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Charcot-Marie-Tooth Neuropathy X Type 1

Synonyms: CMTX1, GJB1-Related Charcot-Marie-Tooth Neuropathy
, MD
Seattle VA Medical Center
Departments of Neurology and Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Revision: March 7, 2013.

Summary

Disease characteristics. Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is characterized by a moderate to severe motor and sensory neuropathy in affected males and usually mild to no symptoms in carrier females. Sensorineural deafness and central nervous system symptoms also occur in some families.

Diagnosis/testing. Molecular genetic testing of GJB1 (Cx32) detects about 90% of cases of CMTX1.

Management. Treatment of manifestations: treatment by a team including a neurologist, physiatrist, orthopedic surgeon, and 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.

Prevention of secondary complications: Daily heel cord stretching to prevent Achilles' tendon shortening.

Surveillance: Regular foot examination for pressure sores.

Agents/circumstances to avoid: Obesity (makes ambulation more difficult); medications (such as vincristine, isoniazid, nitrofurantoin) known to cause nerve damage.

Genetic counseling. CMTX1 is inherited in an X-linked dominant manner. Affected males pass the altered gene to all of their daughters and none of their sons. Females who are carriers are at a 50% risk of passing the disease-causing mutation to each offspring. Sons who inherit the mutation will be affected; daughters who inherit the mutation may have mild to no symptoms. Prenatal testing is possible when the mutant allele has been identified in an affected family member; however, prenatal testing for typically adult-onset disorders is rarely requested.

Diagnosis

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

Table 1. Summary of Molecular Genetic Testing Used in CMTX1

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected MalesCarrier Females
GJB1Sequence analysis Sequence variants 290% 3See footnote 4
Deletion / duplication analysis 5Partial- and whole-gene deletionsRareRare

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.

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.

Clinical Description

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:

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.

Differential Diagnosis

Acquired (non-genetic) causes of peripheral neuropathy always need to be considered, particularly in simplex cases (i.e., an affected individual with no family history of CMT) (see CMT overview).

Because the clinical presentation of Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) can overlap with CMT1, CMT2, or HNPP, it is appropriate to test individuals with a motor and sensory neuropathy first for the PMP22 duplication that causes CMT1A because CMT1A is more common than CMTX1. Findings in CMTX1 can also be similar to those in CMT1B caused by mutations in MPZ [Young et al 2001]. The clinical findings in females with CMTX1 may be clinically indistinguishable from those found in CMT2 or HNPP. An example is a family with only three severely affected females (mother, daughter, and aunt) [Wicklein et al 1997]. Of note, families in which unequivocal male-to-male transmission of neuropathy occurs cannot have CMTX1.

Adrenomyeloneuropathy and Pelizeaus-Merzbacher disease are two rare X-linked disorders that may also be associated with peripheral neuropathy. Both conditions have central nervous system manifestations usually not seen in CMTX1.

Five other forms of hereditary neuropathy have been linked to markers on the X chromosome. Two of the genes in which mutation is causative have been identified (CMTX5 and CMTX6). Three of the five have other associated findings including intellectual disability, deafness, or optic neuropathy [Huttner et al 2006]:

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 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)

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

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.

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 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.
  • 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.

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 possible 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 conditions 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.

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 an option for some families in which the disease-causing mutation has been identified.

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 X Type 1: Genes and Databases

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 X Type 1 (View All in OMIM)

302800CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1; CMTX1
304040GAP JUNCTION PROTEIN, BETA-1; GJB1

Normal allelic variants. GJB1 consists of two non-coding exons (1 and 2) that are alternatively spliced in a tissue-specific manner and one coding exon (exon 3).

Pathologic allelic variants. More than 250 different mutations in GJB1 have been identified in families with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). These include missense, stop codon, and frame shift mutations [De Jonghe et al 1997, Nelis et al 1999, Lee et al 2002, Umehara et al 2006]. Mutations have been identified in the promoter region of GJB1 and the 5’ non-coding region [Ionasescu et al 1996, Houlden et al 2004, Li et al 2009]. Deletion of exon(s) and of the whole gene have been reported (see Table A).

Table 3. Selected GJB1 Pathologic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.43C>Tp.Arg15Trp NM_000166​.5
NP_000157​.1
c.123G>Cp.Glu41Asp
c.145T>Cp.Ser49Pro
c.164C>Tp.Thr55Ile
c.187G>Ap.Val63Ile
c.223C>Tp.Arg75Trp
c.225delGp.Leu76Cysfs*8
(Arg75fs*83)
c.556G>Ap.Glu186Lys
c.407T>Cp.Val136Ala
c.415G>Ap.Val139Met
c.536G>Ap.Cys179Tyr
c.614A>Gp.Asn205Ser
c.704T>Gp.Phe235Cys
c.571_579dup
(9-bp insertion)
p.Thr191_Phe193dup

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

Normal gene product. Gap junction beta-1 protein is found in peripheral myelin and specifically located in uncompacted folds of Schwann cell cytoplasm at the nodes of Ranvier and at Schmidt-Lanterman incisures. It is also found in central myelin. Gap junction beta-1 protein has two extracellular loops, four transmembrane domains, and three cytoplasmic domains. Gap junctions form direct channels between cells that facilitate transfer of ions and small molecules. Six connexins oligomerize to form hemichannels, or connexins. When properly opposed to each other on cell membranes, two connexins form gap junction channels that permit the diffusion of ions and small molecules [Sáez et al 2005].

Abnormal gene product. GJB1 mutations produce proteins with impaired glial/neuronal interactions and signal transduction. Loss of function of connexin 32 likely explains the pathogenesis of CMTX1. Mutations result in an increased opening of hemichannels that may damage cells through loss of ionic gradients and increased influx of Ca++ [Abrams et al 2001, Abrams et al 2002]. Not all mutations are associated with the inability to form homotypic gap junctions; some mutations lead to abnormal trafficking of Cx32 [Wang et al 2004] or to selective defects in channel permeability [Bicego et al 2006]. Loss of function can result in both peripheral and central demyelination [Sargiannidou et al 2009].

References

Literature Cited

  1. Abrams CK, Bennett MV, Verselis VK, Bargiello TA. Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease. Proc Natl Acad Sci U S A. 2002;99:3980–4. [PMC free article: PMC122634] [PubMed: 11891346]
  2. Abrams CK, Freidin MM, Verselis VK, Bennett MV, Bargiello TA. Functional alterations in gap junction channels formed by mutant forms of connexin 32: evidence for loss of function as a pathogenic mechanism in the X-linked form of Charcot-Marie-Tooth disease. Brain Res. 2001;900:9–25. [PubMed: 11325342]
  3. Ainsworth PJ, Bolton CF, Murphy BC, Stuart JA, Hahn AF. Genotype/phenotype correlation in affected individuals of a family with a deletion of the entire coding sequence of the connexin 32 gene. Hum Genet. 1998;103:242–4. [PubMed: 9760211]
  4. Bähr M, Andres F, Timmerman V, Nelis ME, Van Broeckhoven C, Dichgans J. Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene. J Neurol Neurosurg Psychiatry. 1999;66:202–6. [PMC free article: PMC1736220] [PubMed: 10071100]
  5. Basri R, Yabe I, Soma H, Matsushima M, Tsuji S, Sasaki H. X-linked Charcot-Marie-Tooth disease (CMTX) in a severely affected female patient with scattered lesions in cerebral white matter. Intern Med. 2007;46:1023–7. [PubMed: 17603245]
  6. Bicego M, Morassutto S, Hernandez VH, Morgutti M, Mammano F, D'Andrea P, Bruzzone R. Selective defects in channel permeability associated with Cx32 mutations causing X-linked Charcot-Marie-Tooth disease. Neurobiol Dis. 2006;21:607–17. [PubMed: 16442804]
  7. Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K, Russo P, Kennedy S, Teebi AS, Scavina M, Williams LL, Mancias P, Butler IJ, Krajewski K, Shy M, Lupski JR. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol. 2002;51:190–201. [PubMed: 11835375]
  8. Bone LJ, Deschênes SM, Balice-Gordon RJ, Fischbeck KH, Scherer SS. Connexin32 and X-linked Charcot-Marie-Tooth disease. Neurobiol Dis. 1997;4:221–30. [PubMed: 9361298]
  9. Braathen GJ, Sand JC, Bukholm G, Russell MB. Two novel connexin32 mutations cause early onset X-linked Charcot-Marie-Tooth disease. BMC Neurol. 2007;7:19. [PMC free article: PMC1999495] [PubMed: 17620124]
  10. Casasnovas C, Banchs I, Corral J, Martínez-Matos JA, Volpini V. Clinical and molecular analysis of X-linked Charcot-Marie-Tooth disease type 1 in Spanish population. Clin Genet. 2006;70:516–23. [PubMed: 17100997]
  11. Chung KW, Sunwoo IN, Kim SM, Park KD, Kim WK, Kim TS, Koo H, Cho M, Lee J, Choi BO. Two missense mutations of EGR2 R359W and GJB1 V136A in a Charcot-Marie-Tooth disease family. Neurogenetics. 2005;6:159–63. [PubMed: 15947997]
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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.

Chapter Notes

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
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