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 the GJB1(Cx32) gene detects about 90% of cases of CMTX1. Such testing is clinically available.
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 have 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.
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 [Rouger et al 1997, Hattori et al 2003 , Karadima et al 2005]. 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 the GJB1 gene (encoding the protein connexin 32) and/or a family history consistent with X-linked inheritance, i.e., no male-to-male inheritance
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.—ED.
Gene. GJB1 is the only gene known to be associated with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1).
Clinical uses
Carrier detection
Preimplantation genetic diagnosis
Clinical testing
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.
Mutation scanning. The types of mutations detected using mutation scanning techniques are equivalent to those detected by sequence analysis. Sensitivity varies by technique used and laboratory performing the analysis but may not be as high as that of sequence analysis.
Table 1 summarizes molecular genetic testing for this disorder.
Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability |
---|---|---|---|
Sequence analysis | GJB1 sequence variants | 90% | Clinical |
Mutation scanning |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
No other phenotypes are associated with mutations in GJB1.
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, or, more often, have mild to moderate signs and symptoms [Bone et al 1997]. 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. Life span is not decreased.
Hearing loss is occasionally reported and auditory evoked potentials may be abnormal [Nicholson & Corbett 1996, 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].
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. 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].
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.
Males with a nonsense GJB1 mutation have earlier onset and a more severe phenotype than males with a missense mutation [Birouk et al 1998].
A few families with deletions (null mutations) of the GJB1 gene 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 164C>T GJB1 mutation [Panas et al 2001].
Central visual, acoustic, and motor pathway involvement has been reported in a family with a p.Asn205Ser GJB1 mutation [Bahr et al 1999].
The p.Arg5Trp 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].
Deafness has been reported in individuals with p.Val63Ile and p.Glu86Lys GJB1 mutations [Takashima et al 2003].
Protein 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 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 mutation in EGR2 [Chung et al 2005].
A girl with a p.Phe235Cys GJB1 mutation had severe neuropathy and leaky Cx32 hemichannels [Liang et al 2005].
Penetrance is complete in males with GJB1 mutations.
Anticipation is not reported.
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 syndrome. In studies of unrelated individuals with CMT, Boerkoel et al (2002) found GJB1 mutations in 11/153 (7%) 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].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
Four other forms of hereditary neuropathy have been linked to markers on the X chromosome. None of the causative genes has been identified. Three of the four have other associated findings such as mental retardation, deafness, or optic neuropathy [Huttner et al 2006]:
CMTX2 with mental retardation maps to Xp22.2 [Ionasescu et al 1991, Ionasescu et al 1992].
CMTX3 with spasticity and pyramidal tract signs maps to Xq26. [Ionasescu et al 1991, Ionasescu et al 1992, Huttner et al 2006].
CMTX4 (Cowchock syndrome) with deafness and mental retardation maps to Xq24-q26.1 [Cowchock et al 1985, Priest et al 1995].
CMTX5 with deafness and optic neuropathy maps to Xq21.3-q24 [Kim et al 2005]. Mutations in PRPS1 (p.Glu43Asp, p.Met115Thr) have been found in two American/European and Korean families. The gene encodes a phosphoribosyl pyrophosphate synthetase enzyme critical for nucleotide biosynthesis [Kim et al 2007].
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 is symptomatic and affected individuals are often evaluated and managed by a team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Carter et al 1995].
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 [Carter et al 1995].
Orthopedic surgery may be required to correct severe pes cavus deformity [Holmes & Hansen 1993].
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.
No treatment for CMT that reverses or slows the natural disease process exists.
Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.
Regular foot examination for pressure sores or poorly fitting footwear is appropriate.
Obesity because it makes walking more difficult
Drugs and medications such as vincristine, isoniazid, and nitrofurantoin that are known to cause nerve damage [Graf et al 1996]
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Career and employment choices may be influenced by persistent weakness of hands and/or feet.
Genetics clinics are a source of 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.
Support groups have been established for individuals and families to provide information, support, and contact with other affected individuals. The Resources section may include disease-specific and/or umbrella support organizations.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is inherited in an X-linked dominant manner.
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 [Meggouh et al 1998]. 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 gene to all of their daughters and none of their sons.
Offspring of a female proband. Women with a GJB1(Cx32) gene mutation have a 50% chance of transmitting the gene to each child; sons who inherit the gene will be affected; daughters will have a range of possible phenotypic expression.
Other family members of a proband. If a parent of the proband is found to also have 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 upon their genetic relationship to the proband.
Carrier testing for at-risk family members is available on a clinical basis once the mutation has been identified in the family.
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 same 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 resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)
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.
DNA banking. 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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 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, careful 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 in an affected family member. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
GJB1 | Xq13.1 | Gap junction beta-1 protein |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
Gene Symbol | Locus Specific | Entrez Gene | HGMD |
---|---|---|---|
GJB1 | GJB1 | 2705 (MIM No. 304040) | GJB1 |
For a description of the genomic databases listed, click here.
Note: HGMD requires registration.
Normal allelic variants: GJB1 consists of two non-coding exons (1A and 1B) that are alternatively spliced in a tissue-specific manner and one coding exon (exon 2).
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, Suzuki et al 2006]. Mutations have been identified in the promoter region of GJB1 [Ionasescu et al 1996, Houlden et al 2004]. (For more information, see Genomic Databases table above.)
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 [Saez et al 2005].
Abnormal gene product: GJB1 mutations produce proteins with impaired glial/neuronal interactions and signal transduction [Oh et al 1997]. 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].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
Charcot-Marie-Tooth Association
2700 Chestnut Street
Chester PA 19013-4867
Phone: 800-606-CMTA (800-606-2682); 610-499-9264; 610-499-9265
Fax: 610-499-9267
Email: info@charcot-marie-tooth.org
www.charcot-marie-tooth.org
European Charcot-Marie-Tooth Consortium
Department of Molecular Genetics
University of Antwerp
Antwerp B-2610
Belgium
Fax: 03 2651002
Email: gisele.smeyers@ua.ac.be
The Hereditary Neuropathy Foundation
1751 2nd Ave Suite 103
New York NY 10128
Phone: 877-463-1287; 212-722-8396
Email: email: info@hnf-cure.org
www.hnf-cure.org
National Library of Medicine Genetics Home Reference
Charcot-Marie-Tooth disease
NCBI Genes and Disease
Charcot-Marie-Tooth syndrome
European Neuromuscular Centre (ENMC)
Lt. Gen. van Heutszlaan 6
3743 JN Baarn
Netherlands
Phone: 035 54 80 481
Fax: 035 54 80 499
Email: info@enmc.org
www.enmc.org
Muscular Dystrophy Association (MDA)
3300 East Sunrise Drive
Tucson AZ 85718-3208
Phone: 800-FIGHT-MD (800-344-4863); 520-529-2000
Fax: 520-529-5300
Email: mda@mdausa.org
www.mdausa.org
Muscular Dystrophy Campaign
7-11 Prescott Place
SW4 6BS
United Kingdom
Phone: (+44) 0 020 7720 8055
Fax: (+44) 0 020 7498 0670
Email: info@muscular-dystrophy.org
www.muscular-dystrophy.org
Teaching Case-Genetic Tools
Cases designed for teaching genetics in the primary care setting.
Case 7. Resident Receives a Troubling Phone Call about Peripheral Neuropathy from a Patient's Relative
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
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