Goal 1.

Describe the clinical characteristics of CMT hereditary neuropathy.

Goal 2.

Review the causes of CMT hereditary neuropathy.

Goal 3.

Provide an evaluation strategy to identify the cause of CMT hereditary neuropathy in a proband (when possible).

Goal 4.

Review management of CMT hereditary neuropathy.

Goal 5.

Inform genetic counseling of family members of an individual with CMT hereditary neuropathy.

Clinical Findings

Individuals with CMT manifest symmetric, slowly progressive distal motor neuropathy of the arms and legs usually beginning in the first to third decade and resulting in weakness and atrophy of the muscles in the feet and/or hands. The affected individual typically has distal muscle weakness and atrophy, weak ankle dorsiflexion, depressed tendon reflexes, and pes cavus foot deformity (i.e., high-arched feet).

Muscle weakness is often associated with mild to moderate distal sensory loss. Although usually described as "painless," the neuropathy can be painful [Azevedo et al 2018]. Sensory loss can most easily be demonstrated by a decreased appreciation of vibration, but can also include impaired sensation of pain/pinprick, temperature, and joint position.

Sensorineural hearing loss can occur.

The clinical diagnosis of CMT in a symptomatic person is based on characteristic findings of peripheral neuropathy on medical history and physical examination.

Classification of CMT Type

Traditional classification of CMT (e.g., CMT1, CMT2, and DI-CMT [dominant intermediate]) was based on peripheral neuropathy type as determined by nerve conduction velocity (NCV) and mode of inheritance as determined by family history. As understanding of the genetic basis of CMT gradually evolved, letters in alphabetic order were assigned to the CMT type to represent the gene involved (e.g., CMT1A).

In general the three autosomal dominant neuropathy types based on NCV (normal >40-45 meters/second) were the following [Stojkovic 2016]:

• Demyelinating (CMT1) defined as NCV <35 m/s. The clinical findings of distal muscle weakness and atrophy and sensory loss were usually slowly progressive and often associated with pes cavus foot deformity and bilateral foot drop. Affected individuals usually became symptomatic between ages five and 25 years. Fewer than 5% of individuals became wheelchair dependent. Life span was not shortened.
• Axonal (non-demyelinating) (CMT2) defined as NCV >45m/s. The clinical findings were distal muscle weakness and atrophy. Although axonal peripheral neuropathy shows extensive clinical overlap with demyelinating peripheral neuropathy, in general individuals with axonal neuropathy tended to be less disabled and have less sensory loss than individuals with demyelinating neuropathy.
• Dominant intermediate CMT (DI-CMT) defined as NCV 35-45 m/s. The clinical findings are a relatively typical CMT phenotype. NCVs are so variable that within a family some affected individuals fall in the demyelinating neuropathy range, whereas others fall in the axonal neuropathy range.

Newly proposed CMT naming system. As more genes causing CMT were identified and as the overlap of neuropathy phenotypes and modes of inheritance became apparent, the above alphanumeric classification system proved unwieldy and inadequate. In 2018, Magy et al [2018] proposed a gene-based classification of inherited neuropathies (see Table 4, which includes a comprehensive list of CMT-associated genes and correlation with the alphanumeric classification). An additional advantage of the Magy et al [2018] classification system is that an individual's findings can be described in terms of mode of inheritance, neuropathy type, and gene (see Evaluation Strategies).

Nomenclature

Distal hereditary motor neuropathy (dHMN) and distal spinal muscular atrophy (DSMA) = CMT. In their study of distal hereditary motor neuropathies (the clinically and genetically heterogeneous group of disorders characterized by lower motor neuron dysfunction), Bansagi et al [2017] reported that pathogenic variants in the same genes can cause the phenotypes known as dHMN and DSMA, leading them to conclude that dHMN and motor CMT should not be classified differently.

Dejerine-Sottas syndrome (DSS) originally referred to a severe demyelinating neuropathy of infancy and childhood associated with very slow NCVs, elevated CSF protein, marked clinical weakness, and hypertrophic nerves with onion bulb formation. Although the term "DSS" is still sometimes used to indicate a clinical phenotype, it does not imply an inheritance pattern or a specific genetic defect [Parman et al 2004].

Differential Diagnosis of CMT

CMT – the subject of this overview – needs to be distinguished from the following entities: systemic disorders with neuropathy, other types of hereditary neuropathy (Table1), distal myopathies (Table 2), hereditary sensory neuropathies (HSN), and acquired disorders. Note: These entities are not discussed elsewhere in this overview.

Family History

A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or review of their medical records, including the results of molecular genetic testing and EMG and NCV studies.

Individuals with CMT may have a negative family history for many reasons, including mild subclinical expression in other family members, autosomal recessive inheritance, or a de novo heterozygous pathogenic variant in a gene associated with autosomal dominant inheritance [Rudnik-Schöneborn et al 2016] or X-linked inheritance.

Molecular Genetic Testing

Health care providers ordering genetic testing should be familiar with the genetics of CMT. Given the complexity of interpreting genetic test results and their implications for genetic counseling, health care providers should consider referral to a neurogenetics center or a genetic counselor specializing in neurogenetics (see NSGC – Find a Genetic Counselor).

Molecular genetic testing approaches can include gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array). Gene-targeted testing requires the clinician to hypothesize which gene(s) are likely involved, whereas genomic testing does not.

Treatment of Manifestations

Reviews of treatment approaches to CMT [Carter et al 2008, Young et al 2008, Reilly & Shy 2009, Corrado et al 2016] as well as reviews of the diagnosis, natural history, and management of CMT [Pareyson & Marchesi 2009a, Pareyson & Marchesi 2009b, Cornett et al 2017, Sivera Mascaró et al 2024] are available. Guidelines for the management of the pediatric population with CMT have been published [Yiu et al 2022].

Treatment is symptomatic. Affected individuals are often evaluated and managed by a multidisciplinary team that includes neurologists, physiatrists, orthopedic surgeons, and physical and occupational therapists [Grandis & Shy 2005, McCorquodale et al 2016].

Quality of life and defining disability have been measured and compared among various groups of individuals with CMT [Burns et al 2010, Ramchandren et al 2015]. Persistent weakness of the hands and/or feet has important career and employment implications; anticipatory counseling is appropriate.

Special shoes, including those with good ankle support, may be needed. Affected individuals often require ankle/foot orthoses (AFOs) to correct foot drop and aid walking. Night splints have not improved ankle range of motion [Refshauge et al 2006, Kenis-Coskun & Matthews 2016].

Some individuals require forearm crutches or canes for gait stability; fewer than 5% of individuals need wheelchairs.

Daily heel cord stretching exercises to prevent Achilles tendon shortening are desirable, as well as gripping exercises for hand weakness [Vinci et al 2005b].

Exercise is encouraged within the individual's capability and many individuals remain physically active [Sman et al 2015].

Orthopedic surgery may be required to correct severe pes cavus deformity [Guyton 2006, Casasnovas et al 2008, Ward et al 2008]. Clinical assessment and management approaches to foot deformities that may be associated with CMT are reviewed in Laurá et al [2024]. Management regarding surgery referral and intervention ideally involves multidisciplinary input (i.e., neurology, physical therapy, and orthopedics). Surgery is sometimes required for hip dysplasia [Chan et al 2006].

The cause of any pain should be identified as accurately as possible [Padua et al 2006].

• Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory agents [Carter et al 1998].
• Neuropathic pain may respond to tricyclic antidepressants or drugs such as carbamazepine or gabapentin.

Modafinil has been used to treat fatigue [Carter et al 2006].

Those at increased risk for vocal cord paralysis (see Table 4) warrant consultation with specialists in otolaryngology at the time of diagnosis; evidence of vocal cord paralysis (hoarseness and/or stridor) at any time warrants periodic monitoring by specialists in otolaryngology to detect vocal cord hypomotility and quantify the degree of airway obstruction, a potentially lethal complication [Zambon et al 2017].

In a study of five individuals with CMT-associated sensorineural hearing loss and auditory neuropathy spectrum disorder, Farber et al [2024] found that cochlear implants were safe and reliable and improved both hearing and speech. Note: Four of the described individuals were from a family with the PMP22 pathogenic variant c.199G>C (p.Ala67Pro) [Kovach et al 1999].

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.

Chemotherapy for cancer that includes vincristine may be especially damaging to peripheral nerves and severely worsen CMT [Graf et al 1996, Nishikawa et al 2008].

Pregnancy Management

CMT appears to be an independent risk factor for maternal complications during pregnancy and delivery [Pisciotta et al 2020]. In a study of 157 deliveries in 193 pregnancies Pisciotta et al found that:

• In 9.3% of pregnancies, new manifestations of CMT can appear and existing manifestations (including reduced strength and sensitivity, cramps, and pain) can worsen, and may persist following pregnancy;
• Placenta previa (1.6%) abnormal nonvertex presentation (8.4%), and preterm delivery (20.3%) occurred more frequently in the pregnancies of mothers with CMT.

Mode of Inheritance

CMT hereditary neuropathy can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Given the complexity of the genetics of CMT, health care providers should consider referring at-risk relatives to a neurogenetics center or genetic counselor specializing in neurogenetics (see NSGC – Find a Genetic Counselor search tool).

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• Most individuals diagnosed with autosomal dominant CMT have an affected parent.
• Some individuals diagnosed with autosomal dominant CMT have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by a de novo pathogenic variant varies depending on the involved gene. In a study of 1,206 index cases, Rudnik-Schöneborn et al [2016] identified de novo variants in 1.3% of individuals with a PMP duplication and 25% of those with MPZ variants.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Germline mosaicism has been reported [Fabrizi et al 2001].
• The family history of some individuals diagnosed with autosomal dominant CMT may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known CMT-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.
• If the parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for CMT because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with autosomal dominant CMT has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance – Risk to Family Members

Parents of a proband

• The parents of an individual diagnosed with autosomal recessive CMT are obligate heterozygotes (i.e., carriers of one pathogenic variant).
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. The offspring of an individual with autosomal recessive CMT are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a pathogenic variant.

Carrier detection. Carrier testing for at-risk relatives requires prior identification of the CMT-related pathogenic variants in the family.

X-Linked Inheritance – 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 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 pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., represents a simplex case), the mother may be a heterozygote or the affected male may have a de novo pathogenic variant, in which case the mother is not heterozygous. The frequency of males with a de novo pathogenic variant is not known.

Parents of a female proband

• A female proband may have inherited the 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 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 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 or may not be affected.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of 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 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 (carriers) and may or may not be affected.
• If the father of the proband has a pathogenic variant, he will transmit it to all of 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 pathogenic variant cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is low but greater than that of the general population because of the theoretic possibility of germline mosaicism.

Offspring of a proband

• Affected males transmit the pathogenic variant to all of their daughters and none of their sons.
• Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child; sons who inherit the pathogenic variant will be affected; daughters may or may not be affected.

Other family members. If a parent of the proband also has a pathogenic variant, the parent's female family members may be at risk of being heterozygotes (asymptomatic or symptomatic) and the parent's male family members may be at risk of being affected depending on their genetic relationship to the proband.

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 pathogenic variant has been identified in the proband.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the CMT-related pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including, but not limited to, socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years). For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

In a family with an established diagnosis of CMT it is appropriate to consider testing of symptomatic individuals regardless of age.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant or X-linked condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the CMT-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Revision History

• 11 July 2024 (tb) Revision: ITPR3 added to Table 4 [Beijer et al 2024]
• 25 April 2024 (tb) Revision: Laurá et al [2024] added to Management
• 14 March 2024 (tb) Revision: information regarding cochlear implants added to Management; clinical practice guidelines [Sivera Mascaró et al 2024] added to Management
• 23 February 2023 (tb) Revision: SARS1 added to Table 4 [He et al [2023]
• 29 September 2022 (tb) Revision: Setlere et al [2022] added to Table 4 (AARS1)
• 24 February 2022 (tb) Revision: added Yiu et al [2022] guidelines for pediatric management
• 9 September 2021 (tb) Revision: added comment on SPTLC1 in Table 4 [Johnson et al 2021]
• 20 May 2021 (tb) Revision: CADM3 added to Table 4 [Rebelo et al 2021]
• 18 March 2021 (tb) Revision: VWA1 added to Table 4
• 4 March 2021 (tb) Revision: Pregnancy Management section added [Pisciotta et al 2020]
• 14 May 2020 (tb) Revision: SORD added to Table 4 [Cortese et al 2020]
• 2 January 2020 (tb) Revision: correction (PNKP) to Table 4 [Leal et al 2018]
• 12 December 2019 (aa) Revision: information on GJB1 added to Table 4
• 24 January 2019 (aa) Revision: gene (PMP2) added to Table 4
• 28 June 2018 (bp) Comprehensive update posted live
• 31 May 2011 (me) Comprehensive update posted live
• 31 August 2007 (me) Comprehensive update posted live
• 27 April 2005 (me) Comprehensive update posted live
• 28 March 2003 (me) Comprehensive update posted live
• 20 June 2001 (me) Comprehensive update posted live
• 28 September 1998 (pb) Overview posted live
• April 1996 (tb) Original submission

Literature Cited

• Azevedo H, Pupe C, Pereira R, Nascimento OJM. Pain in Charcot-Marie-Tooth disease: an update. Arq Neuropsiquiatr. 2018;76:273-6. [PubMed: 29742248]
• Bansagi B, Griffin H, Whittaker RG, Antoniadi T, Evangelista T, Miller J, Greenslade M, Forester N, Duff J, Bradshaw A, Kleinle S, Boczonadi V, Steele H, Ramesh V, Franko E, Pyle A, Lochmüller H, Chinnery PF, Horvath R. Genetic heterogeneity of motor neuropathies. Neurology. 2017;88:1226-34 [PMC free article: PMC5373778] [PubMed: 28251916]
• Beijer D, Dohrn MF, Rebelo A, Danzi MC, Grosz BR, Ellis M, Kumar KR, Vucic S, Vais H, Weissenrieder JS, Lunko O, Paudel U, Simpson LC, Raposo J, Saporta M, Arcia Y, Xu I, Feely S, Record CJ, Blake J, Reilly MM, Scherer S, Kennerson M, Lee YC, Foskett JK, Shy M, Zuchner S. A recurrent missense variant in ITPR3 causes demyelinating Charcot-Marie-Tooth with variable severity. Brain. 2024. Epub ahead of print. [PubMed: 38938188]
• Brewer MH, Chaudhry R, Qi J, Kidambi A, Drew AP, Menezes MP, Ryan MM, Farrar MA, Mowat D, Subramanian GM, Young HK, Zuchner S, Reddel SW, Nicholson GA, Kennerson ML. Whole genome sequencing identifies a 78 kb insertion from chromosome 8 as the cause of Charcot-Marie-Tooth neuropathy CMTX3. PLoS Genet. 2016;12:e1006177 [PMC free article: PMC4954712] [PubMed: 27438001]
• Burns J, Ramchandren S, Ryan MM, Shy M, Ouvrier RA. Determinants of reduced health-related quality of life in pediatric inherited neuropathies. Neurology. 2010;75:726–31. [PMC free article: PMC2931653] [PubMed: 20733147]
• Carter GT, Han JJ, Mayadev A, Weiss MD. Modafinil reduces fatigue in Charcot-Marie-Tooth disease type 1A: a case series. Am J Hosp Palliat Care. 2006;23:412–6. [PubMed: 17060310]
• Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, Abresch RT, Bird TD. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998;79:1560–4. [PubMed: 9862301]
• Carter GT, Weiss MD, Han JJ, Chance PF, England JD. Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2008;10:94–102. [PubMed: 18334132]
• Casasnovas C, Cano LM, Albertí A, Céspedes M, Rigo G. Charcot-Marie-tooth disease. Foot Ankle Spec. 2008;1:350–4. [PubMed: 19825739]
• Chan G, Bowen JR, Kumar SJ. Evaluation and treatment of hip dysplasia in Charcot-Marie-Tooth disease. Orthop Clin North Am. 2006;37:203–9. [PubMed: 16638451]
• Cornett KM, Menezes MP, Bray P, Halaki M, Shy RR, Yum SW, Estilow T, Moroni I, Foscan M, Pagliano E, Pareyson D, Laurá M, Bhandari T, Muntoni F, Reilly MM, Finkel RS, Sowden J, Eichinger KJ, Herrmann DN, Shy ME, Burns J, Inherited Neuropathies Consortium. Phenotypic variability of childhood Charcot-Marie-Tooth disease. JAMA Neurol. 2016;73:645-51. [PMC free article: PMC4916861] [PubMed: 27043305]
• Cornett KMD, Menezes MP, Shy RR, Moroni I, Pagliano E, Pareyson D, Estilow T, Yum SW, Bhandari T, Muntoni F, Laura M, Reilly MM, Finkel RS, Eichinger KJ, Herrmann DN, Bray P, Halaki M, Shy ME, Burns J, CMTPedS Study Group. Natural history of Charcot-Marie-Tooth disease during childhood. Ann Neurol. 2017;82:353-9. [PMC free article: PMC8294172] [PubMed: 28796392]
• Corrado B, Ciardi G, Bargigli C. Rehabilitation management of the Charcot-Marie-Tooth syndrome: a systematic review of the literature. Medicine (Baltimore). 2016;95:e3278. [PMC free article: PMC4998680] [PubMed: 27124017]
• Cortese A, Zhu Y, Rebelo AP, Negri S, Courel S, Abreu L, Bacon CJ, Bai Y, Bis-Brewer DM, Bugiardini E, Buglo E, Danzi MC, Feely SME, Athanasiou-Fragkouli A, Haridy NA, Isasi R, Khan A, Laurà M, Magri S, Pipis M, Pisciotta C, Powell E, Rossor AM, Saveri P, Sowden JE, Tozza S, Vandrovcova J, Dallman J, Grignani E, Marchioni E, Scherer SS, Tang B, Lin Z, Al-Ajmi A, Schüle R, Synofzik M, Maisonobe T, Stojkovic T, Auer-Grumbach M, Abdelhamed MA, Hamed SA, Zhang R, Manganelli F, Santoro L, Taroni F, Pareyson D, Houlden H, Herrmann DN, Reilly MM, Shy ME, Zhai RG, Zuchner S, et al. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet. 2020;52:473-81. [PMC free article: PMC8353599] [PubMed: 32367058]
• Fabrizi GM, Ferrarini M, Cavallaro T, Jarre L, Polo A, Rizzuto N (2001) A somatic and germline mosaic mutation in MPZ/P(0) mimics recessive inheritance of CMT1B. Neurology. 57:101-5. [PubMed: 11445635]
• Farber NI, Chin OY, Mills DM, Diaz RC, Brodie HA, Sagiv D. Cochlear implantation in Charcot-Marie-Tooth patients: speech perception and quality of life. Ann Otol Rhinol Laryngol. 2024;133:469-75. [PubMed: 38361273]
• Frasquet M, Chumillas MJ, Vílchez JJ, Márquez-Infante C, Palau F, Vázquez-Costa JF, Lupo V, Espinós C, Sevilla T. Phenotype and natural history of inherited neuropathies caused by HSJ1 c.352+1G>A mutation. J Neurol Neurosurg Psychiatry. 2016;87:1265-8. [PubMed: 27083531]
• Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996;77:1356–62. [PubMed: 8608515]
• Grandis M, Shy ME. Current therapy for Charcot-Marie-Tooth disease. Curr Treat Options Neurol. 2005;7:23–31. [PubMed: 15610704]
• Guyton GP. Current concepts review: orthopaedic aspects of Charcot-Marie-Tooth disease. Foot Ankle Int. 2006;27:1003–10. [PubMed: 17144969]
• He J, Liu XX, Ma MM, Lin JJ, Fu J, Chen YK, Xu GR, Xu LQ, Fu ZF, Xu D, Chen WF, Cao CY, Shi Y, Zeng YH, Zhang J, Chen XC, Zhang RX, Wang N, Kennerson M, Fan DS, Chen WJ. Heterozygous Seryl-tRNA synthetase 1 variants cause Charcot-Marie-Tooth disease. Ann Neurol. 2023;93:244-56. [PubMed: 36088542]
• Higuchi Y, Okunushi R, Hara T, Hashiguchi A, Yuan J, Yoshimura A, Murayama K, Ohtake A, Ando M, Hiramatsu Y, Ishihara S, Tanabe H, Okamoto Y, Matsuura E, Ueda T, Toda T, Yamashita S, Yamada K, Koide T, Yaguchi H, Mitsui J, Ishiura H, Yoshimura J, Doi K, Morishita S, Sato K, Nakagawa M, Yamaguchi M, Tsuji S, Takashima H. Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. Brain. 2018;141:1622-36 [PMC free article: PMC5972596] [PubMed: 29718187]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Johnson JO, Chia R, Miller DE, Li R, Kumaran R, Abramzon Y, Alahmady N, Renton AE, Topp SD, Gibbs JR, Cookson MR, Sabir MS, Dalgard CL, Troakes C, Jones AR, Shatunov A, Iacoangeli A, Al Khleifat A, Ticozzi N, Silani V, Gellera C, Blair IP, Dobson-Stone C, Kwok JB, Bonkowski ES, Palvadeau R, Tienari PJ, Morrison KE, Shaw PJ, Al-Chalabi A, Brown RH Jr, Calvo A, Mora G, Al-Saif H, Gotkine M, Leigh F, Chang IJ, Perlman SJ, Glass I, Scott AI, Shaw CE, Basak AN, Landers JE, Chiò A, Crawford TO, Smith BN, Traynor BJ, et al. Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis. JAMA Neurol. 2021;78:1236-48. [PMC free article: PMC8406220] [PubMed: 34459874]
• Kanhangad M, Cornett K, Brewer MH, Nicholson GA, Ryan MM, Smith RL, Subramanian GM, Young HK, Züchner S, Kennerson ML, Burns J, Menezes MP. Unique clinical and neurophysiologic profile of a cohort of children with CMTX3. Neurology. 2018;90:e1706-10 [PMC free article: PMC10681066] [PubMed: 29626178]
• Kenis-Coskun O, Matthews DJ. Rehabilitation issues in Charcot-Marie-Tooth disease. J Pediatr Rehabil Med. 2016;9:31-4. [PubMed: 26966798]
• Kovach MJ, Lin JP, Boyadjiev S, Campbell K, Mazzeo L, Herman K, Rimer LA, Frank W, Llewellyn B, Jabs EW, Gelber D, Kimonis VE. A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am J Hum Genet. 1999;64:1580-93. [PMC free article: PMC1377901] [PubMed: 10330345]
• Lassuthova P, Rebelo AP, Ravenscroft G, Lamont PJ, Davis MR, Manganelli F, Feely SM, Bacon C, Brožková DŠ, Haberlova J, Mazanec R, Tao F, Saghira C, Abreu L, Courel S, Powell E, Buglo E, Bis DM, Baxter MF, Ong RW, Marns L, Lee YC, Bai Y, Isom DG, Barro-Soria R, Chung KW, Scherer SS, Larsson HP, Laing NG, Choi BO, Seeman P, Shy ME, Santoro L, Zuchner S. Mutations in ATP1A1 cause dominant Charcot-Marie-Tooth type 2. Am J Hum Genet. 2018;102:505-14. [PMC free article: PMC5985288] [PubMed: 29499166]
• Laurá M, Barnett J, Benfield J, Ramdharry GM, Welck MJ. Foot surgery for adults with Charcot-Marie-Tooth disease. Pract Neurol. 2024;24:275-84. [PubMed: 38631902]
• Leal A, Bogantes-Ledezma S, Ekici AB, Uebe S, Thiel CT, Sticht H, Berghoff M, Berghoff C, Morera B, Meisterernst M, Reis A. The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25. Neurogenetics. 2018;19:215-25. [PMC free article: PMC6280876] [PubMed: 30039206]
• Lupo V, Aguado C, Knecht E, Espinós C. Chaperonopathies: spotlight on hereditary motor neuropathies. Front Mol Biosci. 2016;3:81. [PMC free article: PMC5155517] [PubMed: 28018906]
• Magy L, Mathis S, Le Masson G, Goizet C, Tazir M, Vallat JM. Updating the classification of inherited neuropathies: results of an international survey. Neurology. 2018;90:e870-6 [PubMed: 29429969]
• McCorquodale D, Pucillo EM, Johnson NE. Management of Charcot-Marie-Tooth disease: improving long-term care with a multidisciplinary approach. J Multidiscip Healthc. 2016;9:7-19. [PMC free article: PMC4725690] [PubMed: 26855581]
• Nishikawa T, Kawakami K, Kumamoto T, Tonooka S, Abe A, Hayasaka K, Okamoto Y, Kawano Y. Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30:519–21. [PubMed: 18797198]
• Padua L, Aprile I, Cavallaro T, Commodari I, La Torre G, Pareyson D, Quattrone A, Rizzuto N, Vita G, Tonali P, Schenone A, Italian CMT. QoL Study Group. Variables influencing quality of life and disability in Charcot Marie Tooth (CMT) patients: Italian multicentre study. Neurol Sci. 2006;27:417–23. [PubMed: 17205227]
• Pareyson D, Marchesi C. Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 2009a;8:654–67. [PubMed: 19539237]
• Pareyson D, Marchesi C. Natural history and treatment of peripheral inherited neuropathies. Adv Exp Med Biol. 2009b;652:207–24. [PubMed: 20225028]
• Parman Y, Battaloglu E, Baris I, Bilir B, Poyraz M, Bissar-Tadmouri N, Williams A, Ammar N, Nelis E, Timmerman V, De Jonghe P, Najafov A, Deymeer F, Serdaroglu P, Brophy PJ, Said G. Clinicopathological and genetic study of early-onset demyelinating neuropathy. Brain. 2004;127:2540–50. [PubMed: 15469949]
• Pisciotta C, Calabrese D, Santoro L, Tramacere I, Manganelli F, Fabrizi GM, Schenone A, Cavallaro T, Grandis M, Previtali SC, Allegri I, Padua L, Pazzaglia C, Saveri P, Quattrone A, Valentino P, Tozza S, Gentile L, Russo M, Mazzeo A, Trapasso MC, Parazzini F, Vita G, Pareyson D, et al. Pregnancy in Charcot-Marie-Tooth disease: data from the Italian CMT national registry. Neurology. 2020;95:e3180-e3189. [PMC free article: PMC7836663] [PubMed: 32928981]
• Ramchandren S, Shy M, Feldman E, Carlos R, Siskind C. Defining disability: development and validation of a mobility-Disability Severity Index (mDSI) in Charcot-Marie-tooth disease. J Neurol Neurosurg Psychiatry. 2015;86:635-9. [PMC free article: PMC4920058] [PubMed: 25157034]
• Rebelo AP, Cortese A, Abraham A, Eshed-Eisenbach Y, Shner G, Vainshtein A, Buglo E, Camarena V, Gaidosh G, Shiekhattar R, Abreu L, Courel S, Burns DK, Bai Y, Bacon C, Feely SME, Castro D, Peles E, Reilly MM, Shy ME, Zuchner S. A CADM3 variant causes Charcot-Marie-Tooth disease with marked upper limb involvement. Brain. 2021;144:1197-213. [PMC free article: PMC8105037] [PubMed: 33889941]
• Rebelo AP, Saade D, Pereira CV, Farooq A, Huff TC, Abreu L, Moraes CT, Mnatsakanova D, Mathews K, Yang H, Schon EA, Zuchner S, Shy ME. SCO2 mutations cause early-onset axonal Charcot-Marie-Tooth disease associated with cellular copper deficiency. Brain. 2018;141:662-72. [PMC free article: PMC5837310] [PubMed: 29351582]
• Refshauge KM, Raymond J, Nicholson G, van den Dolder PA. Night splinting does not increase ankle range of motion in people with Charcot-Marie-Tooth disease: a randomised, cross-over trial. Aust J Physiother. 2006;52:193–9. [PubMed: 16942454]
• Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009;80:1304–14. [PubMed: 19917815]
• Rotthier A, Baets J, Timmerman V, Janssens K. Mechanisms of disease in hereditary sensory and autonomic neuropathies. Nat Rev Neurol. 2012;8:73–85. [PubMed: 22270030]
• Rudnik-Schöneborn S, Tölle D, Senderek J, Eggermann K, Elbracht M, Kornak U, von der Hagen M, Kirschner J, Leube B, Müller-Felber W, Schara U, von Au K, Wieczorek D, Bußmann C, Zerres K. Diagnostic algorithms in Charcot-Marie-Tooth neuropathies: experiences from a German genetic laboratory on the basis of 1206 index patients. Clin Genet. 2016;89:34-43 [PubMed: 25850958]
• Setlere S, Jurcenko M, Gailite L, Rots D, Kenina V. Alanyl-tRNA synthetase 1 gene variants in hereditary neuropathy: genotype and phenotype overview. Neurol Genet. 2022;8:e200019. [PMC free article: PMC9450682] [PubMed: 36092982]
• Sivera Mascaró R, García Sobrino T, Horga Hernández A, Pelayo Negro AL, Alonso Jiménez A, Antelo Pose A, Calabria Gallego MD, Casasnovas C, Cemillán Fernández CA, Esteban Pérez J, Fenollar Cortés M, Frasquet Carrera M, Gallano Petit MP, Giménez Muñoz A, Gutiérrez Gutiérrez G, Gutiérrez Martínez A, Juntas Morales R, Ciano-Petersen NL, Martínez Ulloa PL, Mederer Hengstl S, Millet Sancho E, Navacerrada Barrero FJ, Navarrete Faubel FE, Pardo Fernández J, Pascual Pascual SI, Pérez Lucas J, Pino Mínguez J, Rabasa Pérez M, Sánchez González M, Sotoca J, Rodríguez Santiago B, Rojas García R, Turon-Sans J, Vicent Carsí V, Sevilla Mantecón T. Clinical practice guidelines for the diagnosis and management of Charcot-Marie-Tooth disease. Neurologia (Engl Ed). 2024. Epub ahead of print. [PubMed: 38431252]
• Sman AD, Hackett D, Fiatarone Singh M, Fornusek C, Menezes MP, Burns J. Systematic review of exercise for Charcot-Marie-Tooth disease. J Peripher Nerv Syst. 2015;20:347-62. [PubMed: 26010435]
• Stojkovic T. Hereditary neuropathies: an update. Rev Neurol (Paris). 2016;172:775-8 [PubMed: 27866730]
• Vinci P, Villa LM, Castagnoli L, Marconi C, Lattanzi A, Manini MP, Calicchio ML, Vitangeli L, Di Gianvito P, Perelli SL, Martini D. Handgrip impairment in Charcot-Marie-Tooth disease. Eura Medicophys. 2005b;41:131–4. [PubMed: 16200028]
• Ward CM, Dolan LA, Bennett DL, Morcuende JA, Cooper RR. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease. J Bone Joint Surg Am. 2008;90:2631–42. [PMC free article: PMC2663331] [PubMed: 19047708]
• Yiu EM, Bray P, Baets J, Baker SK, Barisic N, de Valle K, Estilow T, Farrar MA, Finkel RS, Haberlová J, Kennedy RA, Moroni I, Nicholson GA, Ramchandren S, Reilly MM, Rose K, Shy ME, Siskind CE, Yum SW, Menezes MP, Ryan MM, Burns J. Clinical practice guideline for the management of paediatric Charcot-Marie-Tooth disease. J Neurol Neurosurg Psychiatry. 2022;93:530-8. [PubMed: 35140138]
• Young P, De Jonghe P, Stögbauer F, Butterfass-Bahloul T. Treatment for Charcot-Marie-Tooth disease. Cochrane Database Syst Rev. 2008;(1):CD006052. [PMC free article: PMC6718225] [PubMed: 18254090]
• Zambon AA, Natali Sora MG, Cantarella G, Cerri F, Quattrini A, Comi G, Previtali SC, Bolino A. Vocal cord paralysis in Charcot-Marie-Tooth type 4b1 disease associated with a novel mutation in the myotubularin-related protein 2 gene: a case report and review of the literature. Neuromuscul Disord. 2017;27:487-91 [PMC free article: PMC5425401] [PubMed: 28190646]