Clinical Diagnosis

Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is diagnosed in males and females with the following:

• Peripheral motor and sensory neuropathy
• Slow nerve conduction velocities (NCVs). NCVs range from nearly normal (>40 m/s) to moderately slow, often in the 23-40 m/s range [Hattori et al 2003, Karadima et al 2006]. NCV can vary from nerve to nerve in a single individual [Gutierrez et al 2000]. NCVs can also vary significantly within and between families. Electrophysiologic findings support evidence of a primary axonal neuropathy with demyelinating features.
• A disease-causing mutation in GJB1 (encoding the protein connexin 32) and/or a family history consistent with X-linked inheritance, i.e., no male-to-male inheritance

Molecular Genetic Testing

Gene. GJB1 is the only gene known to be associated with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1).

Clinical testing

• Sequence analysis
  • Sequence analysis is used to detect mutations in the GJB1 coding region, which account for about 90% of mutations in individuals with CMTX1.
  • Deletions of the entire GJB1 coding region have been documented in rare cases [Nakagawa et al 2001] and may be detectable in males by sequence analysis; whole-gene deletions are not detectable in females by sequence analysis.
• Deletion/duplication analysis. Complete deletions of the entire coding region of GJB1 are rare and testing is only available from a few laboratories [Ainsworth et al 1998, Takashima et al 2003]. No duplications of this gene have been reported.

Table 1. Summary of Molecular Genetic Testing Used in CMTX1

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Affected Males	Carrier Females
GJB1	Sequence analysis	Sequence variants 2	90% 3	See footnote 4	Clinical
	Deletion / duplication analysis 5	Partial- and whole-gene deletions	Rare	Rare

Test Availability refers to availability in the GeneTests™ Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests™ Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.

3. In affected males, lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome; confirmation may require additional testing by deletion/duplication analysis.

4. In carrier females, sequence analysis of genomic DNA cannot detect deletion of an exon(s) or a whole gene on the X chromosome.

5. 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. See CMA.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To establish the diagnosis in a proband. Clinical findings and molecular genetic testing are the basis of diagnosis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.

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.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are associated with mutations in GJB1.

Natural History

Males with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) have a progressive peripheral motor and sensory neuropathy that tends to be more severe than that seen in CMT1A. Females with CMTX1 may be normal (but with abnormal EMG/NCV), or, more often, have mild to moderate signs and symptoms that may progress [Bone et al 1997, Mazzeo et al 2008, Hyman et al 2009]. Clinical manifestations can vary considerably, even within families. Symptoms typically develop between age five and 25 years, with onset commonly within the first decade in males. Earlier onset with delayed walking in infancy as well as later onset in the fourth and subsequent decades can occur. In some, the disease can be extremely mild and go unrecognized by the affected individual and physician.

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 affected adult has bilateral foot drop, symmetrical atrophy of muscles below the knee (stork leg appearance), pes cavus, atrophy of intrinsic hand muscles, especially the thenar muscles of the thumb, and absent tendon reflexes in both upper and lower extremities. Proximal muscles usually remain strong. Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet.

CMTX1 is progressive over many years, but individuals experience long plateau periods without obvious deterioration [Shy et al 2007]. Life span is not decreased.

Hearing loss is occasionally reported and auditory evoked potentials may be abnormal [Bahr et al 1999, Stojkovic et al 1999, Lee et al 2002, Takashima et al 2003].

Occasional signs of central nervous system involvement have been reported, including extensor plantar responses [Marques et al 1999, Kassubek et al 2005] and involvement of the cerebellum [Kawakami et al 2002]. A female with CNS white matter involvement has been reported [Basri et al 2007].

Paulson et al [2002] described two individuals with CMTX1 with transient ataxia, dysarthria, and weakness at altitudes greater than 8,000 feet. Schelhaas et al [2002] described similar phenomena during a febrile illness and also hyperventilation [Srinivasan et al 2008]. Hanemann et al [2003] and Taylor et al [2003] reported transient and recurrent CNS symptoms including weakness and aphasia associated with white matter abnormalities on MRI. The findings sometimes mimic multiple sclerosis [Isoardo et al 2005]. Persistent dysarthria and ataxia have been reported [Siskind et al 2009].

Delayed central somatosensory evoked potentials and reduced cerebellar blood flow on SPECT analysis have been reported [Kawakami et al 2002].

Histology rarely reveals nerve hypertrophy or onion bulb formation. Prominent demyelination consistent with a CMT1 phenotype can be found in some cases, whereas most affected individuals appear to have a primary axonal neuropathy with axonal sprouting [Tabaraud et al 1999, Lewis 2000, Hahn et al 2001, Vital et al 2001, Hattori et al 2003].

Pathophysiology. Connexin 32 is found in both the central and the peripheral nervous systems.

Genotype-Phenotype Correlations

A number of genotype-phenotype correlations have been noted:

• Males with a nonsense GJB1 mutation have earlier onset and a more severe phenotype than males with a missense mutation.
• A few families with deletions (null mutations) of GJB1 have been reported. They have a typical CMTX1 phenotype without more severe findings [Ainsworth et al 1998, Nakagawa et al 2001, Takashima et al 2003].
• Episodic generalized weakness has been reported with a p.Thr55Ile GJB1 mutation [Panas et al 2001].
• Central visual, acoustic, and motor pathway involvement has been reported in families with p.Asn205Ser and p.Val139Met GJB1 mutations [Bahr et al 1999, Halbrich et al 2008].
• The p.Arg15Trp mutation has been associated with prominent symptoms and signs of neuropathy in females with moderately slow NCV [Wicklein et al 1997].
• The p.Ser49Pro mutation has been associated with progressive and marked slowing of NCV [Street et al 2002]. The mutations p.Leu76CysfsX8 and p.Cys179Tyr mutations have been associated with early onset and severe weakness [Braathen et al 2007].
• Deafness has been reported in individuals with p.Val63Ile and p.Glu186Lys GJB1 mutations [Takashima et al 2003].
• Protein p.Arg75Trp and several other mutations such as p.Glu41Asp are associated with CNS symptoms [Taylor et al 2003, Murru et al 2006].
• An intermediate phenotype with late onset and a p.Thr191_Phe193dup (9-bp GJB1 insertion) has been reported by Vazza et al [2006].
• A female with severe neuropathy had a p.Val136Ala mutation in GJB1 and a p.Arg359Trp (c.1075C>T) mutation in EGR2 (reference sequence NP_000390.2) [Chung et al 2005].
• A girl with a p.Phe235Cys GJB1 mutation had severe neuropathy and leaky Cx32 hemichannels [Liang et al 2005].

Penetrance

Penetrance is complete in males with GJB1 mutations.

Nomenclature

CMT used to be called peroneal muscular atrophy. It may also be referred to as hereditary motor/sensory neuropathy (HMSN).

Prevalence

The overall prevalence of hereditary neuropathies is estimated at 30:100,000 population. More than half of these cases are CMT type 1 (15:100,000).

CMTX1 represents at least 10%-20% of those with the CMT neuropathy.

• In studies of unrelated individuals with CMT, Boerkoel et al [2002] found GJB1 mutations in 7% (11/153) and Szigeti et al [2006] in 8%.
• Dubourg et al [2001] found GJB1 mutations in 44% of families with CMT and NCV in the 30-40 m/s range.
• A large study of a Spanish CMT population has been reported [Casasnovas et al 2006].
• 19.3% of 114 Italians with CMT1 (excluding CMT1A) and CMT2 had GJB1 mutations [Mandich et al 2008].

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), the following evaluations are recommended:

• Physical examination to determine extent of weakness and atrophy, pes cavus, gait stability, and sensory loss
• NCV to determine axonal, demyelinating, or mixed features
• Detailed family history

Treatment of Manifestations

Treatment is symptomatic and affected individuals are often evaluated and managed by a team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists.

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

Affected individuals often require ankle/foot orthoses (AFO) to correct foot drop and aid walking.

Orthopedic surgery may be required to correct severe pes cavus deformity.

Some individuals require forearm crutches or canes for gait stability; fewer than 5% need wheelchairs.

Exercise is encouraged within the affected individual's capability, and many remain physically active.

Prevention of Primary Manifestations

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

Prevention of Secondary Complications

Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.

Surveillance

Regular foot examination for pressure sores or poorly fitting footwear is appropriate.

Agents/Circumstances to Avoid

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

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

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

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Other

Career and employment choices may be influenced by persistent weakness of hands and/or feet.

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is inherited in an X-linked dominant manner.

Risk to Family Members

Parents of a male proband

• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
  • A mother who is a carrier may have a de novo gene mutation or she may have inherited the disease-causing mutation either from her mother or from her father.
• The father of an affected male will neither have the disease nor be a carrier of the mutation.
• Five to ten percent of affected males have no family history of CMTX1. If pedigree analysis reveals that the proband is the only affected family member, five possible genetic explanations exist and it is appropriate to test the proband's mother and her relatives to determine risks to family members. Possible explanations:
  • The mother is not a carrier and the proband has a de novo mutation. In this instance, the proband's mother does not have a gene mutation and the only other family members at risk are the offspring of the proband. De novo mutations are unusual in CMTX1 but have been reported. Dubourg et al [2001] estimated that 5% of cases represented de novo mutations [Boerkoel et al 2002].
  • The affected individual's mother has a de novo disease-causing mutation that occurred in one of the following ways:
    • As a germline mutation, i.e., present in the egg or sperm at the time of her conception, and thus present in every cell of her body and detectable in her DNA; or
    • As a somatic mutation, i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism, in which the mutation is present in some but not all cells and may or may not be detectable in her DNA; or
    • As germline mosaicism in which some germ cells have the mutation and some do not, and in which the mutation is not detectable in DNA extracted from leukocytes. Germline mosaicism has not been reported in CMTX1, but it has been observed in many X-linked disorders and should be considered in the genetic counseling of at-risk family members.
  • The mother is a carrier of a mutation that occurred in a previous generation and was passed on silently for more than two generations.
• A woman has germline mosaicism if she has more than one affected son and the mutation found in the sons cannot be detected in DNA extracted from her leukocytes.

Parents of a female proband

• If the proband is a female and if pedigree analysis reveals that she is the only affected family member, it is reasonable to offer molecular genetic testing to both of her parents to determine risks to family members.
• If the proband's father is asymptomatic, it is possible, but not likely, that he has the mutation in some cells in his body (somatic mosaicism). If her father is asymptomatic and does not have somatic mosaicism for the altered gene, the possible genetic explanations for the origin of the proband's gene mutation are the same as for a male proband with a negative family history.

Sibs of a proband

• The risk to the sibs of a proband depends on the genetic status of the parents.
  • If the mother has a disease-causing mutation, the chance of transmitting the GJB1 mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and may or may not be affected.
  • If the father of a female proband is affected, all female sibs will inherit the mutation and may or may not be affected. None of the male sibs will inherit the mutation.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low but greater than that of the general population.
  • If the disease-causing mutation cannot be detected in the DNA of either parent of the proband, two possible explanations are germline mosaicism in a parent or a de novo mutation in the proband.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a male proband. Affected males transmit the mutation to all of their daughters and none of their sons.

Offspring of a female proband. Women with a GJB1 (Cx32) mutation have a 50% chance of transmitting it to each child; sons who inherit the mutation will be affected; daughters will have a range of possible phenotypic expression.

Other family members of a proband. If a parent of the proband also has a disease-causing mutation, his or her female family members may be at risk of being carriers (asymptomatic or symptomatic) and his or her male family members may be at risk of being affected depending on their genetic relationship to the proband.

Carrier Detection

Carrier testing for at-risk female relatives is possible if the disease-causing mutation in the family has been identified.

Related Genetic Counseling Issues

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. Testing of at-risk asymptomatic adults for CMTX1 is available using the techniques described in Molecular Genetic Testing. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals for CMTX1, an affected family member should be tested first to confirm that the disorder in the family is actually CMTX1. Because no treatment is available for individuals in the early stages of the disease, such testing is for personal decision making only.

Testing of at-risk asymptomatic individuals during childhood. Consensus holds that asymptomatic individuals at risk for adult-onset disorders who are younger than age 18 years should not have testing. See also the National Society of Genetic Counselors Position statement on genetic testing of minors for adult-onset condintions 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.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, 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, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member 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.

Requests for prenatal testing for typically adult-onset conditions such as CMTX1 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. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) of CMTX1 has been reported [Iacobelli et al 2003, Sharapova et al 2004] and may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Suggested Reading

1. Lupski JR, Garcia CA. Charcot-Marie-Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 227. Available online. Accessed 3-4-13.

Revision History

• 7 March 2013 (tb) Revision: addition to Differential Diagnosis - mutations in AIFM1 causative of CMTX4
• 14 February 2013 (tb) Revision: to include mutation in PDK3 as causative of CMTX6
• 29 March 2011 (tb) Revision: addition to Differential Diagnosis
• 27 May 2010 (cd) Revision: edits to Agents/Circumstances to Avoid
• 15 April 2010 (me) Comprehensive update posted live
• 6 September 2007 (tb) Revision: mutations in PRPS1 identified in individuals with CMTX5 (Differential Diagnosis)
• 26 June 2007 (me) Comprehensive update posted to live Web site
• 15 April 2005 (me) Comprehensive update posted to live Web site
• 23 February 2004 (cd) Revision: mutation scanning and mutation analysis
• 22 April 2003 (tb) Revision: Diagnosis and Clinical Description
• 10 April 2003 (me) Comprehensive update posted to live Web site
• 14 August 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
• 18 June 1999 (tb) Author revisions
• 12 October 1998 (tb) Author revisions
• 24 August 1998 (tb) Author revisions
• 18 June 1998 (pb) Review posted to live Web site
• April 1996 (tb) Original submission