Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1) and primary peripheral axonal ... Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1) and primary peripheral axonal (type 2) neuropathies. The demyelinating neuropathies classified as CMT type 1, also known as HMSN I, are characterized by severely reduced motor nerve conduction velocities (NCV) (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy (see CMT1B; 118200). The axonal neuropathies classified as CMT type 2, also known as HMSN II, are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; 118210). Distal hereditary motor neuropathy (dHMN) (see 158590) is a spinal type of CMT characterized by exclusive motor involvement and sparing of sensory nerves (Pareyson, 1999). There are X-linked, autosomal dominant (see 118200), and autosomal recessive (see 214400) forms of CMT. The form of Charcot-Marie-Tooth neuropathy that maps to chromosome Xq13 (CMTX1) is X-linked dominant or X-linked intermediate; heterozygous females are more mildly affected than are hemizygous males. - Genetic Heterogeneity of X-linked Charcot-Marie-Tooth Disease CMTX5 (311070) is due to mutation in the PRPS1 gene (311850) on chromosome Xq21-q24. Ionasescu et al. (1991) presented data suggesting the existence of 2 separate loci for X-linked recessive disorders mapping to other sites: CMTX2 (302801), which maps to chromosome Xp22.2, and CMTX3 (302802), which maps to chromosome Xq26 (302802). Cowchock syndrome (310490), which maps to chromosome Xq24-q26, is referred to as CMTX4. CMTX6 (300905) is caused by mutation in the PDK3 gene (300906) on Xp22.
Montenegro et al. (2011) reported the use of exome sequencing to identify a mutation in the GJB1 gene (V95M; 304040.0011) in affected members of a large family with Charcot-Marie-Tooth disease and a questionable inheritance pattern. Affected individuals had ... Montenegro et al. (2011) reported the use of exome sequencing to identify a mutation in the GJB1 gene (V95M; 304040.0011) in affected members of a large family with Charcot-Marie-Tooth disease and a questionable inheritance pattern. Affected individuals had classic features of the disease, with onset between ages 14 and 40 years of distal sensory impairment and muscle weakness and atrophy affecting the upper and lower limbs. Nerve conduction velocities were in the intermediate range.
CMTX has both demyelinating and axonal features (Bergoffen et al., 1993, Hahn et al., 1990).
Phillips et al. (1985) described a large family with a pattern of X-linked dominant inheritance. Clinically and electrophysiologically, the phenotype was ... CMTX has both demyelinating and axonal features (Bergoffen et al., 1993, Hahn et al., 1990). Phillips et al. (1985) described a large family with a pattern of X-linked dominant inheritance. Clinically and electrophysiologically, the phenotype was similar to HMSN of the 'intermediate' type, in accordance with the Allan rule (Allan, 1939). Men were more severely affected than women, with very slow nerve conduction velocities. NCVs were mildly slow or normal in women. Hypertrophic nerves were not found. Hahn et al. (1990) reported clinical, neuropathologic, and electrophysiologic observations on a French Canadian family with HMSN transmitted as an X-linked dominant disorder over 6 generations. The disorder was characterized by onset in early childhood, pes cavus, atrophy and weakness of peroneal muscles and intrinsic hand muscles, and sensory abnormalities. Males were severely affected, whereas females had mild or subclinical disease. Electrophysiologic observations indicated a substantial loss of distal motor and sensory nerve fibers. Evoked muscle action potentials were absent or severely reduced and peroneal motor nerve conduction velocities were mildly reduced to a mean of 36.5 m/s. Nerve biopsies showed loss of myelinated and unmyelinated nerve fibers, regenerative sprouting, and secondary demyelination. The authors concluded that this form of HMSN is the result of primary axonal degeneration. Fain et al. (1994) examined 52 affected individuals from 4 multigenerational kindreds. All affected males had distal muscle weakness, atrophy, depressed deep tendon reflexes, and motor NCV less than 38 m/s. All females who were considered affected had mild distal muscle weakness, hypoactive reflexes, and NCV less than 38 m/s, consistent with a demyelinating neuropathy. The majority of affected females showed significant weakness beyond the fourth decade. Variable pes cavus deformity and variable degree of sensory loss were present in both affected males and females. Le Guern et al. (1994) reported a large family with X-linked dominant Charcot-Marie-Tooth disease. There were 7 affected males with NCV between 31 and 35 m/s in the median nerve and 12 affected females with NCV ranging from 31 to 52 m/s in the median nerve. Four of the women were asymptomatic but demonstrated electrophysiologic abnormalities. No male-to-male transmission was detected. Birouk et al. (1998) examined 48 CMTX patients from 10 families with CMTX1, confirmed by mutation analysis. Males were more severely affected than females, although 6 females were severely disabled. Motor NCV ranged from 30 to 40 m/s in males. Sural nerve biopsies showed axonal neuropathy. The authors concluded that this was an axonal neuropathy rather than a demyelinating disease. Yiu et al. (2011) provided a retrospective review of 17 children with X-linked CMT, 8 of whom (6 boys and 2 girls) had proven pathogenic mutations in the GJB1 gene. Most children with CMTX1 presented in infancy or early childhood with gait disturbances, although 3 presented with atypical features: a boy with hand tremor at age 12 years, a girl with sensorineural hearing loss at age 3 years, and a boy with transient CNS disturbance after hyperventilation at age 10 years, although in retrospect he had always walked flat-footed. Clinical features included toe walking (3 of 8), Achilles contractures (5), delayed motor development (3), frequent falls (4), hand weakness (2), hand tremor (3), and ankle sprains (2). Physical examination findings included pes cavus (5 of 8), distal lower limb wasting (4), distal upper limb wasting (5), difficulty walking on heels (6), distal lower limb weakness (6), distal upper limb weakness (3), absent ankle jerks (7), and distal sensory loss (3). Nerve conduction velocity studies in 3 boys ranged from 30 to 50 m/s and in 1 girl ranged from 41 to 46 m/s. The girl who presented with hearing loss had no other neurologic abnormalities. Two patients had sural nerve biopsies showing a reduction in myelinated nerve fiber density, thin myelin sheaths, and onion bulb formations. Muscle biopsy from 1 patient showed neurogenic changes with marked fiber size variation and type 1 fiber predominance. Five obligate carrier mothers had an abnormal neurologic examination, with distal upper and lower limb wasting and weakness with foot deformities. One girl and an unrelated carrier mother had recurrent pathologic fractures, an unusual feature. - Central Nervous System Involvement There are reports of CNS involvement in CMTX1 with (Panas et al., 1998; Marques et al., 1999) and without (Stojkovic et al., 1999; Nicholson et al., 1998) cerebral abnormalities on MRI. Schelhaas et al. (2002) presented a 14-year-old boy with CMTX1 who developed subacute respiratory distress and a pseudobulbar syndrome after an episode of fever. MRI of the brain showed confluent cerebral white matter lesions. The clinical features and cerebral white matter lesions in this patient resolved spontaneously. Hanemann et al. (2003) reported a family in which 3 members were affected with X-linked CMT. In addition to classic CMT clinical findings, all 3 patients had transient CNS symptoms correlating with transient and reversible white matter lesions on MRI. CNS symptoms included paraparesis, monoparesis, tetraparesis, dysarthria, aphasia, and cranial nerve palsies. Taylor et al. (2003) reported a 12-year-old boy with X-linked CMT who had 3 consecutive episodes of transient neurologic dysfunction over the course of 3 days, with complete recovery between each episode. Deficits included numbness of the face, paresis of the face and limbs, dysarthria, complete motor aphasia, and loss of gag reflex. MRI showed abnormal signals in the posterior frontal and parietal white matter, which improved 11 weeks later.
Shy et al. (2007) evaluated 73 male patients with CMTX1, ranging from 9 to 76 years of age, who had a total of 28 distinct GJB1 mutations. Two patients had a complete deletion of the GJB1 gene, and ... Shy et al. (2007) evaluated 73 male patients with CMTX1, ranging from 9 to 76 years of age, who had a total of 28 distinct GJB1 mutations. Two patients had a complete deletion of the GJB1 gene, and all others had truncating or missense mutations affecting various regions of the protein. Disability was relatively mild in the first 2 decades but progressed to severe after age 60, regardless of the mutation. There was no correlation between disease severity and specific mutations, and there was considerable variability among many patients carrying the same mutation. Moreover, virtually all patients of a given age had similar severity scores regardless of the mutation, and similar phenotypes resulted from deletions, missense, and nonsense mutations. Electrophysiologic studies indicated that axonal loss progressed with age, whereas conduction slowing did not clearly correlate with age. Functional disability correlated with motor axonal loss. Shy et al. (2007) concluded that GJB1 mutations result in a loss of function.
In affected persons from 8 CMTX families, Bergoffen et al. (1993) demonstrated point mutations in the connexin-32 gene (e.g., 304040.0001). The families in which mutations were identified included one studied by William Allan (1939), who had pointed out ... In affected persons from 8 CMTX families, Bergoffen et al. (1993) demonstrated point mutations in the connexin-32 gene (e.g., 304040.0001). The families in which mutations were identified included one studied by William Allan (1939), who had pointed out that this disorder is one of the entities that, like spastic paraplegia and retinitis pigmentosa, demonstrate autosomal dominant inheritance in some families, autosomal recessive inheritance in others, and X-linked inheritance in yet others. Tabaraud et al. (1999) reported findings of prominent demyelination as the cause of X-linked Charcot-Marie-Tooth disease in a 71-year-old woman with late-onset disease. Electrophysiologic studies revealed a nonuniform slowing of motor conduction velocities and dispersion of compound action potentials indicative of a demyelinating process which was confirmed by nerve biopsy. Such electrophysiologic features are unusual in hereditary neuropathies and are more commonly found with acquired chronic demyelinating neuropathies. The patient was found to have a truncating mutation in the connexin-32 gene predicted to result in a protein of 102 codons rather than the normal 283 (304040.0013). The authors noted that the pathology of CMTX in other reported cases had variably been interpreted as axonal, demyelinating, or showing both features. Casasnovas et al. (2006) identified 34 GJB1 mutations, including 6 novel mutations, in 59 patients from 34 CMT families of Spanish or Portuguese descent. The extracellular loop domains were affected in 64.6% of mutations.
Abe et al. (2011) identified GJB1 mutations in 19 (8.5%) of 227 Japanese patients with demyelinating CMT and in 6 (4.7%) of 127 Japanese patients with axonal CMT.
Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) is diagnosed in males and females with the following:...
DiagnosisClinical DiagnosisCharcot-Marie-Tooth neuropathy X type 1 (CMTX1) is diagnosed in males and females with the following:Peripheral motor and sensory neuropathy Slow nerve conduction velocities (NCVs). NCVs range from nearly normal (>40 m/s) to moderately slow, often in the 23-40 m/s range [Hattori et al 2003, Karadima et al 2006]. NCV can vary from nerve to nerve in a single individual [Gutierrez et al 2000]. NCVs can also vary significantly within and between families. Electrophysiologic findings support evidence of a primary axonal neuropathy with demyelinating features. A disease-causing mutation in GJB1 (encoding the protein connexin 32) and/or a family history consistent with X-linked inheritance, i.e., no male-to-male inheritance Molecular Genetic TestingGene. GJB1 is the only gene known to be associated with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). Clinical testing Sequence analysis 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. Deletion/duplication analysis. Complete deletions of the entire coding region of GJB1 are rare [Ainsworth et al 1998, Takashima et al 2003]. No duplications of this gene have been reported.Table 1. Summary of Molecular Genetic Testing Used in CMTX1View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityAffected MalesCarrier FemalesGJB1Sequence analysis Sequence variants 290% 3See footnote 4ClinicalDeletion / duplication analysis 5Partial- and whole-gene deletionsRareRare1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected.3. In affected males, lack of amplification by PCR prior to sequence analysis can suggest a putative exonic or whole-gene deletion on the X chromosome; confirmation may require additional testing by deletion/duplication analysis. 4. In carrier females, sequence analysis of genomic DNA cannot detect deletion of an exon(s) or a whole gene on the X chromosome.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To establish the diagnosis in a proband. Clinical findings and molecular genetic testing are the basis of diagnosis.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: (1) Carriers are heterozygotes for this X-linked disorder and may develop clinical findings related to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and then, if no mutation is identified, by methods to detect gross structural abnormalities.Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo 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 (but with abnormal EMG/NCV), or, more often, have mild to moderate signs and symptoms that may progress [Bone et al 1997, Mazzeo et al 2008, Hyman et al 2009]. Clinical manifestations can vary considerably, even within families. Symptoms typically develop between age five and 25 years, with onset commonly within the first decade in males. Earlier onset with delayed walking in infancy as well as later onset in the fourth and subsequent decades can occur. In some, the disease can be extremely mild and go unrecognized by the affected individual and physician....
Natural HistoryMales with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) have a progressive peripheral motor and sensory neuropathy that tends to be more severe than that seen in CMT1A. Females with CMTX1 may be normal (but with abnormal EMG/NCV), or, more often, have mild to moderate signs and symptoms that may progress [Bone et al 1997, Mazzeo et al 2008, Hyman et al 2009]. Clinical manifestations can vary considerably, even within families. Symptoms typically develop between age five and 25 years, with onset commonly within the first decade in males. Earlier onset with delayed walking in infancy as well as later onset in the fourth and subsequent decades can occur. In some, the disease can be extremely mild and go unrecognized by the affected individual and physician.The typical presenting symptom is weakness of the feet and ankles. The initial physical findings are depressed or absent tendon reflexes with weakness of foot dorsiflexion at the ankle. The typical affected adult has bilateral foot drop, symmetrical atrophy of muscles below the knee (stork leg appearance), pes cavus, atrophy of intrinsic hand muscles, especially the thenar muscles of the thumb, and absent tendon reflexes in both upper and lower extremities. Proximal muscles usually remain strong. Mild to moderate sensory deficits of position, vibration, and pain/temperature commonly occur in the feet.CMTX1 is progressive over many years, but individuals experience long plateau periods without obvious deterioration [Shy et al 2007]. Life span is not decreased. Hearing loss is occasionally reported and auditory evoked potentials may be abnormal [Bahr et al 1999, Stojkovic et al 1999, Lee et al 2002, Takashima et al 2003].Occasional signs of central nervous system involvement have been reported, including extensor plantar responses [Marques et al 1999, Kassubek et al 2005] and involvement of the cerebellum [Kawakami et al 2002]. A female with CNS white matter involvement has been reported [Basri et al 2007].Paulson et al [2002] described two individuals with CMTX1 with transient ataxia, dysarthria, and weakness at altitudes greater than 8,000 feet. Schelhaas et al [2002] described similar phenomena during a febrile illness and also hyperventilation [Srinivasan et al 2008]. Hanemann et al [2003] and Taylor et al [2003] reported transient and recurrent CNS symptoms including weakness and aphasia associated with white matter abnormalities on MRI. The findings sometimes mimic multiple sclerosis [Isoardo et al 2005]. Persistent dysarthria and ataxia have been reported [Siskind et al 2009].Delayed central somatosensory evoked potentials and reduced cerebellar blood flow on SPECT analysis have been reported [Kawakami et al 2002]. Histology rarely reveals nerve hypertrophy or onion bulb formation. Prominent demyelination consistent with a CMT1 phenotype can be found in some cases, whereas most affected individuals appear to have a primary axonal neuropathy with axonal sprouting [Tabaraud et al 1999, Lewis 2000, Hahn et al 2001, Vital et al 2001, Hattori et al 2003]. Pathophysiology. Connexin 32 is found in both the central and the peripheral nervous systems.
A number of genotype-phenotype correlations have been noted:...
Genotype-Phenotype CorrelationsA number of genotype-phenotype correlations have been noted:Males with a nonsense GJB1 mutation have earlier onset and a more severe phenotype than males with a missense mutation. A few families with deletions (null mutations) of GJB1 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 p.Thr55Ile GJB1 mutation [Panas et al 2001]. Central visual, acoustic, and motor pathway involvement has been reported in families with p.Asn205Ser and p.Val139Met GJB1 mutations [Bahr et al 1999, Halbrich et al 2008]. The p.Arg15Trp 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]. The mutations p.Leu76Cysfs*8 and p.Cys179Tyr mutations have been associated with early onset and severe weakness [Braathen et al 2007].Deafness has been reported in individuals with p.Val63Ile and p.Glu186Lys GJB1 mutations [Takashima et al 2003]. Protein p.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 p.Thr191_Phe193dup (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 (c.1075C>T) mutation in EGR2 (reference sequence NP_000390.2) [Chung et al 2005]. A girl with a p.Phe235Cys GJB1 mutation had severe neuropathy and leaky Cx32 hemichannels [Liang et al 2005].
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)....
Differential DiagnosisAcquired (non-genetic) causes of peripheral neuropathy always need to be considered, particularly in simplex cases (i.e., an affected individual with no family history of CMT) (see CMT overview).Because the clinical presentation of Charcot-Marie-Tooth neuropathy X type 1 (CMTX1) can overlap with CMT1, CMT2, or HNPP, it is appropriate to test individuals with a motor and sensory neuropathy first for the PMP22 duplication that causes CMT1A because CMT1A is more common than CMTX1. Findings in CMTX1 can also be similar to those in CMT1B caused by mutations in MPZ [Young et al 2001]. The clinical findings in females with CMTX1 may be clinically indistinguishable from those found in CMT2 or HNPP. An example is a family with only three severely affected females (mother, daughter, and aunt) [Wicklein et al 1997]. Of note, families in which unequivocal male-to-male transmission of neuropathy occurs cannot have CMTX1.Adrenomyeloneuropathy and Pelizeaus-Merzbacher disease are two rare X-linked disorders that may also be associated with peripheral neuropathy. Both conditions have central nervous system manifestations usually not seen in CMTX1.Five other forms of hereditary neuropathy have been linked to markers on the X chromosome. Two of the genes in which mutation is causative have been identified (CMTX5 and CMTX6). Three of the five have other associated findings including intellectual disability, deafness, or optic neuropathy [Huttner et al 2006]:CMTX2 with intellectual disability maps to Xp22.2 [Ionasescu et al 1992]. CMTX3 with spasticity and pyramidal tract signs maps to Xq26 [Huttner et al 2006]. CMTX4 (Cowchock syndrome) with deafness and intellectual disability maps to Xq24-q26.1 [Cowchock et al 1985, Priest et al 1995]. Rinaldi et al [2012] identified a missense mutation (p.Glu493Val) in AIFM1 (encoding apoptosis-inducing factor 1) in a member of the original family.CMTX5 with deafness and optic neuropathy maps to Xq21.3-q24 [Kim et al 2005]. Mutations (p.Glu43Asp and p.Met115Thr) in PRPS1 (NP_002755.1) 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]. CMTX6. Males have childhood onset of a slowly progressive motor and sensory neuropathy that is largely axonal (variable mild conduction slowing) with steppage gait and absent tendon reflexes. Carrier females may have a mild sensory motor axonal neuropathy [Kennerson et al 2013]. Kennerson et al [2009] have described an X-linked form of distal hereditary motor neuropathy with a CMT phenotype linked to Xq13.1-21 and associated with missense mutations in ATP7A, the same gene involved in Menkes disease [Kennerson et al 2010].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsTreatment 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 ManifestationsNo treatment that reverses or slows the natural process of CMT exists.Prevention of Secondary ComplicationsDaily heel cord stretching exercises to prevent Achilles' tendon shortening are desirable.SurveillanceRegular foot examination for pressure sores or poorly fitting footwear is appropriate.Agents/Circumstances to AvoidObesity is to be avoided because it makes walking more difficult.Medications which are toxic or potentially toxic to persons with CMT comprise a range of risks including:Definite high risk. Vinca alkaloids (Vincristine)This category should be avoided by all persons with CMT, including those who are asymptomaticOther potential risk levels. See Table 2. For more information, click here (pdf)Table 2. Medications Potentially Toxic to Persons with CMTView in own windowModerate to Significant Risk 1- Amiodarone (Cordarone) - Bortezomib (Velcade) - Cisplatin & Oxaliplatin - Colchicine (extended use) - Dapsone - Didanosine (ddI, Videx) - Dichloroacetate - Disulfiram (Antabuse) - Gold salts - Leflunomide (Arava) - Metronidazole/Misonidazole (extended use) - Nitrofurantoin (Macrodantin, Furadantin, Macrobid) - Nitrous oxide (inhalation abuse or Vitamin B12 deficiency) - Perhexiline (not used in US) - Pyridoxine (mega dose of Vitamin B6) - Stavudine (d4T, Zerit) - Suramin - Taxols (paclitaxel, docetaxel) - Thalidomide - Zalcitabine (ddC, Hivid)Click here (pdf) for additional medications in lesser-risk categories.The medications listed here present differing degrees of potential risk for worsening CMT neuropathy. Always consult your treating physician before taking or changing any medication.1. Based on: Weimer & Podwall [2006]. See also Graf et al [1996]; Nishikawa et al [2008], and Porter et al [2009].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.OtherCareer and employment choices may be influenced by persistent weakness of hands and/or feet.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDGJB1Xq13.1Gap junction beta-1 proteinThe Connexin-deafness homepage IPN Mutations, GJB1 GJB1 homepage - Leiden Muscular Dystrophy pagesGJB1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Charcot-Marie-Tooth Neuropathy X Type 1 (View All in OMIM) View in own window 302800CHARCOT-MARIE-TOOTH DISEASE, X-LINKED DOMINANT, 1; CMTX1 304040GAP JUNCTION PROTEIN, BETA-1; GJB1Normal allelic variants. GJB1 consists of two non-coding exons (1 and 2) that are alternatively spliced in a tissue-specific manner and one coding exon (exon 3). Pathologic allelic variants. More than 250 different mutations in GJB1 have been identified in families with Charcot-Marie-Tooth neuropathy X type 1 (CMTX1). These include missense, stop codon, and frame shift mutations [De Jonghe et al 1997, Nelis et al 1999, Lee et al 2002, Umehara et al 2006]. Mutations have been identified in the promoter region of GJB1 and the 5’ non-coding region [Ionasescu et al 1996, Houlden et al 2004, Li et al 2009]. Deletion of exon(s) and of the whole gene have been reported (see Table A). Table 3. Selected GJB1 Pathologic Allelic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid Change (Alias 1)Reference Sequencesc.43C>Tp.Arg15Trp NM_000166.5 NP_000157.1c.123G>Cp.Glu41Aspc.145T>Cp.Ser49Proc.164C>Tp.Thr55Ilec.187G>Ap.Val63Ilec.223C>Tp.Arg75Trpc.225delGp.Leu76Cysfs*8 (Arg75fs*83)c.556G>Ap.Glu186Lysc.407T>Cp.Val136Alac.415G>Ap.Val139Metc.536G>Ap.Cys179Tyrc.614A>Gp.Asn205Serc.704T>Gp.Phe235Cysc.571_579dup (9-bp insertion)p.Thr191_Phe193dupSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. Gap junction beta-1 protein is found in peripheral myelin and specifically located in uncompacted folds of Schwann cell cytoplasm at the nodes of Ranvier and at Schmidt-Lanterman incisures. It is also found in central myelin. Gap junction beta-1 protein has two extracellular loops, four transmembrane domains, and three cytoplasmic domains. Gap junctions form direct channels between cells that facilitate transfer of ions and small molecules. Six connexins oligomerize to form hemichannels, or connexins. When properly opposed to each other on cell membranes, two connexins form gap junction channels that permit the diffusion of ions and small molecules [Sáez et al 2005]. Abnormal gene product. GJB1 mutations produce proteins with impaired glial/neuronal interactions and signal transduction. Loss of function of connexin 32 likely explains the pathogenesis of CMTX1. Mutations result in an increased opening of hemichannels that may damage cells through loss of ionic gradients and increased influx of Ca++ [Abrams et al 2001, Abrams et al 2002]. Not all mutations are associated with the inability to form homotypic gap junctions; some mutations lead to abnormal trafficking of Cx32 [Wang et al 2004] or to selective defects in channel permeability [Bicego et al 2006]. Loss of function can result in both peripheral and central demyelination [Sargiannidou et al 2009].