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GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
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.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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.
Disease characteristics. Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) is a classic axonal peripheral sensorimotor neuropathy characterized by earlier and more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Most affected individuals develop symptoms in the first orf second decade. Although some individuals become dependent on crutches or a wheelchair, most do not.
Diagnosis/testing. The diagnosis is established by clinical and molecular genetic findings. MFN2, associated with the subtype CMT2A2, is the major gene known to be associated with CMT2A. KIF1B is associated with the subtype CMT2A1. Molecular genetic testing of both genes is available on a clinical basis.
Management. Treatment of manifestations: treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses 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; acetaminophen or nonsteroidal anti-inflammatory agents for musculoskeletal pain; treatment of neuropathic pain with tricyclic antidepressants or drugs like carbamazepine or gabapentin. Surveillance: annual neurologic evaluation of gait, strength, and visual acuity. Agents/circumstances to avoid: obesity (makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage; alcohol and malnutrition (can cause or exacerbate neuropathy). Other: career/employment counseling.
Genetic counseling. CMT2A is inherited in an autosomal dominant manner. Most individuals diagnosed with CMT2A have an affected parent. The proportion of cases caused by de novo mutations is unknown. Each child of an individual with CMT2A has a 50% chance of inheriting the mutation. Prenatal diagnosis for pregnancies at increased risk for CMT2A caused by MFN2 mutations is possible if the disease-causing mutation has been identified in an affected family member; prenatal diagnosis for pregnancies at risk for CMT2A caused by KIF1B mutations may be available through laboratories offering custom prenatal testing if the disease-causing mutation has been identified in an affected family member.
Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) is a classic axonal peripheral sensorimotor neuropathy diagnosed by molecular genetic testing of MFN2.
No specific findings distinguish CMT2A from other types of CMT2. Typical findings include the following:
Involvement of the lower extremities earlier and more severely than the upper extremities
Involvement of the distal upper extremities as the neuropathy progresses
More prominent motor deficits than sensory deficits
Normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs) [Saito et al 1997, Züchner et al 2004]
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.
Gene. MFN2 is the primary gene known to be associated with CMT2A.
Other genes. It is possible (though at present highly unlikely) that the gene KIF1B is involved in rare families with CMT2A1. The KIF1B gene is in the same chromosomal locus as MFN2. In a single family from Japan, a functionally significant mutation in the KIF1B gene segregates with the clinical phenotype; of note, studies of MFN2 in this family were inconclusive [Zhao et al 2001]. However, a mutation in KIF1B was not confirmed in a second family [Bissar-Tadmouri et al 2004, Züchner et al 2004].
Clinical testing
MFN2. Sequence analysis detects a mutation in nearly 100% of individuals with CMT2A2.
KIF1B. Except for the original single family reported, no family or individual has been reported with a KIF1B mutation [Zhao et al 2001].
Table 1 summarizes molecular genetic testing for this disorder.
| Test Method | Mutations Detected | Proportion of CMT2A Attributed to Mutations in This Gene | Mutation Detection Frequency 1 | Test Availability |
|---|---|---|---|---|
| Sequence analysis | MFN2 sequence variants | Nearly 100% | Nearly 100% | Clinical
 |
| KIF1B sequence variants | Rare | Unknown | Clinical
|
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To establish the diagnosis in a proband, identification of a disease-causing mutation in MFN2 or KIF1B is necessary.
Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
MFN2. No phenotypes other than the CMT2A2 phenotype discussed in Clinical Description have been associated with mutations in MFN2.
KIF1B. No phenotypes associated with mutation in KIF1B have been reported other than that described in the one family found to have this mutation [Zhao et al 2001].
The age at onset and disease progression of Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) vary within and among families; onset ranges from age one year to the sixth decade. Most individuals develop symptoms in the first orf second decade. The initial finding is often foot drop or foot weakness. Pes cavus foot deformity may occur.
Motor signs (weakness and atrophy) predominate, but mild sensory loss in the feet is common. Tendon reflexes are usually absent, but occasionally intact.
Some individuals with MFN2 mutations are asymptomatic and have only mild findings on examination; however, those might eventually convert to late-onset cases [Lawson et al 2005].
Postural tremor is common [Muglia et al 2001, Bissar-Tadmouri et al 2004].
Affected individuals with early onset (age <10 years) tend to have more severe disability than those with later onset [Chung et al 2006]. Those with early onset may show optic atrophy, hoarse voice, and proximal weakness. Subacute onset of optic atrophy with subsequent slow recovery in 60% of individuals with early onset was reported by Züchner et al (2006) and confirmed by Verhoeven et al (2006) and Chung et al (2006).
Note: The association of CMT2A and optic atrophy is also known as hereditary motor and sensory neuropathy VI (HMSN VI) (see Nomenclature).
CMT2 with pyramidal signs, also known as HMSN VII, has been associated with MFN2 mutations [Zhu et al 2005]. HMSN VII is characterized by an axonal CMT phenotype with mild pyramidal signs, including extensor plantar responses, mild increase in tone, and preserved or increased reflexes, but no spastic gait [Vucic et al 2003].
The disease course is progressive. Although some individuals become dependent on crutches or a wheelchair, most do not [Muglia et al 2001]. Life span is usually not reduced.
Neuroimaging. Periventricular and subcortical white matter lesions on brain MRI have been reported in a few individuals [Chung et al 2006, Züchner et al 2006].
Neuropathology. Neuropathologic findings include loss of myelinated nerve fibers, especially large fibers, mitochondrial abnormalities and, rarely, onion bulb formation [Saito et al 1997, Muglia et al 2001, Verhoeven et al 2006].
No apparent genotype-phenotype correlation has been reported except in one family in which truncation of the protein led to a more severe phenotype with visual impairment [Züchner et al 2006].
The penetrance is considered to be complete. Some individuals with MFN2 mutations are asymptomatic and have only mild findings on examination; in these cases, however, the disease may prove to be late onset [Lawson et al 2005].
While some authors have considered the possibility of anticipation in CMT2A, it has not been reported [Muglia et al 2001].
CMT2A is an axonal neuropathy (indicated by the number 2) and was the first CMT2 form to be linked to a chromosomal locus (indicated by the letter A).
In addition to the pure CMT2A phenotype, CMT2 with optic atrophy, also known as hereditary motor and sensory neuropathy VI (HMSN VI), has been reported in a number of individuals [Züchner et al 2006].
Chung et al (2006) suggested the division into "early-onset severe CMT2A phenotype" and "late-onset mild CMT2A phenotype" owing to MFN2 mutations. All reported persons with HMSN VI with MFN2 mutations had early-onset severe CMT2.
All reported persons with HMSN VI with MFN2 mutations had early-onset severe CMT2.
The proportion of CMT caused by mutations in MFN2 varies by study:
Züchner et al (2004) reported seven MFN2 mutations in 36 families with CMT2, indicating that 19.5% of CMT2 could be caused by mutations in this gene.
Chung et al (2006) reported that 24% of 62 families with CMT2 in South Korea had mutations in MFN2.
Verhoeven et al (2006) reported that 33% of families with CMT2 in a European/USA study had mutations in MFN2.
Engelfried et al (2006) reported that 8% (6/73) of persons with CMT2, including simplex cases (i.e., a single occurrence in a family), had MFN2 mutations.
The majority of reported cases of optic atrophy associated with the CMT2 phenotype (previously called HMSN VI) resulted from de novoMFN2 mutations.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
See Charcot-Marie-Tooth Hereditary Neuropathy Overview and Charcot-Marie-Tooth Hereditary Neuropathy Type 2.
All CMT forms in which axonal phenotypes have been reported, including CMT1A (caused by mutations in PMP22), CMT1B (caused by mutations in MPZ), and CMTX (caused by mutations in GJB1, the gene encoding the protein connexin 32), need to be considered in the differential diagnosis of CMT2A.
MFN2 mutations may prove to be the most common cause of autosomal dominant CMT2. As many as one-third of all individuals with CMT2 with a positive family history have a mutation in MFN2 [Verhoeven et al 2006]. Thus, testing of MFN2 is probably the first genetic test to consider in families with an axonal neuropathy demonstrating male-to-male transmission.
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A), the following evaluations are recommended:
Neurologic examination
EMG with NCV
Visual evoked potentials
The affected individual is often managed by a multidisciplinary team that includes a neurologist, physiatrist, orthopedic surgeon, and physical and occupational therapists [Carter et al 1995]. Treatment is symptomatic and may include the following:
Daily heel cord stretching exercises to prevent Achilles tendon shortening
Special shoes, including those with good ankle support
Ankle/foot orthoses to correct foot drop and aid walking [Carter et al 1995]
Orthopedic surgery to correct severe pes cavus deformity [Holmes & Hansen 1993, Guyton & Mann 2000]
Forearm crutches or canes for gait stability
Wheelchairs for mobility because of gait instability
Exercise within the individual's capability
Treatment of musculoskeletal pain with acetaminophen or nonsteroidal anti-inflammatory agents [Carter et al 1998]
Treatment of neuropathic pain with tricyclic antidepressants or drugs such as carbamazepine or gabapentin
Career and employment counseling because of persistent weakness of hands and/or feet
Annual neurologic evaluation of gait, strength, and visual acuity is appropriate.
The medications vincristine, Taxol®, cisplatin, isoniazid, and nitrofurantoin, which are known to cause nerve damage [Graf et al 1996, Chaudhry et al 2003]
Obesity, which can make walking more difficult
Alcohol and malnutrition, which can cause or exacerbate neuropathy
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Dyck et al (1982), Donaghy et al (2000), and Ginsberg et al (2004) have described a few individuals with CMT1 and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin has produced variable levels of improvement. No similar report on CMT2A exists.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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.
Charcot-Marie-Tooth hereditary neuropathy type 2A (CMT2A) is inherited in an autosomal dominant manner.
Parents of a proband
Most individuals diagnosed with CMT2A have an affected parent.
A proband with CMT2A may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown.
It is appropriate to evaluate the parents of an individual with CMT2A in order to determine which, if either, is symptomatic, both to assure appropriate medical management for that individual and for genetic counseling of the family.
Note: Although most individuals diagnosed with CMT2A 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 the 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. Each child of an individual with CMT2A 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, his or her family members are at risk.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, 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.
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 the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk for CMT2A caused by MFN2 mutations is possible 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 of an affected family member must be identified or linkage established in the family 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 molecular genetic testing for prenatal diagnosis for CMT2A caused by KIF1B mutations are listed in the GeneTests Laboratory Directory. However, prenatal testing may be available for families in which the 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 perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
| Locus Name | Gene Symbol | Chromosomal Locus | Protein Name |
|---|---|---|---|
| CMT2A1 | KIF1B | 1p36.2 | Kinesin-like protein KIF1B |
| CMT2A2 | MFN2 | 1p36.2 | Mitofusin-2 |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
| 118210 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A1; CMT2A1 |
| 605995 | KINESIN FAMILY MEMBER 1B; KIF1B |
| 608507 | MITOFUSIN 2; MFN2 |
| 609260 | CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2 |
| Gene Symbol | Locus Specific | Entrez Gene | HGMD |
|---|---|---|---|
| KIF1B | KIF1B | 23095 (MIM No. 605995) | KIF1B |
| MFN2 | MFN2 | 9927 (MIM No. 608507) | MFN2 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
The disease mechanism leading to CMT is unknown.
Normal allelic variants: MFN2 has 17 exons and 4,546 necleotides in the open reading frame.
Pathologic allelic variants: To date, more than 50 mutations have been reported. The majority were missense muations; frameshift and nonsense mutations have also been reported [Züchner et al 2004, Verhoeven et al 2006].
Normal gene product: MFN2 encodes a large GTPase of 757 amino acids that is situated at the outer mitochondrial membrane [Rojo et al 2002]. It has been shown that MFN2 accounts for the fusion/fission balance of mitochondria [Santel & Fuller 2001]. Recently, evidence for direct involvement of MFN2 in fusion of mitochondria has been reported [Koshiba et al 2004]. The gene is ubiquitously expressed [Santel & Fuller 2001].
Abnormal gene product: Most mutations are in the GTPase domain, but other parts of the protein are also affected. The GTPase domain may be crucial for the development of peripheral neuropathy. Mutations may affect both mitochondrial fusion and energy metabolism [Pich et al 2005]. Baloh et al (2007) reported altered axonal mitochondrial transport resulting from CMT2A-related MFN2 mutations.
Normal allelic variants: KIF1B has 41 exons. It encodes at least two major splice variants, KIF1Bα and KIF1Bβ. The gene consists of 10,551 nucleotides in an open reading frame.
Pathologic allelic variants: One pathogenic mutation, p.Gln98Leu, segregating in a small pedigree, has been reported [Zhao et al 2001].
Normal gene product: The protein has 1,770 amino acids and belongs to the kinesin super-family of large motor proteins. These proteins carry organelles (e.g., vesicles, mitochondria) along microtubules within axons of nerves. Knockout mice develop symptoms comparable to a peripheral neuropathy [Zhao et al 2001].
Abnormal gene product: Vero cells transfected with the p.Gln98Leu mutant showed reduced transport of KIF1B to the periphery of the cells. Knockout mice developed a phenotype consistent with peripheral neuropathy.
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select
for the most up-to-date Resources information.—ED.
Charcot-Marie-Tooth Association
2700 Chestnut Street
Chester PA 19013-4867
Phone: 800-606-CMTA (800-606-2682); 610-499-9264; 610-499-9265
Fax: 610-499-9267
Email: info@charcot-marie-tooth.org
www.charcot-marie-tooth.org
European Charcot-Marie-Tooth Consortium
Department of Molecular Genetics
University of Antwerp
Antwerp B-2610
Belgium
Fax: 03 2651002
Email: gisele.smeyers@ua.ac.be
The Hereditary Neuropathy Foundation
1751 2nd Ave Suite 103
New York NY 10128
Phone: 877-463-1287; 212-722-8396
Email: email: info@hnf-cure.org
www.hnf-cure.org
European Neuromuscular Centre (ENMC)
Lt. Gen. van Heutszlaan 6
3743 JN Baarn
Netherlands
Phone: 035 54 80 481
Fax: 035 54 80 499
Email: info@enmc.org
www.enmc.org
Muscular Dystrophy Association (MDA)
3300 East Sunrise Drive
Tucson AZ 85718-3208
Phone: 800-FIGHT-MD (800-344-4863); 520-529-2000
Fax: 520-529-5300
Email: mda@mdausa.org
www.mdausa.org
Muscular Dystrophy Campaign
7-11 Prescott Place
SW4 6BS
United Kingdom
Phone: (+44) 0 020 7720 8055
Fax: (+44) 0 020 7498 0670
Email: info@muscular-dystrophy.org
www.muscular-dystrophy.org
National Library of Medicine Genetics Home Reference
Charcot-Marie-Tooth disease
NCBI Genes and Disease
Charcot-Marie-Tooth syndrome
Teaching Case-Genetic Tools
Cases designed for teaching genetics in the primary care setting.
Case 7. Resident Receives a Troubling Phone Call about Peripheral Neuropathy from a Patient's Relative
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
12 September 2007 (me) Comprehensive update posted to live Web site
23 January 2006 (cd) Revision: prenatal diagnosis for MFN2 mutations clinically available
18 February 2005 (me) Review posted to live Web site
13 September 2004 (sz) Original submission
