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 affected individual.

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.

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 is 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 (or likely pathogenic) variant in GJB1 identified 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 (or likely pathogenic) variant in GJB1 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a hemizygous or heterozygous GJB1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, 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).

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:

• Extensor plantar responses [Marques et al 1999, Hisama et al 2001, Lee et al 2002, Kassubek et al 2005, Karadima et al 2006, Kleopa et al 2006]
• Hyperreflexia and/or spasticity [Hisama et al 2001, Kleopa et al 2006]
• Ataxia with upper motor neuron signs in a large kindred (SCA-X1) [Caramins et al 2013] and ataxia with dysarthria [Siskind et al 2009]
• Vocal cord paresis with dysphonia and dysphagia (reported in 4/8 affected members of a single family) [Chung et al 2005]
• Hearing loss (occasionally reported) [Stojkovic et al 1999, Lee et al 2002, Takashima et al 2003]

Other imaging findings can include:

• MRI evidence of fixed pathology in CNS myelin [Bort et al 1997, Hisama et al 2001, Lee et al 2002, Kassubek et al 2005, Karadima et al 2006, Basri et al 2007, Siskind et al 2009];
• Reduced cerebellar blood flow on SPECT analysis [Kawakami et al 2002].

Other electrophysiologic findings

• Most affected individuals show abnormalities in visual, brain stem auditory, and/or somatosensory evoked responses (reviewed in Abrams & Freidin [2015]).
• Most GJB1 variants cause subclinical abnormalities of visual evoked responses and brain stem auditory evoked responsess [Nicholson & Corbett 1996, Cao et al 1998, Nicholson et al 1998, Panas et al 1998, Bähr et al 1999, Stojkovic et al 1999, Seeman et al 2001, Huang et al 2005, Murru et al 2006, Srinivasan et al 2008].
• Abnormal motor evoked potentials [Kassubek et al 2005], sensory evoked potentials [Kawakami et al 2002], and transcranial magnetic stimulation evoked central motor conduction [Zambelis et al 2008] have also been reported.

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.

From a severity standpoint, most pathogenic variants cause a similar phenotype [Shy et al 2007, Record et al 2023]. Some data suggest that the relatively common c.-17G>A pathogenic variant produces a more severe phenotype than other common pathogenic variants, while missense pathogenic variants in the intracellular domain of GJB1 cause a less severe phenotype [Record et al 2023].

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 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).

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.

Treatment of Manifestations

Treatment is symptomatic.

Surveillance

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.

Affected individuals should be informed of the small possibility of stroke-like episodes, which appears to be higher in younger individuals with a family history or in individuals who have a variant previously associated with such events (see Table 4). The author recommends advising affected individuals 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

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. Note: There may not be clinical trials for this disorder.

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

• The father of an affected male will not have the disorder nor will he be hemizygous for the GJB1 pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the GJB1 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. Presumed somatic and germline mosaicism has been reported in CMT1X [Borgulová et al 2013].
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo GJB1 pathogenic variant (in which case the mother is not a heterozygote). About 5% to 10% of affected males represent apparently simplex cases. While Dubourg et al [2001] estimated that 5% of individuals had a de novo pathogenic variant, no de novo variants were identified in a more recent study of 40 individuals with CMT1X [Rudnik-Schöneborn et al 2016].

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, the parent's 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/preimplantation genetic 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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 GJB1 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

• 25 April 2024 (tb) Revision: add new findings from Record et al [2023]
• 20 February 2020 (bp) Comprehensive update posted live
• 15 April 2010 (me) Comprehensive update posted live
• 26 June 2007 (me) Comprehensive update posted live
• 15 April 2005 (me) Comprehensive update posted live
• 10 April 2003 (me) Comprehensive update posted live
• 25 August 2000 (me) Comprehensive update posted live
• 18 June 1998 (pb) Review posted live
• April 1996 (tb) Original submission

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 1-19-22.
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2018. Accessed 1-19-22.

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