Charcot-Marie-Tooth Neuropathy Type 2

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Charcot-Marie-Tooth Neuropathy Type 2

[CMT2; Hereditary Motor and Sensory Neuropathy; HMSN2. Includes:

Charcot-Marie-Tooth Disease, Neuronal Type; Charcot-Marie-Tooth Disease, Axonal

Type; CMT2A; CMT2B; CMT2C; CMT2D; CMT2E]

Author:

D Bird, MD

University of Washington, Seattle

Last update:

25 August 2000

Last revision:

24 July 2001

Original posting:

24 September 1998

Summary

Disease characteristics. CMT type 2 is a non-demyelinating peripheral

neuropathy characterized by distal muscle weakness and atrophy, mild sensory

loss, and normal nerve conduction velocities. CMT2 is clinically similar to

CMT1, although typically less severe. Peripheral nerves are not enlarged or

hypertrophic. Several genetic subtypes have been identified by linkage analysis,

and the genes have been identified for CMT2A and CMT2E.

Diagnosis/testing. The diagnosis is based on clinical findings and EMG/NCV

characteristics. Molecular genetic testing is available for CMT type 2 only.

Genetic counseling. CMT2 is inherited in an autosomal dominant manner. Most

probands with CMT2 have inherited the disease-causing mutation from an affected

parent. The offspring of an affected individual have a 50% risk of inheriting

the altered gene. Prenatal testing is not possible.

Diagnosis

The diagnosis of CMT2 is based on clinical findings and family history.

Molecular genetic testing of CMT2A, 2B, 2C, and 2D is available on a research

basis only. Molecular genetic testing of CMT2E is available on a clinical basis.

Clinical Diagnosis

CMT type 2 is diagnosed in patients with:

A progressive peripheral motor and sensory neuropathy

Normal or near-normal nerve conduction velocities (NCV)

Abnormal EMG with such findings as positive waves, polyphasic potentials, or

fibrillations and reduced amplitudes of evoked motor and sensory responses [Dyck

et al 1993, Nicholson 1991, Dyck et al 1994].

A family history consistent with autosomal dominant inheritance.

Testing

Nerve conduction velocities are usually within the normal range, although

occasionally they fall in the low normal or mildly abnormal range as noted above

[Dyck et al 1993, Saito et al 1997].

EMG testing shows evidence of an axonal neuropathy.

Nerve biopsies do not show hypertrophy or onion bulb formation but instead show

loss of myelinated fibers with signs of regeneration and atrophic axons with

neurofilaments [berciano 1986, Ono 1993].

Molecular Genetic Testing

The five subtypes of CMT2 are identical clinically and are distinguished solely

on genetic linkage findings. The chromosomal loci for CMT2A, CMT2B, and CMT2D

have been mapped, and the genes for CMT2A (KIF1B) and CMT2E

(neurofilament-light, NF-L) have been identified [Mersiyanova et al 2000, De

Jonghe 2001, Zhao et al 2001]. DNA-based testing is available on a clinical

basis for CMT2E. The frequencies of the various types of CMT2 are unknown and no

single type is known to predominate [Timmerman et al 1996]. CMT2C refers to two

families with autosomal dominant axonal neuropathy associated with frequent

vocal cord and phrenic nerve paralysis sometimes requiring tracheotomy [Dyck et

al 1994]. The condition does not link to the CMT2A or CMT2B loci.

Table 1. Molecular Genetic Testing of CMT2

Subtype of CMT2

% of Patients

Genetic Mechanism

Test Availability

CMT2A

Unknown

Mutation of KIF1Bß

Research

CMT2B

Unknown

CMT2C

CMT2D

CMT2E

Mutation of NF-L

Clinical [GeneTests]

Clinical Description

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

typical patient 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. Nerve conduction velocities (NCVs) are normal or mildly slow

(30-40m/s). The clinical syndrome overlaps extensively with CMT1. In general,

the patients with CMT2 (except for those with CMT2B) tend to be less disabled

and have less sensory loss than those with CMT1.

Patients usually become symptomatic between ages five and 25 years [berciano

1986, et al 1995, Saito 1997]. However, the range extends from earlier

onset with delayed walking in infancy onset 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 typical adult patient has bilateral foot drop,

symmetrical atrophy of muscles below the knee (stork leg appearance) and absent

tendon reflexes in the lower extremities. Atrophy of intrinsic hand muscles is

less frequent and tendon reflexes may be intact in the upper limbs [Dyck et al

1993]. Proximal muscles usually remain strong. Mild sensory loss including

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%

of patients.

A few patients have vocal cord or phrenic nerve involvement resulting in

difficulty with voice or breathing. CMT2 is progressive over many years, but

patients experience long plateau periods without obvious deterioration. In some,

the disease can be so mild as to go unrecognized by patient and physician. The

disease does not decrease life span.

CMT2B has prominent sensory loss with distal ulceration; controversy exists

regarding its exact classification [DeJonghe et al 1997, Elliott et al 1997].

The genetic locus is 3q13-q22 and additional phenotype information is described

by Auer-Grumbach et al (2000).

CMT2C is associated with vocal chord and phrenic nerve paralysis [Dyck 1994].

CMT2D has prominent weakness and atrophy of the hands [ionasescu et al 1996].

CMT2C refers to two families with autosomal dominant axonal neuropathy

associated with frequent vocal cord and phrenic nerve paralysis sometimes

requiring tracheotomy [Dyck et al 1994].

CMT2D is characterized by predominately distal motor weakness with wasting of

the hand muscles [ionasescu et al 1996]. This phenotype is similar to that of

hereditary motor neuropathy type 5 (HMN V) and the two disorders may be allelic

[sambuughin et al 1998].

CMT2E has been reported in two families, one from Russia and one from Belgium,

with a progressive sensory and motor neuropathy. The Russian family had

relatively normal NCV and hyperkeratosis [Merisyanova 2000]. The Belgian family

had NCVs ranging from 25 to 42 m/s [De Jonghe 2001].

-Bigas et al (2001) have described an autosomal dominant neuropathy

associated with hearing impairment caused by a mutation in the connexin 31 (GJB3

) gene. Although the sural nerve pathology showed demyleination compatible with

CMT1, the nerve condition velocities were not markedly slow and might suggest a

clinical diagnosis of CMT2.

Neuropathology. The disease process is presumed to be occurring in the axon or

cytoplasm of the anterior horn cell neuron and anterior horn cell loss has been

found in two reported autopsies [berciano 1986, Ono 1993].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known. Mutations have been reported in

the neurofilament-light gene in a Russian family and this has been designated

CMT2E. Some members of this family have hyperkeratosis, but it is not certain if

that represents a coincidence or variable expression of the CMT2E phenotype

[Mersiyanova et al 2000]. A Belgian family with a mutation in the NF-L gene has

NCV that overlap both axonal and demyelinating phenotypes [DeJonghe 2001].

Deafness and papillary changes in some families with specific MPZ mutations have

been reported (see Differential Diagnosis and Chapon et al 1999, Misu et al

2000).

Prevalence

The overall prevalence of hereditary neuropathies is estimated to be

approximately 30 per 100,000 population. About 30% of these cases may be CMT

type 2 (10 per 100,000). The prevalences of the various subtypes of CMT type 2

are unknown. CMT2A was the first to have a linkage assignment to chromosome Ip

and an additional large Italian family with this subtype has been reported

[Muglia 2001].

Differential Diagnosis

It is always important to exclude potential causes of acquired neuropathy (see

CMT Overview).

CMT2 can sometimes be difficult to distinguish from CMT1 and CMTX [Timmerman

1996] and from chronic idiopathic axonal neuropathy [Teunissen 1997].

The CMT2 phenotype with only mild slowing of NCV is sometimes caused by

mutations in myelin P 0 (MPZ), which typically cause CMT1B, including a single

mutation that has occurred in several families (Thr124Met) [senderak et al

2000]. The same mutation has also been associated with the CMT2 phenotype with

deafness and Argyll on pupils [Chapon et al 1999]. Misu et al (2000) have

reported an axonal (CMT2) phenotype with marked sensory impairment and often

with Adie's pupil and deafness with the T124M or D75V mutations.

The CMT2 phenotype can also occur in families with CMTX (connexin-32 mutations),

but such families do not show male-to-male transmission [Gutierrez et al 2000].

Another form of dominant motor and sensory neuropathy from Okinawa has been

mapped to 3q13 [Takashima et al 1997, 1999]. The relationship of this entity to

CMT2B linked to a similar region is undetermined.

There are several different types of autosomal dominant hereditary axonal

neuropathies that may cause predominantly sensory symptoms, including a family

with the " burning feet syndrome " [stogbauer et al 1999].

Management

No treatment for CMT that reverses or slows the natural disease process exists.

Treatment is symptomatic and patients are often evaluated and managed by a

multidisciplinary team that includes neurologists, physiatrists, orthopedic

surgeons, and physical and occupational therapists [ et al 1995]. Daily

heel cord stretching exercises to prevent Achilles' tendon shortening are

desirable. Special shoes, including those with good ankle support, may be

needed. Patients often require ankle/foot orthoses (AFO) to correct foot drop

and aid walking [Dyck et al 1994, et al 1995]. Orthopedic surgery may be

required to correct severe pes cavus deformity. Some patients require forearm

crutches or canes for gait stability, but less than 5% of patients need

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

Exercise is encouraged within the patient's capability and many individuals

remain physically active. Important career and employment implications may exist

because of the persistent weakness of hands and/or feet. Drugs and medications

such as vincristine, isoniazid, and nitrofurantoin that are known to cause nerve

damage should be avoided [Graf et al 1996].

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 or cultural issues that individuals may face or to

substitute for consultation with a genetics professional. To find a genetics or

prenatal diagnosis clinic, see [clinic directory] . —ED.

Mode of Inheritance

CMT2 is inherited in an autosomal dominant manner.

Risk To Family Members

Parents of a proband. Most individuals with CMT2 will have inherited the gene

from an affected parent. It is appropriate to evaluate the parents of an

individuals with CMT2 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. Occasionally neither parent will show signs of

the disorder. Reasons for this include failure to recognize mild symptoms in a

parent who has the mutated gene, early death of a parent before the onset of

symptoms, late onset of the disease in the affected parent, a new gene mutation

in the proband, non disclosure of adoption and false paternity.

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 is 50%.

Offspring of a proband. Affected individuals have a 50% chance of passing the

altered CMT2 gene on to each offspring.

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 have a

disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

Testing at-risk asymptomatic adults. Asymptomatic adults at risk of having

inherited a CMT2 gene 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

children at risk who are asymptomatic is not appropriate. (See also the National

Society of Genetic Counselors statement 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. DNA banking is the storage of DNA that has been extracted from

white blood cells for possible future use. Since it is likely that testing

methodologies and our understanding of genes, mutations, and diseases will

improve in the future, consideration should be given to banking DNA

particulately when:

Molecular genetic testing is not available. For example, the disease-causing

mutation in a family has not yet been elucidated or testing is available on a

research or linkage basis only.

Interpretation of results is difficult. For example, if an affected family

member chooses not to be tested, interpretation of a " negative " result in

at-risk family members is difficult. An affected family member who chooses not

to be tested may be willing to have DNA banked for future use by other family

members.

For laboratories offering DNA banking, see [GeneTests] .

Prenatal Testing

Prenatal testing for CMT2 is not available.

Molecular Genetics

Table 2. Molecular Genetics of CMT2 Disease Name Gene Symbol Locus Normal Gene

Product Genomic

Databases

CMT2A CMT2A 1p36-p35 KIF1Bß [OMIM] [LocusLink]

[GeneCards] [GenAtlas] [GDB] [CMT]

CMT2B CMT2B 3q13-q22 [OMIM] [LocusLink]

[GeneCards] [GenAtlas] [GDB]

CMT2C CMT2C ?

CMT2D CMT2D 7p15 [OMIM] [LocusLink]

[GeneCards] [GenAtlas] [GDB]

CMT2E CMT2E 8p21 NF-L

CMT2A links to chromosome 1p [ben Othmane et al 1993 ]. The gene for CMT2A is

KIF1Bß, which codes for a kinesin molecular motor protein involved in axonal

transport of synaptic vesicle precursors [Zhao et al 2001]. CMT2B links to 3q

[De Jonghe et al 1997, Auer-Grumbach et al 2000], and CMT2D links to 7p

[ionasescu et al 1996, Sambuughin et al 1998 ]. CMT2C refers to two families

with autosomal dominant axonal neuropathy associated with frequent vocal cord

and phrenic nerve paralysis sometimes requiring tracheotomy [Dyck et al 1994].

The condition does not link to the CMT2A or CMT2B loci. Other families do not

show any of these linkage relationships and represent further genetic

heterogeneity within the CMT2 phenotype. One family with CMT2E has a mutation in

the first exon of the neurofilament-light gene (NF-L) [Mersiyanova et al 2000]

and another family have a double missence mutation also in the first exon [De

Jonghe et al 2001].

Resources

GeneClinics provides information about selected national organizations and

resources for the benefit of the reader. GeneClinics is not responsible for

information provided by other organizations. -ED.

CMT International

One Springbank Drive

St. Catharines, Ontario

Canada L2S 2K1

Phone: 905-687-3630

Fax: 905-687-8753

Email: cmtint@...

www.cmtint.org

Charcot-Marie-Tooth Association

2700 Chestnut Street

Chester, PA 19013-4867

Phone: 610-499-9264; 610-499-9265; 1-800-606-CMTA (2682)

Fax: 610-499-9247

Email: CMTAssoc@...

www.charcot-marie-tooth.org

NCBI Genes and Disease Webpage

www.ncbi.nlm.nih.gov/disease/Charcot.html

European Charcot-Marie-Tooth Consortium

Laboratory of Neurogenetics

University of Antwerp

B-2610 Antwerp, Belgium

Fax: 32-3-8202541

Email: gisele@...

Muscular Dystrophy Association - USA

3300 East Sunrise Drive

Tucson, AZ 85718-3208

Phone: 520-529-2000; 800-572-1717

Fax: 520-529-5300

Email: mda@...

www.mdausa.org

Muscular Dystrophy Campaign

7-11 Prescott Place

London SW4 6BS, UK

Phone: +44 (0) 171-720-8055

Fax: +44 (0) 171-498-0670

Email: info@...

www.muscular-dystrophy.org

References

Statements and Policies Regarding Genetic Testing

The National Society of Genetic Counselors (1995) Resolution on prenatal and

childhood testing for adult-onset disorders.

American Society of Human Genetics and American College of Medical Genetics

(1995) Points to consider : ethical, legal, and psychosocial implications of

genetic testing in children and adolescents.

[Past year only.] Articles on Charcot-Marie-Tooth Neuropathy

About GeneClinics Custom Searches

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Profile History

Author

D Bird, MD [AUTHOR SEARCH]

University of Washington, Seattle

About GeneClinics Medline Searches

Last Update/Revision

24 July 2001

Revision History

24 Jul 2001: Au revisions (ca)

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19 Jun 2001: Au revisions (CMT2A gene found) (ca)

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Copyright© 2001, University of Washington, Seattle

Funded by National Library of Medicine, National Human Genome Research

Institute, National Cancer Institute, and Office of Rare Diseases of the NIH

Administrative support from University of Washington, Seattle