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Charcot-Marie-Tooth Neuropathy Type 2A

Synonyms: CMT2A, HMSN2A, HMSNIIA, Hereditary and Motor Sensory Neuropathy IIA
, MD, PhD
Department of Human Genetics
University of Miami Miller School of Medicine
Miami, Florida

Initial Posting: ; Last Update: August 1, 2013.

Summary

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 or second decade. It has recently been suggested that CMT2A represents more than 90% of the severe dominant CMT2 cases. However, milder late-onset cases and unusual presentations have also been described.

Diagnosis/testing. The diagnosis is established by clinical and molecular genetic findings. MFN2 is the only gene in which mutations are known to cause CMT2A.

Management. Treatment of manifestations: Treatment by a team including a neurologist, physiatrist, orthopedic surgeon, and 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 (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage; alcohol and malnutrition (which 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 is possible if the disease-causing mutation has been identified in an affected family member.

Diagnosis

Clinical Diagnosis

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. However, in young and severely affected individuals with CMT2, MFN2 mutations are the most frequent cause of disease. 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
  • Motor deficits more prominent than sensory deficits
  • Normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs) [Saito et al 1997, Züchner et al 2004]
  • Onset before age ten years (however, a wide range of age of onset has been reported)

Molecular Genetic Testing

Gene. MFN2 is the only gene in which mutations are known to cause CMT2A.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Charcot-Marie-Tooth Neuropathy Type 2A

Gene 1Proportion of CMT2A Attributed to Mutations in This GeneTest MethodMutations Detected 2
MFN2Nearly 100%Sequence analysis 3 / mutation scanning 4Sequence variants
Sequence analysis of select exons 5Sequence variants in select exons
Deletion/duplication analysis 6Exon and whole-gene deletions/duplications 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably between laboratories depending on the specific protocol used.

5. Select exons may vary by laboratory.

6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

7. Polke et al [2011]

Testing Strategy

To confirm/establish the diagnosis in a proband, identification of a disease-causing mutation in MFN2 is necessary.

1.

MFN2 sequence analysis should be performed first. If no disease-causing mutation is found by sequence analysis, deletion/duplication analysis of MFN2 should be considered.

2.

If no disease-causing mutation in MFN2 is identified by deletion/duplication analaysis, iterative molecular genetic testing strategies have been suggested for CMT based on extensive genetic testing results [Saporta et al 2011].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

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 or 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 could 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 Chung et al [2006] and Verhoeven et al [2006].

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].

Genotype-Phenotype Correlations

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]. Some rare families with recessive compound heterozygous changes in MFN2 have been reported which all showed early onset of disease [Polke et al 2011]. Individuals with optic atrophy (HMSN VI) tend to show a more severe phenotype; several of these individuals were found to have a de novo mutation [Züchner et al 2006].

Penetrance

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].

Anticipation

While some authors have considered the possibility of anticipation in CMT2A, it has not been reported [Muglia et al 2001].

Nomenclature

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] (see Genetically Related Disorders).

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.

Prevalence

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.
  • Feely et al [2011] reported that CMT2A accounted for 91% of severely impaired individuals with CMT2 but only 11% of mildly or moderately impaired people.
  • The majority of reported cases of optic atrophy associated with the CMT2A phenotype (previously called HMSN VI) resulted from de novo MFN2 mutations.

Differential Diagnosis

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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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
  • Medical genetics consultation

Treatment of Manifestations

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

Surveillance

Annual neurologic evaluation of gait, strength, and visual acuity is appropriate.

Agents/Circumstances to Avoid

Obesity is to be avoided because it makes walking more difficult.

Medications that are toxic or potentially toxic to persons with CMT comprise a range of risks including:

  • Definite high risk. Vinca alkaloids (Vincristine)
    • This category should be avoided by all persons with CMT, including those who are asymptomatic
  • Other potential risk levels. See Table 2. For more information, click here (pdf).

Table 2. 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

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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy type 2A (CMT2A) is inherited an autosomal dominant manner.

Risk to Family Members

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 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. 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 on the status of the proband's parents. If a parent is affected, his or her family members are at risk.

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 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 maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in an affected family member, prenatal testing for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

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

Requests for prenatal testing for conditions which (like CMT2A) 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, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Association CMT France
    13 allée de Grèce
    35140 Saint Aubin du Cormier
    France
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    2700 Chestnut Street
    Chester PA 19013-4867
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
    Email: info@charcot-marie-tooth.org
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Belgium
    Fax: 03 2651002
    Email: gisele.smeyers@ua.ac.be
  • Hereditary Neuropathy Foundation, Inc.
    1751 2nd Avenue
    Suite 103
    New York NY 10128
    Phone: 877-463-1287 (toll-free); 212-722-8396
    Email: info@hnf-cure.org
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • TREAT-NMD
    Institute of Genetic Medicine
    University of Newcastle upon Tyne
    International Centre for Life
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Phone: 44 0 191 241 8605
    Fax: 44 0 191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry 91002
    France
    Phone: +33 01 69 47 28 28
    Fax: 01 69 47 77 12 16
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    JN Baarn 3743
    Netherlands
    Phone: 035 54 80 481
    Fax: 035 54 80 499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    3300 East Sunrise Drive
    Tucson AZ 85718
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy Campaign
    61 Southwark Street
    London SE1 0HL
    United Kingdom
    Phone: 0800 652 6352 (toll-free); +44 0 020 7803 4800
    Email: info@muscular-dystrophy.org
  • RDCRN Patient Contact Registry: Inherited Neuropathies Consortium

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 2A: Genes and Databases

Locus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CMT2A2MFN21p36​.22Mitofusin-2MFN2 homepage - Leiden Muscular Dystrophy pages
IPN Mutations, MFN2
MFN2

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Charcot-Marie-Tooth Neuropathy Type 2A (View All in OMIM)

608507MITOFUSIN 2; MFN2
609260CHARCOT-MARIE-TOOTH DISEASE, AXONAL, TYPE 2A2; CMT2A2

Molecular Genetic Pathogenesis

The disease mechanism leading to CMT is unknown.

MFN2

Gene structure. MFN2 has 17 exons and 4,546 nucleotides in the open reading frame. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic 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].

Larger insertions and duplications are not known to be involved in CMT2A, but could represent rare mutational mechanisms.

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.

References

Literature Cited

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Suggested Reading

  1. Lupski JR, Garcia CA. Charcot-Marie-Tooth Peripheral Neuropathies and Related Disorders. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). Chap 227. New York, NY: McGraw-Hill. Available online. 2014. Accessed 6-24-14.

Chapter Notes

Revision History

  • 1 August 2013 (me) Comprehensive update posted live
  • 10 June 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
  • 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
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