NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Charcot-Marie-Tooth Neuropathy X Type 1

Synonyms: CMTX1, GJB1-Related Charcot-Marie-Tooth Neuropathy

, MD.

Author Information

Initial Posting: ; Last Revision: September 1, 2016.

Estimated reading time: 22 minutes


Clinical 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.


Molecular genetic testing of GJB1 (Cx32) detects approximately 90% of cases of CMTX1.


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 (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage.

Genetic counseling.

CMTX1 is inherited in an X-linked 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 pathogenic variant to each offspring. Sons who inherit the pathogenic variant will be affected; daughters who inherit the variant may have mild to no symptoms. Prenatal testing is possible when the pathogenic variant has been identified in an affected family member; however, prenatal testing for typically adult-onset disorders is rarely requested.


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 pathogenic variant 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.

Molecular Genetic Testing Used in CMTX1

Gene 1Test MethodPathogenic Variants Detected 2Variant Detection Frequency by Test Method 3
Affected MalesCarrier Females
GJB1Sequence analysis 4Sequence variants90% 5See footnote 6
Deletion/duplication analysis 7Partial- and whole-gene deletionsRareRare

See Molecular Genetics for information on allelic variants.


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


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


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


In carrier females, sequence analysis of genomic DNA cannot detect (multi)exon or whole-gene deletions on the X chromosome.


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.

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 pathogenic variants 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 pathogenic variant 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 pathogenic variant is identified, by methods to detect gross structural abnormalities.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

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

Clinical Characteristics

Clinical Description

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 (see CMT Overview). 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, Siskind et al 2011]. 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 [Bähr 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, as well as hyperventilation [Srinivasan et al 2008]. Hanemann et al [2003], Taylor et al [2003], and McKinney et al [2014] 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 is complete in males with GJB1 pathogenic variants.


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


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 mutation of 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]:


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.


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 that are toxic or potentially toxic to persons with CMT comprise a spectrum of risk ranging from definite high risk to negligible risk. Click here (pdf) for an up-to-date list.

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 in the US and in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


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 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 pathogenic variant.
  • 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 pathogenic variant. In this instance, the proband's mother does not have a pathogenic variant and the only other family members at risk are the offspring of the proband. De novo mutation is unusual in CMTX1 but has been reported. Dubourg et al [2001] estimated that 5% of cases were attributable to de novo pathogenic variants [Boerkoel et al 2002].
    • The affected individual's mother has a de novo pathogenic variant that occurred in one of the following ways:
      • As a germline variant, 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 variant, i.e., a change that occurred very early in embryogenesis, resulting in somatic mosaicism, in which the pathogenic variant 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 pathogenic variant and some do not, and in which the pathogenic variant 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 pathogenic variant 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 pathogenic variant 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 pathogenic variant 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 pathogenic variant 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 the GJB1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the pathogenic variant will be affected; female sibs who inherit the pathogenic variant 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 pathogenic variant and may or may not be affected. None of the male sibs will inherit the pathogenic variant.
  • 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 pathogenic variant to all of their daughters and none of their sons.

Offspring of a female proband. Women with a GJB1 (Cx32) pathogenic variant have a 50% chance of transmitting it to each child; sons who inherit the pathogenic variant 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 pathogenic variant, 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 pathogenic variant 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 Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

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

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GJB1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for CMTX1 are possible. Preimplantation genetic diagnosis of CMTX1 has been reported [Iacobelli et al 2003, Sharapova et al 2004].

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.


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
    Phone: 820 077 540; 2 47 27 96 41
  • Charcot-Marie-Tooth Association (CMTA)
    PO Box 105
    Glenolden PA 19036
    Phone: 800-606-2682 (toll-free); 610-499-9264
    Fax: 610-499-9267
  • European Charcot-Marie-Tooth Consortium
    Department of Molecular Genetics
    University of Antwerp
    Antwerp Antwerpen B-2610
    Fax: 03 2651002
  • Hereditary Neuropathy Foundation, Inc.
    432 Park Avenue South
    4th Floor
    New York NY 10016
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
    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 8617
    Fax: 44 (0)191 241 8770
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    Evry cedex 91002
    Phone: +33 01 69 47 28 28
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Phone: 31 35 5480481
    Fax: 31 35 5480499
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
  • 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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Charcot-Marie-Tooth Neuropathy X Type 1 (View All in OMIM)


Gene structure. 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). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 250 different pathogenic variants in GJB1 have been identified in families with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). These include missense, stop codon, and frameshift variants [De Jonghe et al 1997, Nelis et al 1999, Lee et al 2002, Umehara et al 2006]. Pathogenic variants 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 2.

Selected GJB1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein Change
(Alias 1)
Reference Sequences
(9-bp insertion)

Note on variant classification: Variants listed in the table have been provided by the author. 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 (varnomen​ See Quick Reference for an explanation of nomenclature.


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 pathogenic variants produce proteins with impaired glial/neuronal interactions and signal transduction. Loss of function of connexin 32 likely explains the pathogenesis of CMTX1. Mutation of GJB1 results 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 GJB1 pathogenic variants are associated with the inability to form homotypic gap junctions; some variants 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, Abrams & Freidin 2015].


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-17-18. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2017. Accessed 7-17-18.

Literature Cited

  • 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]
  • 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. [PMC free article: PMC4517190] [PubMed: 11325342]
  • Abrams CK, Freidin M. GJB1-associated X-linked Charcot-Marie-Tooth disease, a disorder affecting the central and peripheral nervous systems. Cell Tissue Res. 2015;360:659–73. [PubMed: 25370202]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • 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]
  • Borgulová I, Mazanec R, Sakmaryová I, Havlová M, Safka Brožková D, Seeman P. Mosaicism for GJB1 mutation causes milder Charcot-Marie-Tooth X1 phenotype in a heterozygous man than in a manifesting heterozygous woman. Neurogenetics. 2013;14:189–95. [PubMed: 23912496]
  • 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]
  • Brewer MH, Chaudhry R, Qi J, Kidambi A, Drew AP, Menezes MP, Ryan MM, Farrar MA, Mowat D, Subramanian GM, Young HK, Zuchner S, Reddel SW, Nicholson GA, Kennerson ML. Whole genome sequencing identifies a 78 kb insertion from chromosome 8 as the cause of Charcot-Marie-Tooth neuropathy CMTX3. PLoS Genet. 2016;12:e1006177. [PMC free article: PMC4954712] [PubMed: 27438001]
  • Capponi S, Geroldi A, Pezzini I, Gulli R, Ciotti P, Ursino G, Lamp M, Reni L, Schenone A, Grandis M, Mandich P, Bellone E. Contribution of copy number variations in CMT1X: a retrospective study. Eur J Neurol. 2015;22:406–9. [PubMed: 24724718]
  • 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]
  • 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]
  • Cowchock FS, Duckett SW, Streletz LJ, Graziani LJ, Jackson LG. X-linked motor-sensory neuropathy type-II with deafness and mental retardation: a new disorder. Am J Med Genet. 1985;20:307–15. [PubMed: 3856385]
  • De Jonghe P, Timmerman V, Nelis E, Martin JJ, Van Broeckhoven C. Charcot-Marie-Tooth disease and related peripheral neuropathies. J Peripher Nerv Syst. 1997;2:370–87. [PubMed: 10975746]
  • Dubourg O, Tardieu S, Birouk N, Gouider R, Léger JM, Maisonobe T, Brice A, Bouche P, LeGuern E. The frequency of 17p11.2 duplication and Connexin 32 mutations in 282 Charcot-Marie-Tooth families in relation to the mode of inheritance and motor nerve conduction velocity. Neuromuscul Disord. 2001;11:458–63. [PubMed: 11404117]
  • Gutierrez A, England JD, Sumner AJ, Ferer S, Warner LE, Lupski JR, Garcia CA. Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease. Muscle Nerve. 2000;23:182–8. [PubMed: 10639608]
  • Hahn AF, Ainsworth PJ, Bolton CF, Bilbao JM, Vallat JM. Pathological findings in the x-linked form of Charcot-Marie-Tooth disease: a morphometric and ultrastructural analysis. Acta Neuropathol. 2001;101:129–39. [PubMed: 11271367]
  • Halbrich M, Barnes J, Bunge M, Joshi C. A. V139M mutation also causes the reversible CNS phenotype in CMTX. Can J Neurol Sci. 2008;35:372–4. [PubMed: 18714809]
  • Hanemann CO, Bergmann C, Senderek J, Zerres K, Sperfeld AD. Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with novel connexin 32 mutation. Arch Neurol. 2003;60:605–9. [PubMed: 12707076]
  • Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H, Ohnishi A, Hayasaka K, Onodera O, Baba M, Yasuda H, Saito T, Nakashima K, Kira J, Kaji R, Oka N, Sobue G. Study Group for Hereditary Neuropathy in Japan. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain. 2003;126:134–51. [PubMed: 12477701]
  • Houlden H, Girard M, Cockerell C, Ingram D, Wood NW, Goossens M, Walker RW, Reilly MM. Connexin 32 promoter P2 mutations: a mechanism of peripheral nerve dysfunction. Ann Neurol. 2004;56:730–4. [PubMed: 15470753]
  • Huttner IG, Kennerson ML, Reddel SW, Radovanovic D, Nicholson GA. Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth disease. Neurology. 2006;67:2016–21. [PubMed: 17159110]
  • Iacobelli M, Greco E, Rienzi L, Ubaldi F, Podini D, Nuccitelli A, Tesarik J, Baldi M, Fiorentino F. Birth of a healthy female after preimplantation genetic diagnosis for Charcot-Marie-Tooth type X. Reprod Biomed Online. 2003;7:558–62. [PubMed: 14680548]
  • Ionasescu VV, Searby C, Ionasescu R, Neuhaus IM, Werner R. Mutations of the noncoding region of the connexin32 gene in X-linked dominant Charcot-Marie-Tooth neuropathy. Neurology. 1996;47:541–4. [PubMed: 8757034]
  • Ionasescu VV, Trofatter J, Haines JL, Summers AM, Ionasescu R, Searby C. X-linked recessive Charcot-Marie-Tooth neuropathy: clinical and genetic study. Muscle Nerve. 1992;15:368–73. [PubMed: 1557086]
  • Isoardo G, Di Vito N, Nobile M, Benetton G, Fassio F. X-linked Charcot-Marie-Tooth disease and progressive-relapsing central demyelinating disease. Neurology. 2005;65:1672–3. [PubMed: 16301507]
  • Karadima G, Panas M, Floroskufi P, Kalfakis N, Vassilopoulos D. Four novel connexin 32 mutations in X-linked Charcot-Marie-Tooth disease with phenotypic variability. J Neurol. 2006;253:263–4. [PubMed: 16096811]
  • Kassubek J, Bretschneider V, Sperfeld AD. Corticospinal tract MRI hyperintensity in X-linked Charcot-Marie-Tooth Disease. J Clin Neurosci. 2005;12:588–9. [PubMed: 16051098]
  • Kawakami H, Inoue K, Sakakihara I, Nakamura S. Novel mutation in X-linked Charcot-Marie-Tooth disease associated with CNS impairment. Neurology. 2002;59:923–6. [PubMed: 12297581]
  • Kennerson ML, Nicholson GA, Kaler SG, Kowalski B, Mercer JF, Tang J, Llanos RM, Chu S, Takata RI, Speck-Martins CE, Baets J, Almeida-Souza L, Fischer D, Timmerman V, Taylor PE, Scherer SS, Ferguson TA, Bird TD, De Jonghe P, Feely SM, Shy ME, Garbern JY. Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy. Am J Hum Genet. 2010;86:343–52. [PMC free article: PMC2833394] [PubMed: 20170900]
  • Kennerson M, Nicholson G, Kowalski B, Krajewski K, El-Khechen D, Feely S, Chu S, Shy M, Garbern J. X-linked distal hereditary motor neuropathy maps to the DSMAX locus on chromosome Xq13.1-q21. Neurology. 2009;72:246–52. [PubMed: 19153371]
  • Kennerson ML, Yiu EM, Chuang DT, Kidambi A, Tso SC, Ly C, Chaudhry R, Drew AP, Rance G, Delatycki MB, Züchner S, Ryan MM, Nicholson GA. A new locus for X-linked dominant Charcot-Marie-Tooth disease (CMTX6) is caused by mutations in the pyruvate dehydrogenase kinase isoenzyme 3 (PDK3) gene. Hum Mol Genet. 2013;22:1404–16. [PMC free article: PMC3596851] [PubMed: 23297365]
  • Kim HJ, Hong SH, Ki CS, Kim BJ, Shim JS, Cho SH, Park JH, Kim JW. A novel locus for X-linked recessive CMT with deafness and optic neuropathy maps to Xq21.32-q24. Neurology. 2005;64:1964–7. [PubMed: 15955956]
  • Kim HJ, Sohn KM, Shy ME, Krajewski KM, Hwang M, Park JH, Jang SY, Won HH, Choi BO, Hong SH, Kim BJ, Suh YL, Ki CS, Lee SY, Kim SH, Kim JW. Mutations in PRPS1, which encodes the phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis, cause hereditary peripheral neuropathy with hearing loss and optic neuropathy (cmtx5). Am J Hum Genet. 2007;81:552–8. [PMC free article: PMC1950833] [PubMed: 17701900]
  • Lee MJ, Nelson I, Houlden H, Sweeney MG, Hilton-Jones D, Blake J, Wood NW, Reilly MM. Six novel connexin32 (GJB1) mutations in X-linked Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2002;73:304–6. [PMC free article: PMC1738041] [PubMed: 12185164]
  • Lewis RA. The challenge of CMTX and connexin 32 mutations. Muscle Nerve. 2000;23:147–9. [PubMed: 10639603]
  • Li M, Cheng TS, Ho PW, Chan KH, Mak W, Cheung RT, Ramsden DB, Sham PC, Song Y, Ho SL. -459C>T point mutation in 5' non-coding region of human GJB1 gene is linked to X-linked Charcot-Marie-Tooth neuropathy. J Peripher Nerv Syst. 2009;14:14–21. [PubMed: 19335535]
  • Liang GS, de Miguel M, Gómez-Hernández JM, Glass JD, Scherer SS, Mintz M, Barrio LC, Fischbeck KH. Severe neuropathy with leaky connexin32 hemichannels. Ann Neurol. 2005;57:749–54. [PubMed: 15852376]
  • Mandich P, Grandis M, Geroldi A, Acquaviva M, Varese A, Gulli R, Ciotti P, Bellone E. Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease. J Hum Genet. 2008;53:529–33. [PubMed: 18379723]
  • Marques W Jr, Sweeney JG, Wood NW, Wroe SJ, Marques W. Central nervous system involvement in a novel connexin 32 mutation affecting identical twins. J Neurol Neurosurg Psychiatry. 1999;66:803–4. [PMC free article: PMC1736386] [PubMed: 10400511]
  • Mazzeo A, Di Leo R, Toscano A, Muglia M, Patitucci A, Messina C, Vita G. Charcot-Marie-Tooth type X: unusual phenotype of a novel CX32 mutation. Eur J Neurol. 2008;15:1140–2. [PubMed: 18717720]
  • McKinney JL, De Los Reyes EC, Lo WD, Flanigan KM. Recurrent central nervous system white matter changes in charcot-Marie-tooth type X disease. Muscle Nerve. 2014;49:451–4. [PubMed: 24170412]
  • Murru MR, Vannelli A, Marrosu G, Cocco E, Corongiu D, Tranquilli S, Cherchi MV, Mura M, Barberini L, Mallarini G, Marrosu MG. A novel Cx32 mutation causes X-linked Charcot-Marie-Tooth disease with brainstem involvement and brain magnetic resonance spectroscopy abnormalities. Neurol Sci. 2006;27:18–23. [PubMed: 16688595]
  • Nakagawa M, Takashima H, Umehara F, Arimura K, Miyashita F, Takenouchi N, Matsuyama W, Osame M. Clinical phenotype in X-linked Charcot-Marie-Tooth disease with an entire deletion of the connexin 32 coding sequence. J Neurol Sci. 2001;185:31–7. [PubMed: 11266688]
  • Nelis E, Haites N, Van Broeckhoven C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat. 1999;13:11–28. [PubMed: 9888385]
  • Panas M, Kalfakis N, Karadimas C, Vassilopoulos D. Episodes of generalized weakness in two sibs with the C164T mutation of the connexin 32 gene. Neurology. 2001;57:1906–8. [PubMed: 11723288]
  • Paulson HL, Garbern JY, Hoban TF, Krajewski KM, Lewis RA, Fischbeck KH, Grossman RI, Lenkinski R, Kamholz JA, Shy ME. Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol. 2002;52:429–34. [PubMed: 12325071]
  • Priest JM, Fischbeck KH, Nouri N, Keats BJ. A locus for axonal motor-sensory neuropathy with deafness and mental retardation maps to Xq24-q26. Genomics. 1995;29:409–12. [PubMed: 8666389]
  • Rinaldi C, Grunseich C, Sevrioukova IF, Schindler A, Horkayne-Szakaly I, Lamperti C, Landouré G, Kennerson ML, Burnett BG, Bönnemann C, Biesecker LG, Ghezzi D, Zeviani M, Fischbeck KH. Cowchock syndrome is associated with a mutation in apoptosis-inducing factor. Am J Hum Genet. 2012;91:1095–102. [PMC free article: PMC3516602] [PubMed: 23217327]
  • Sáez JC, Retamal MA, Basilio D, Bukauskas FF, Bennett MV. Connexin-based gap junction hemichannels: gating mechanisms. Biochim Biophys Acta. 2005;1711:215–24. [PMC free article: PMC3617572] [PubMed: 15955306]
  • Sargiannidou I, Vavlitou N, Aristodemou S, Hadjisavvas A, Kyriacou K, Scherer SS, Kleopa KA. Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects. J Neurosci. 2009;29:4736–49. [PMC free article: PMC2721059] [PubMed: 19369543]
  • Schelhaas HJ, Van Engelen BG, Gabreëls-Festen AA, Hageman G, Vliegen JH, Van Der Knaap MS, Zwarts MJ. Transient cerebral white matter lesions in a patient with connexin 32 missense mutation. Neurology. 2002;59:2007–8. [PubMed: 12499506]
  • Sharapova T, Rechitsky S, Verlinsky Y. Preimplantation genetic diagnosis (PGD) for three types of Charcot-Marie-Tooth (CMT) disease. Am J Hum Genet. 2004;S75:A2806.
  • Shy ME, Siskind C, Swan ER, Krajewski KM, Doherty T, Fuerst DR, Ainsworth PJ, Lewis RA, Scherer SS, Hahn AF. CMT1X phenotypes represent loss of GJB1 gene function. Neurology. 2007;68:849–55. [PubMed: 17353473]
  • Siskind C, Feely SM, Bernes S, Shy ME, Garbern JY. Persistent CNS dysfunction in a boy with CMT1X. J Neurol Sci. 2009;279:109–13. [PubMed: 19193385]
  • Siskind CE, Murphy SM, Ovens R, Polke J, Reilly MM, Shy ME. Phenotype expression in women with CMT1X. J Peripher Nerv Syst. 2011;16:102–7. [PubMed: 21692908]
  • Srinivasan J, Leventer RJ, Kornberg AJ, Dahl HH, Ryan MM. Central nervous system signs in X-linked Charcot-Marie-Tooth disease after hyperventilation. Pediatr Neurol. 2008;38:293–5. [PubMed: 18358413]
  • Stojkovic T, Latour P, Vandenberghe A, Hurtevent JF, Vermersch P. Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q). Neurology. 1999;52:1010–4. [PubMed: 10102421]
  • Street VA, Meekins G, Lipe HP, Seltzer WK, Carter GT, Kraft GH, Bird TD. Charcot-Marie-Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes. Neuromuscul Disord. 2002;12:643–50. [PubMed: 12207932]
  • Szigeti K, Nelis E, Lupski JR. Molecular diagnostics of Charcot-Marie-Tooth disease and related peripheral neuropathies. Neuromolecular Med. 2006;8:243–54. [PubMed: 16775379]
  • Tabaraud F, Lagrange E, Sindou P, Vandenberghe A, Levy N, Vallat JM. Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings. Muscle Nerve. 1999;22:1442–7. [PubMed: 10487913]
  • Takashima H, Nakagawa M, Umehara F, Hirata K, Suehara M, Mayumi H, Yoshishige K, Matsuyama W, Saito M, Jonosono M, Arimura K, Osame M. Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease. Acta Neurol Scand. 2003;107:31–7. [PubMed: 12542510]
  • Taylor RA, Simon EM, Marks HG, Scherer SS. The CNS phenotype of X-linked Charcot-Marie-Tooth disease: more than a peripheral problem. Neurology. 2003;61:1475–8. [PubMed: 14663027]
  • Umehara F, Arimura Y, Osame M, Minato S, Nakahara K. New mutation of gap junction protein beta1 (GJB1) gene in X-linked hereditary motor and sensory neuropathy. J Peripher Nerv Syst. 2006;11:96–7. [PubMed: 16519791]
  • Vazza G, Merlini L, Bertolin C, Zortea M, Mostacciuolo ML. A novel 9-bp insertion in the GJB1 gene causing a mild form of X-linked CMT with late onset. Neuromuscul Disord. 2006;16:878–81. [PubMed: 17052905]
  • Vital A, Ferrer X, Lagueny A, Vandenberghe A, Latour P, Goizet C, Canron MH, Louiset P, Petry KG, Vital C. Histopathological features of X-linked Charcot-Marie-Tooth disease in 8 patients from 6 families with different connexin32 mutations. J Peripher Nerv Syst. 2001;6:79–84. [PubMed: 11446387]
  • Wang HL, Chang WT, Yeh TH, Wu T, Chen MS, Wu CY. Functional analysis of connexin-32 mutants associated with X-linked dominant Charcot-Marie-Tooth disease. Neurobiol Dis. 2004;15:361–70. [PubMed: 15006706]
  • Wicklein EM, Orth U, Gal A, Kunze K. Missense mutation (R15W) of the connexin32 gene in a family with X chromosomal Charcot-Marie-Tooth neuropathy with only female family members affected. J Neurol Neurosurg Psychiatry. 1997;63:379–81. [PMC free article: PMC2169726] [PubMed: 9328258]
  • Young P, Grote K, Kuhlenbäumer G, Debus O, Kurlemann H, Halfter H, Funke H, Ringelstein EB, Stögbauer F. Mutation analysis in Chariot-Marie Tooth disease type 1: point mutations in the MPZ gene and the GJB1 gene cause comparable phenotypic heterogeneity. J Neurol. 2001;248:410–5. [PubMed: 11437164]

Suggested Reading

  • 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.

Chapter Notes

Revision History

  • 1 September 2016 (tb) Revision: CMTX3 (Differential Diagnosis)
  • 19 March 2015 (tb) Revision: additions to references
  • 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 live
  • 15 April 2005 (me) Comprehensive update posted live
  • 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 live
  • 14 August 2001 (tb) Author revisions
  • 25 August 2000 (me) Comprehensive update posted live
  • 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 live
  • April 1996 (tb) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source ( and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1374PMID: 20301548


  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...