in LMNA | Clinical
| ||
| CMT2B2 | Linkage analysis | Unknown | Research only | ||
| CMT2C | |||||
| CMT2D | Sequence analysis | Sequence variants in GARS | Clinical
| ||
| CMT2E/1F | Sequence variants in NEFL | Clinical
| |||
| CMT2F | Sequence variants in HSPB1 | Clinical
| |||
| CMT2G | Linkage analysis | Unknown | Research only | ||
| CMT2H | |||||
| CMT2I | Sequence analysis | Sequence variants in MPZ | Clinical
| ||
| CMT2J | Clinical
| ||||
| CMT2K | Sequence variants in GDAP1 | Clinical
| |||
| CMT2L | Sequence analysis | Sequence variants in HSPB8 | Clinical
|
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To establish the diagnosis of a CMT2 subtype the proband should first be tested for mutations in MFN2 as they are most common. Bienfait et al (2007) found a genetic mutation in three of 18 (17%) families with CMT2.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
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 mutations or 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 SNP in LMNA (1908C/T) associated with obesity-related traits in Canadian Oji-Cree
Autosomal recessive mandibuloacral dysplasia (MAD). A compound heterozygous mutation (p.Arg471Cys in exon 8/p.Arg527Cys in exon 9) 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, LMNA 150330 for additional references regarding other laminopathies.
GARS. In addition to CMT2D, the other phenotype associated with mutations in GARS is hereditary motor neuropathy type 5 (HMN V) [Sambuughin et al 1998, 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, CMT1B is associated with mutations in MPZ (see CMT1) [Senderak et al 2000].
GDAP1. In addition to CMT2K, autosomal recessive CMT4A is associated with mutations in GDAP1.
HSPB8. Mutations have been reported in distal hereditary motor neuropathy type 2 (dHMNII) [Irobi, Van Impe et al 2004].
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. 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 [Pareyson et al 2006].
Affected individuals usually become symptomatic between ages five and 25 years [Saito et al 1997], 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. Atrophy of intrinsic hand muscles is less frequently present and tendon reflexes may be intact in the upper limbs. Proximal muscles usually remain strong.
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].
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, Mersiyanova et al (2004) 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 [De Jonghe et al 1997, Elliott et al 1997]. 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]. 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, Mersiyanova et al 2004]. 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, De Jonghe et al 2004].
CMT2G has been reported in a single Spanish family [Nelis et al 2004].
CMT2H has associated pyramidal features [Barhoumi et al 2001].
CMT2I has only mild slowing of NCV [Li et al 2006].
CMT2J. The MPZ mutation p.Thr124Met has been associated with an axonal neuropathy with deafness and Argyll Robertson pupils [Chapon et al 1999]. In addition the p.Thr124Met mutation and the p.Asp75Val mutation have been associated with axonal neuropathy and marked sensory impairment, Adie's pupil, and deafness [Misu et al 2000].
CMT2K is associated with the p.Arg120Trp mutations in GDAP1 [Claramunt et al 2005].
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].
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].
Few specific genotype-phenotype correlations are known. Considerable variability of phenotype has been observed within a family [Züchner, Mersiyanova et al 2004].
Optic atrophy is associated with mutations in MFN2 [Verhoeven et al 2006, Züchner et al 2006].
Penetrance is usually nearly complete; however, some subtypes of CMT2 are associated with adult onset of symptoms.
Anticipation has not been observed.
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).
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.
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 are unknown.
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 [Teunissen et al 1997].
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 gene 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-Grambach 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 1997, Takashima et al 1999]. The relationship of this entity to CMT2B, which is linked to a similar region, is undetermined.
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) [Villanova et al 1998]. Motor NCVs in these families usually range between 25 and 50 m/sec.
At least two chromosomal loci (10q and 19p) for this intermediate form have been identified by linkage analysis [Kennerson et al 2001, Verhoeven et al 2001].
Lopez-Bigas et al (2001) have described an autosomal dominant neuropathy associated with hearing impairment caused by a mutation in the gene 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.
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 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 1997, 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 [Carter 1997]
Orthopedic surgery to correct severe pes cavus deformity [Guyton & Mann 2001]
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 [Carter et al 1998, Gemignani et al 2004, Padua et al 2006].
Daily heel cord stretching exercises are helpful in preventing Achilles' tendon shortening.
Gait and condition of feet should be monitored to determine need for bracing, special shoes, or surgery.
Obesity makes walking more difficult and should be avoided.
Drugs and medications known to cause nerve damage (e.g., vincristine, isoniazid, taxol, cisplatin, nitrofurantoin) should be avoided [Chaudhry et al 2003].
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
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 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.
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.
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 upon 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 upon the status of the proband's parents. If a parent is found to be affected and/or to have a disease-causing mutation, his or her family members are at risk.
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 testing for at-risk family members for CMT2B1 and for CMT2K is available on a clinical basis once the mutations have been identified in the family.
Carrier testing for the other autosomal recessive CMT2 subtypes is not offered because it is not clinically available.
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 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 (Genetic Testing; pdf).
DNA banking. 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. DNA banking is particularly relevant in situations in which molecular genetic testing is available on a research basis only or when the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk for CMT2A2, CMT2B, CMT2B1, CMT2D, CMT2E/1F, CMT2F, CMT2I, CMT2J, or CMT2K is available by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 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.
No laboratories offering prenatal testing for the other subtypes of CMT2 are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which a disease-causing mutation has been identified. For laboratories offering custom prenatal testing, see
.
Requests for prenatal testing for conditions such as CMT2 that 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 about prenatal testing to be the choice of the parents, careful 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) has/have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| 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 |
| 600287 | GLYCYL-tRNA SYNTHETASE; GARS |
| 600882 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B; CMT2B |
| 601472 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2D; CMT2D |
| 602195 | HEAT-SHOCK 27-KD PROTEIN 1; HSPB1 |
| 602298 | RAS-ASSOCIATED PROTEIN RAB7; RAB7 |
| 605588 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B1 |
| 605589 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2B2; CMT2B2 |
| 605995 | KINESIN FAMILY MEMBER 1B; KIF1B |
| 606071 | HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC |
| 606595 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2F |
| 606598 | GANGLIOSIDE-INDUCED DIFFERENTIATION-ASSOCIATED PROTEIN 1; GDAP1 |
| 607677 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2I |
| 607684 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2E |
| 607731 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2H |
| 607736 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2J |
| 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 |
| 609260 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2 |
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].
KIF1B
Normal allelic variants: KIF1B comprises 47 exons and 167.13 kb of DNA.
Pathologic allelic variants: A p.Gly98Leu mutation was reported in a single family [Zhao et al 2001]. See also Table A: locus-specific databases and HGMD.
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 microtubles.
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 ORF.
Pathologic allelic variants: Züchner, Vorgerd et al (2004) and Verhoeven et al (2006) have reported more than 25 missense mutations in MFN2. See also Table A: locus-specific databases and HGMD.
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: RAB7Ahas six exons and 87.9 kb of DNA.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD.
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: locus-specific databases and HGMD.
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 Allelic Disorders).
GARS
Normal allelic variants: GARS is a 40-kb gene with 17 exons.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD.
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: The NEFL gene contains four coding exons; the 5' UTRs are highly conserved.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD.
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
Normal allelic variants: HSPB1 contains three exons with a central HSP20-α-crystallin domain.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD.
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: The MPZ gene spans approximately seven kilobases and contains six exons.
Pathologic allelic variants: More than 56 point mutations in the MPZ gene have been reported [De Jonghe et al 1997, Nelis et al 1999]. More than 70% of the mutations are localized in exons 2 and 3 of the MPZ gene coding for the extracellular domain, indicating the functional importance of this domain (see Table A: locus-specific databases and HGMD).
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-nt ORF.
Pathologic allelic variants: See Table A: locus-specific databases and HGMD.
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
Normal allelic variants: HSPB8 has three exons and spans about 16 kb.
Pathologic allelic variants: Three mutations have been reported: c.423G>T, c.423G>C (p.Lys141Asn), and c.421A>G (p.Lys141Glu) [Irobi, Van Impe et al 2004; Tang et al 2005].
Normal gene product: HSPB8 (also called HSP22) is a phosphor protein that interacts with HSPB1.
Abnormal gene product: Mutations in HSPB8 interact with HSPB1 and form aggregates that may lead to dysfunctional axonal transport and dysregulation of the cytoskeleton [Irobi, Van Impe et al 2004].
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.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
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
