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GJB1 Disorders: Charcot Marie Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes

, MD, PhD.

Author Information

Initial Posting: ; Last Update: February 20, 2020.

Estimated reading time: 28 minutes

Summary

Clinical characteristics.

GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic.

Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).

Diagnosis/testing.

The diagnosis of CMT1X is established in a male by identification of a hemizygous GJB1 pathogenic variant on molecular genetic testing and in a female by identification of a heterozygous GJB1 pathogenic variant.

Management.

Treatment of manifestations: Treatment by a multidisciplinary team includes special shoes and/or ankle/foot orthoses to correct foot drop and to aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; daily heel cord stretching to prevent Achilles' tendon shortening; exercise as tolerated. Treatment of stroke-like episodes is supportive, as these are self limited.

Surveillance: Yearly examinations by: a neurologist of motor function and pain; a physical therapist of gross motor skills and activities of daily living (ADL), an occupational therapist of fine motor skills and ADL; a foot care specialist for pressure sores and/or poorly fitting footwear. More frequent self-foot examination by the patient.

Agents/circumstances to avoid: Obesity (makes ambulation more difficult); medications that are toxic or potentially toxic to persons with CMT.

Genetic counseling.

CMT1X is inherited in an X-linked manner. Affected males transmit the GJB1 pathogenic variant to all of their daughters and none of their sons. Women with a GJB1 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, mild-to-moderate manifestations that may progress. Once the GJB1 pathogenic variant has been identified in an affected family member, molecular genetic testing of at-risk female relatives to determine their genetic status, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Diagnosis

Suggestive Findings

GJB1 Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) should be suspected in an individual with the following clinical findings, electrophysiologic findings, and family history.

Clinical findings

  • Peripheral motor and sensory neuropathy with or without the following:
    • Occasionally fixed CNS abnormalities
    • Acute, self-limited episodes of transient neurologic dysfunction, especially weakness and dysarthria
  • Stroke-like episodes. Acute fulminant episodes of reversible CNS dysfunction, usually with peripheral neuropathy or a family history of peripheral neuropathy
  • Familial ataxia with peripheral neuropathy

Electrophysiologic findings. Nerve conduction velocities (NCVs):

  • Forearm NCVs are typically in the "intermediate" range of 30-40 m/sec for males; in females NCVs from 30-60 m/sec are seen [Jerath et al 2016].
  • Median nerve conductions are more severely affected than those of the ulnar nerve [Tsai et al 2013].
    Note: NCV can vary from nerve to nerve in a single individual [Gutierrez et al 2000]. NCVs can also vary significantly within and between families.

Family history consistent with X-linked inheritance (i.e., no male-to-male inheritance). Because females can be as severely affected as males, some family histories will have multi-generation involvement of males and females. If the family is large enough, the fact that no male-to-male transmission is observed may be helpful.

Establishing the Diagnosis

Male proband. The diagnosis of CMT1X is established in a male proband with suggestive findings and a hemizygous pathogenic variant in GJB1 identifed by molecular genetic testing (see Table 1).

Female proband. The diagnosis of CMT1X is usually established in a female proband with suggestive findings and a heterozygous pathogenic variant in GJB1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of CMT1X is broad and overlaps with other forms of CMT, individuals with the findings of peripheral neuropathy described in Suggestive Findings are likely to be diagnosed using gene-targeted testing, often using a multigene panel (see Option 1), whereas those with stroke-like episodes in whom the diagnosis of a CMT1X has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

Single-gene testing is probably most appropriate when X-linked inheritance is possible and the proband has both peripheral nervous system and CNS manifestations typical of CMT1X.

Sequence analysis of GJB1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, gene-targeted deletion/duplication analysis is performed to detect intragenic deletions or duplications. Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

Note: Disease-causing variants have been reported in the upstream regulatory region, 5'UTR, noncoding exons and splice sites, and 3'UTR (see Molecular Genetics); therefore, sequence analysis should include these regions of GJB1.

An inherited neuropathy multigene panel that includes GJB1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (1) The genes included in multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Multigene panels generally include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1). (5) Variants in upstream regulatory regions, 5' untranslated regions, and putative splice sites as well as 3'UTR variants have been shown to cause CMT1X [Tomaselli et al 2017]. Because these variants are outside of typically sequenced gene regions, they may not be identified in inherited neuropathy panels (see Molecular Genetics).

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

Comprehensive genomic testing does not require the clinician to determine which gene[s] are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in GJB1 Charcot-Marie-Tooth Neuropathy with or without CNS Dysfunction (CMT1X)

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
GJB1Sequence analysis 3, 4>99% 5, 6
Gene-targeted deletion/duplication analysis 7Rare 8
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

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.

4.

Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.

5.
6.

Note, disease-associated variants in the upstream regulatory region, 5'UTR, non-coding exons, and 3'UTR are frequently associated with disease; therefore, sequence analysis should include these regions [Tomaselli et al 2017]. See Molecular Genetics for additional details.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

8.

Clinical Characteristics

Clinical Description

Neuropathy. Manifestations typically develop between ages five and 25 years; many males are symptomatic by early adolescence [Dubourg et al 2001, Shy et al 2007]. Earlier onset with delayed walking in infancy as well as later onset in the fourth and subsequent decades can occur. In some individuals, manifestations can be extremely mild and go unrecognized by the individual and/or physician. Clinical manifestations can vary, even within the same family.

Although both men and women are affected, manifestations tend to be less severe in women because of X-chromosome inactivation, as a result of which some women may remain asymptomatic [Siskind et al 2011, Jerath et al 2016].

Signs and symptoms are those of progressive peripheral motor and sensory neuropathy including sensory loss, weakness and atrophy of the distal muscles of the upper and lower extremities, and loss of deep tendon reflexes. The typical affected adult has bilateral foot drop, symmetric 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 upper and lower extremities. The dominant hand may be more involved than the non-dominant one [Arthur-Farraj et al 2012]. Proximal muscles usually remain strong.

Mild-to-moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet.

Fixed CNS abnormalities can include fixed dysarthria, ataxia, spasticity, hyperreflexia, extensor plantar response, and/or MRI abnormalities in the myelinated tracts of the brain. These have been recently reviewed [Abrams 2019].

Stroke-like episodes are acute self-limited often recurrent episodes of CNS dysfunction. Findings typically include upper motor neuron weakness and dysarthria. Ataxia, respiratory distress, dysphagia, and altered consciousness have also been described. Symptoms last between a few hours and a few weeks. While some episodes appear to occur without provocation [Halbrich et al 2008, Srinivasan et al 2008], most are associated with stressors such as hyperventilation or exertion [Hanemann et al 2003, Taylor et al 2003, Srinivasan et al 2008, Basu et al 2011], re-acclimatization after return from high altitude [Paulson et al 2002, Sagnelli et al 2014], fever [Schelhaas et al 2002, Fusco et al 2010], head trauma [Halbrich et al 2008], or minor infections [Hanemann et al 2003, Anand et al 2010].

MRI changes, seen on both diffusion-weighted and T2-weighted sequences, preferentially involve subcortical white matter and the splenium of the corpus callosum [Paulson et al 2002, Schelhaas et al 2002, Hanemann et al 2003, Halbrich et al 2008, Srinivasan et al 2008, Anand et al 2010, Fusco et al 2010, Rosser et al 2010, Kim et al 2014]. While diffusion-weighted abnormalities tend to resolve within weeks, T2-weighted changes may persist longer. Most of these episodes have been reported in males, typically younger than age 21 years [Al-Mateen et al 2014]; females with stroke like episodes have also been described [Hanemann et al 2003, Kim et al 2014]. In rare instances stroke-like episodes may precede peripheral neuropathy [Sagnelli et al 2014].

Other fixed central nervous system involvement, reported on occasion:

Other imaging findings can include:

Other electrophysiologic findings

Nerve biopsy. Light microscopy typically reveals axonal loss with evidence of regeneration. Scattered onion bulbs as well as thinly myelinated fibers, resulting from either regeneration and associated remyelination or segmental demyelination and remyelination, are also seen.

Electron microscopy reveals widened collars of adaxonal Schwann cell cytoplasm and separation of axons from their surrounding myelin sheaths [Senderek et al 1998, Senderek et al 1999, Tabaraud et al 1999, Hahn et al 2001, Vital et al 2001].

Nerve biopsies rarely show nerve hypertrophy or generalized onion bulb formation, findings considered to be typical for demyelinating CMT(e.g., CMT type 1A caused by a duplication of a ~1-MB region of chromosome 17 that includes PMP22).

Note that the widespread availability of molecular genetic testing has rendered nerve biopsy unnecessary for diagnosis unless genetic testing is unrevealing.

Genotype-Phenotype Correlations

The six variants that have been reported in multiple unrelated individuals with stroke-like episodes and which may confer a higher risk for this phenotype are included in Table 4. Of note, approximately 20 additional variants have been reported in a single individual or family with stroke-like episodes.

Nomenclature

The term XL-CMTIn-GJB1 may be used to describe CMT1X. This term is based on the classification system proposed by Magy et al [2018] in which expression of a particular type of CMT combines three elements: mode of inheritance, neuropathy type (i.e., axonal, demyelinating, or intermediate), and the gene involved.

See the CMT Overview for a review of other approaches to CMT classification.

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 to 20:100,000).

CMT1X represents at least 10%-20% of those with the CMT neuropathy (see CMT Overview).

Differential Diagnosis

Neuropathy. See CMT Overview.

Stroke-like episodes and peripheral neuropathy. Disorders to consider in the differential diagnosis include the following:

Isolated stroke-like episodes. The vast differential diagnosis includes many genetic and acquired conditions. In particular, the autosomal recessive disorder acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) (OMIM 618384), caused by biallelic pathogenic variants in SLC13A3, should be considered, as the phenotype is remarkably similar to that seen in CMT1X [Dewulf et al 2019].

Management

Individuals with GJB1 Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, physical therapists, and occupational therapists.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with CMT1X , the evaluations summarized in Table 2 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 2.

Recommended Evaluations Following Initial Diagnosis in Individuals with CMT1X

System/ConcernEvaluationComment
NeurologicNeurologic evaluation
  • To determine extent of weakness & atrophy, pes cavus, gait stability, & sensory loss
  • To evaluate for pain
  • To evaluate for less common fixed manifestations (e.g., spasticity, hyperreflexia, ataxia)
  • To determine if patient &/or any family member has had episodes of acute transient neurologic dysfunction
MusculoskeletalOrthopedics / physical medicine & rehabilitation / PT/OT evaluationTo incl assessment of:
  • Gross motor & fine motor skills & need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
  • Feet for evidence of pes cavus, need for AFOs, specialized shoes
  • Mobility, activities of daily living, & need for adaptive devices
  • Need for handicapped parking
HearingAudiologic evaluationAssessment for hearing loss if concerns
Miscellaneous/
Other
Consultation w/clinical geneticist &/or genetic counselorTo incl genetic counseling

OT = occupational therapy; PT = physical therapy

Treatment of Manifestations

Treatment is symptomatic.

Neuropathy

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

Ankle/foot orthoses (AFO) are often required to correct foot drop and aid walking. Daily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.

Orthopedic surgery may be required to correct severe pes cavus deformity interfering with ambulation; however, it should be reserved for patients in whom the gait cannot be corrected by use of appropriate orthotic devices.

Forearm crutches or canes may be required for gait stability. Use of a wheelchair may occasionally be required.

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

Stroke-Like Episodes

Treatment is supportive, as these are self limited. See Agents/Circumstances to Avoid for lifestyle recommendations to potentially reduce the risk of these episodes.

Surveillance

Table 3.

Recommended Surveillance for Individuals with CMT1X

System/ConcernEvaluationFrequency
Neurologic
  • Screening neurologic examination focused on motor system & cerebellar function
  • Evaluation for pain
Annually
Musculoskeletal
  • PT (gross motor skills) & ADL
  • OT (fine motor skills) & ADL
Foot examinationFor pressure sores or poorly fitting footwearAnnually by physician; more often by patient

ADL = activities of daily living; OT = occupational therapy; PT = physical therapy

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. See the Charcot-Marie-Tooth Association website (pdf) for an up-to-date list.

Patients should be informed of the small possibility of stroke-like episodes, which appears to be higher in younger patients with a family history or in individuals who have a variant previously associated with such events (see Table 4). The author recommends advising patients that the avoidance of known precipitants such as hyperventilation or exertion [Hanemann et al 2003, Taylor et al 2003, Srinivasan et al 2008, Basu et al 2011], re-acclimatization after return from high altitude [Paulson et al 2002, Sagnelli et al 2014], fever [Schelhaas et al 2002, Fusco et al 2010], head trauma [Halbrich et al 2008], or minor infections [Hanemann et al 2003, Anand et al 2010] may reduce the likelihood of such events. However, these recommendations must be balanced with quality-of-life considerations.

Evaluation of Relatives at Risk

Examination of at-risk relatives is recommended since individuals with few manifestations may go unrecognized. Even individuals with few manifestations may benefit from use of orthotics.

It may be appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual when the apparent risk for stroke-like episodes may be higher (family history or a variant previously associated with such episodes; see Table 4), since avoidance of precipitating factors may be warranted to help reduce the incidence of such events.

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

Therapies Under Investigation

A currently active trial for CMT1X testing a drug called ACE-083 is not recruiting at this time.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

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

GJB1 Charcot-Marie-Tooth neuropathy with or without central nervous system dysfunction (CMT1X) is inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

Parents of a female proband

  • A female proband may have inherited the GJB1 pathogenic variant from either her mother or her father, or the pathogenic variant may be de novo.
  • Detailed evaluation of the parents and review of the extended family history may help distinguish probands with a de novo GJB1 pathogenic variant from those with an inherited pathogenic variant. Molecular genetic testing of the mother (and possibly the father, or subsequently the father) can determine if the pathogenic variant was inherited.

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

  • If the mother of the proband has a GJB1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, have mild-to-moderate signs and symptoms that may progress.
  • If the proband represents a simplex case and if the GJB1 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism.

Sibs of a female proband. The risk to sibs depends on the genetic status of the parents:

  • If the mother of the proband has a GJB1 pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have mild-to-no manifestations or, more often, have mild-to-moderate signs and symptoms that may progress
  • If the father of the proband has a GJB1 pathogenic variant, he will transmit it to all his daughters and none of his sons.
  • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the GJB1 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a male proband. Affected males transmit the GJB1 pathogenic variant to all of their daughters and none of their sons.

Offspring of a female proband. Women with a GJB1 pathogenic variant have a 50% chance of transmitting the pathogenic variant to each child.

Other family members. If a parent of the proband also has a GJB1 pathogenic variant, his or her family members may be at risk of having a GJB1 pathogenic variant.

Note: Molecular genetic testing may be able to identify the family member in whom a de novo pathogenic variant arose – information that could help determine genetic risk status of the extended family.

Heterozygote Detection

Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the GJB1 pathogenic variant has been identified in the proband.

Note: (1) Females who are heterozygous for this X-linked disorder may have no clinical findings of peripheral neuropathy (but an abnormal EMG/NCV); or, more often, have mild-to-moderate signs and symptoms that may progress (see Clinical Description). (2) Identification of female heterozygotes requires either (a) prior identification of the GJB1 pathogenic variant in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk 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 adult males who are affected (i.e., hemizygous) or females who are known to be heterozygous or who are at increased risk of being heterozygotes.

Prenatal Testing and Preimplantation Genetic Testing

Once the GJB1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

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 use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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
    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
    Email: info@cmtausa.org
  • CMT Research Foundation
    4062 Peachtree Street
    Suite A209
    Atlanta GA 30319
    Phone: 404-806-7180
  • 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
    Phone: 855-435-7268 (toll-free); 212-722-8396
    Fax: 917-591-2758
    Email: info@hnf-cure.org
  • My46 Trait Profile
  • 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 8617
    Fax: 44 (0)191 241 8770
    Email: info@treat-nmd.eu
  • Association Francaise contre les Myopathies (AFM)
    1 Rue de l'International
    BP59
    Evry cedex 91002
    France
    Phone: +33 01 69 47 28 28
    Email: dmc@afm.genethon.fr
  • European Neuromuscular Centre (ENMC)
    Lt Gen van Heutszlaan 6
    3743 JN Baarn
    Netherlands
    Phone: 31 35 5480481
    Fax: 31 35 5480499
    Email: enmc@enmc.org
  • Muscular Dystrophy Association - USA (MDA)
    222 South Riverside Plaza
    Suite 1500
    Chicago IL 60606
    Phone: 800-572-1717
    Email: mda@mdausa.org
  • Muscular Dystrophy UK
    61A Great Suffolk Street
    London SE1 0BU
    United Kingdom
    Phone: 0800 652 6352 (toll-free); 020 7803 4800
    Email: info@musculardystrophyuk.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.

GJB1 Disorders: Charcot Marie Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes: 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 GJB1 Disorders: Charcot Marie Tooth Neuropathy (CMT1X) and Central Nervous System Phenotypes (View All in OMIM)

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

GJB1 encodes gap junction beta-1 protein (GJB1; also known as connexin 32 or Cx32), which is expressed 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. GJB1 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 connexons. When properly apposed to each other on cell membranes, two connexins form gap junction channels that permit the diffusion of ions and small molecules [Abrams 2019].

Mechanism of disease causation. The exact mechanism by which GJB1 pathogenic variants produce disease is unknown. Some variants likely lead to little or no protein production, including deletion of the entire coding sequence for Cx32 [Ainsworth et al 1998, Lin et al 1999, Hahn et al 2000, Nakagawa et al 2001, Takashima et al 2003, Capponi et al 2015], start codon [Brozková et al 2010, Chen et al 2011, Schabhüttl et al 2014, Hong et al 2017] and nonsense variants in the upstream part of the coding sequence [Ionasescu et al 1996a, Panosyan et al 2017]. Pathogenic variants in the upstream regulatory region, 5' untranslated region, splice junctions of non-coding exons, and 3' untranslated region [Ionasescu et al 1996b, Flagiello et al 1998, Houlden et al 2004, Beauvais et al 2006, Li et al 2009, Kabzińska et al 2011, Murphy et al 2011, Tsai et al 2013, Kulshrestha et al 2017, Panosyan et al 2017, Tomaselli et al 2017] are also likely to reduce or eliminate protein expression.

Almost all disease-associated variants are predicted to be loss-of-function variants. Some cause Cx32 to traffic inappropriately, thus leading to a failure to form gap junction plaques [Omori et al 1996, Deschênes et al 1997, Martin et al 2000, Matsuyama et al 2001, Kleopa et al 2002, Yum et al 2002, Abrams et al 2003]. Others form gap junctions but interfere with gap junction function by reducing pore size [Oh et al 1997, Bicego et al 2006], increasing sensitivity to acidification-induced closure [Ressot et al 1998, Abrams et al 2003], or most commonly by stabilizing the closed state of the channel [Oh et al 1997, Ri et al 1999, Abrams et al 2000, Abrams et al 2013]. See recent reviews for further details [Abrams & Freidin 2015, Abrams 2019]. Evidence suggests that in the central nervous system some variants have a toxic gain-of-function consequence [Olympiou et al 2016].

Gap junction-independent mechanisms may also play a role. At least one disease-associated GJB1 variant shows increased opening of hemichannels that may damage cells through loss of ionic gradients and increased influx of Ca++ [Abrams et al 2002]. A number of studies have suggested roles for connexins in regulation of cell growth [Omori & Yamasaki 1998, Moorby & Patel 2001, Qin et al 2002, Freidin et al 2009] and resistance to both apoptotic and necrotic cell death [Abdipranoto et al 2003], independent of formation of functional gap junction channels. One example is the demonstration that Schwann cell proliferation is regulated by Cx32 in a gap junction-independent manner [Freidin et al 2009]. Other non-junctional actions of connexins include binding to other proteins and possibly acting as trafficking or scaffolding proteins [Giepmans 2004, Stout et al 2004].

GJB1-specific laboratory technical considerations. GJB1 consists of two promotors – P1 and P2 – that are expressed in a tissue-specific manner [Neuhaus et al 1996]. The P1 promotor is upstream of the P2 promotor and each promoter produces a transcript with a unique noncoding exon 1 and the entire coding sequence in a single exon 2. It is thought that only the P2 promoted transcript (NM_000166) is expressed in Schwann cells. Therefore, noncoding variants that fall outside of this transcript and its regulatory regions are highly unlikely to be causal for CMT1X. (Note that in the literature the first [P1 promoted] exon is sometimes referred to as 1A, the second [P2 promoted] exon as 1B, and the third coding exon as exon 2.) As noted and referenced in Establishing the Diagnosis, pathogenic variants have been identified in the upstream regulatory region, 5' untranslated region, splice between exon one and exon two, and 3' untranslated region of NM_000166.

Table 4.

Notable GJB1 Pathogenic Variants

Reference
Sequences
DNA
Nucleotide
Change (Alias 1)
Predicted
Protein
Change
Comment [Reference]
NM_000166​.5
NP_000157​.1
c.-103C>T
(-459C>T)
Recurrent pathogenic variant in noncoding exon (1B) [Ionasescu et al 1996b, Li et al 2009, Tsai et al 2013, Tomaselli et al 2017]
c.-17G>AMost common noncoding pathogenic variant in a large international study (4% of total) at splice site [Panosyan et al 2017]
c.44G>Ap.Arg15GlnMost common coding pathogenic variant ~7% of total in a large international study [Panosyan et al 2017]
c.65G>Ap.Arg22GlnObserved in 2 unrelated cases w/stroke-like episodes [Srinivasan et al 2008, Rosser et al 2010]
c.223C>Tp.Arg75TrpObserved in 3 unrelated cases w/stroke-like episodes [Taylor et al 2003; Parissis et al 2017; SS Scherer, personal communication]
c.283G>Ap.Val95MetApparently common pathogenic variant in Korea (6/63 families) [Hong et al 2017]
c.415G>Ap.Val139Met2 unrelated cases w/stroke like episodes [Halbrich et al 2008, Al-Mateen et al 2014]
c.424C>Tp.Arg142TrpObserved in 3 unrelated cases w/stroke-like episodes [Paulson et al 2002; SS Scherer, personal communication]
c.425G>Ap.Arg142GlnObserved in 2 unrelated cases w/stroke-like episodes [Kulkarni et al 2015, Lu et al 2017]
c.490C>Tp.Arg164TrpObserved in 2 unrelated cases w/stroke-like episodes [Schelhaas et al 2002, Isoardo et al 2005]; common pathogenic variant in Korea (4/63 families) [Hong et al 2017]
c.491G>Ap.Arg164GlnApparently common pathogenic variant in Korea (5/63 families) [Hong et al 2017]

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

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

1.

Variant designation that does not conform to current naming conventions

References

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 6-3-20. [PubMed: 23428972]
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 6-3-20.

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Chapter Notes

Author Notes

Author's laboratory website

Charles K Abrams directs a laboratory at the University of Illinois College of Medicine at Chicago (UIC) studying the role of connexins including connexin 32 in the central and peripheral nervous system. A major area of focus is understanding how pathogenic variants in Cx32 cause CMT1X. He also directs the CMTA association sponsored inherited peripheral neuropathies clinic at UIC.

Acknowledgments

Dr Abrams acts as a paid consultant for Atheneum Partners, Sarepta Therapeutics, and Stealth Biotherapeutics. Dr Abrams' work on CMT1X is supported by grants from the MDA, CMTA, and NIH.

Author History

Charles K Abrams, MD, PhD (2020-present)
Thomas D Bird, MD; Seattle VA Medical Center (1998-2020)

Revision History

  • 20 February 2020 (bp) Comprehensive update posted live
  • 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
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