Laboratory Studies

Results of all routine laboratory tests are within the reference range in Charcot-Marie-Tooth disease (CMT). Specific genetic tests are available for some types of CMT. A study by Murphy et al demonstrates that a molecular diagnosis can currently be achieved in over 60% of patients with CMT.^[65]A molecular diagnosis is much more likely in patients with CMT-1 rather than CMT-2. Four genes commonly available for testing, PMP22 ( CMT-1A-PMP22 gene duplication; HNPP-PMP22 gene deletion), GJB1 ( CMT-1X), MPZ ( CMT-1B ), and MFN2 ( CMT-2A) account for over 90% of all CMT molecular diagnoses.

It is possible to narrow down the most likely gene based on nerve conduction studies and family history. Flow charts have been published using nerve conduction velocities to direct genetic testing, usually with the aid of family history information.^[66]

CMT-1A - Pulsed-field gel electrophoresis or a specialized fluorescent in situ hybridization (FISH) assay is the most reliable genetic test to detect PMP22 gene duplication in CMT-1A and PMP22 gene deletion in HNPP.^[67]DNA-based testing for the PMP22 duplication (CMT-1A) is widely available and detects more than 98% of patients with CMT-1A (see following image). Point mutations in the PMP-22 gene cause fewer than 2% of cases of CMT-1A and are identified by this technique. Approximately 70-80% of cases of CMT-1 are designated as CMT-1A, caused by duplication of the PMP-22 gene (locus 17p11).^{[16, 68]}See the image below.

Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).
View Media Gallery
CMT-1B - Genetic testing is performed primarily on a research basis, but it is available from a few commercial laboratories. Approximately 5-10% of CMT-1 is designated CMT-1B and is caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosomal locus 1q22).^{[20, 69]}
CMT-1C and CMT-1D - Very rarely, mutations occur in the EGR-2 (early growth response 2) gene or in the LITAF gene, causing CMT-1D and CMT-1C, respectively, for which molecular genetic testing also is clinically available.
CMT-2 - Clinically indistinguishable, the 4 subtypes of CMT-2 are distinguished solely from genetic linkage findings. The relative proportions of CMT-2A, CMT-2B, CMT-2C, and CMT-2D have not yet been determined. The chromosomal loci for CMT-2A, CMT-2B, CMT-2C, CMT-2D, CMT-2E, CMT-2F, CMT-2G, and CMT-2L have been mapped, but the genes have not been identified. Molecular genetic testing is clinically available only for CMT-2A, CMT-2B1, CMT-2E, and CMT-2F.
CMT-X - Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases. Such testing is clinically available.

Imaging Studies

High-resolution ultrasonography of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis in Charcot-Marie-Tooth disease type 1A.^{[5, 6, 7, 8, 9, 10]}

Other Tests

Nerve biopsy rarely is indicated for the diagnosis of Charcot-Marie-Tooth disease (CMT), especially because genetic testing is available. Biopsies sometimes are performed in cases of diagnostic dilemmas. Findings vary in different types of CMT, as follows:

In CMT-1, peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. Concentric hypertrophy of the lamellar sheaths is seen. Onion bulb formation, made up of circumferentially directed Schwann cells and their processes, frequently is observed.
In CMT-2, axon loss with wallerian degeneration generally is found.
In CMT-3, or Dejerine-Sottas disease, demyelination with thinning of the myelin sheath is observed.
Inflammatory infiltrate, indicating an autoimmune demyelinating process, should not be present.

Procedures

Electromyography/nerve conduction study (EMG/NCS)^{[5, 6, 7, 8, 9, 10]}

If Charcot-Marie-Tooth disease (CMT) is suggested, perform an EMG/NCS first. Findings vary depending on the type of CMT.
In demyelinating types of CMT, such as CMT-1, diffuse and uniform slowing of nerve conduction velocities is observed (see following images).

Nerve conduction study showing decreased nerve conduction velocity in the median nerve in an 18-year-old woman with Charcot-Marie-Tooth disease type 1.
View Media Gallery

Right ulnar motor nerve conduction study in a 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
View Media Gallery

Left ulnar motor nerve conduction study in 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
View Media Gallery
Harding and Thomas criteria for diagnosing CMT-1 include median motor nerve conduction velocity of less than 38 meters per second (m/s), with compound motor action potential (CMAP) and amplitude of at least 0.5 millivolts (mV). No focal conduction block or slowing should be present unless associated with other focal demyelinating processes.
All sensory and motor nerves that are tested show the same degree of marked slowing.
Absolute values vary, but they are approximately 20-25 m/s in CMT-1 and less than 10 in Dejerine-Sottas disease and congenital hypomyelination. Slowing of nerve conduction can also be found in asymptomatic individuals. In X- linked CMTs, motor nerve conduction velocities are faster than in CMT1A.^[70]
In neuronal (ie, axonal) types of CMT, nerve conduction velocity usually is normal, but markedly low amplitudes are noted in sensory (ie, sensory nerve action potential [SNAP]) and motor (ie, CMAP) nerve studies.
In neuronal (ie, axonal) types of CMT, increased insertional activity is evident, with fibrillation potentials and positive sharp waves seen. Motor unit potentials show decreased recruitment patterns and neuropathic changes in morphology.

Histologic Findings

In Charcot-Marie-Tooth disease type 1 (CMT-1), peripheral nerves contain few myelinated fibers, intramuscular nerves are surrounded by a rich connective tissue and hyperplastic neurilemma, and lengths of myelin are atrophic along the fibers.

Concentric hypertrophy of the lamellar sheaths is seen. Formation of the typical onion bulb, made up of circumferentially directed Schwann cells and their processes, is noted.

In CMT-2, axonal degeneration is observed.

In CMT-3, Dejerine-Sottas disease, demyelination with thinning of the myelin sheath can be seen.^[71]

No inflammatory infiltrate should be present, indicating an autoimmune demyelinating process.

Treatment & Management

Dyck PJ, Chance P, Lebo RV. Hereditary motor and sensory neuropathies. Dyck PJ, Thomas PK, Griffen JW, et al, eds. Peripheral Neuropathy. 3rd ed. Saunders; 1993. 1094-136.
Dyck PJ, Karnes JL, Lambert EH. Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology. 1989 Oct. 39(10):1302-8. [QxMD MEDLINE Link].
Burns J, Ryan MM, Ouvrier RA. Evolution of foot and ankle manifestations in children with CMT1A. Muscle Nerve. 2009 Feb. 39(2):158-66. [QxMD MEDLINE Link].
Thomas PK. Overview of Charcot-Marie-Tooth disease type 1A. Ann N Y Acad Sci. 1999 Sep 14. 883:1-5. [QxMD MEDLINE Link].
Birouk N, LeGuern E, Maisonobe T, et al. X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study. Neurology. 1998 Apr. 50(4):1074-82. [QxMD MEDLINE Link].
Elliott JL, Kwon JM, Goodfellow PJ, et al. Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics. Neurology. 1997 Jan. 48(1):23-8. [QxMD MEDLINE Link].
England JD, Garcia CA. Electrophysiological studies in the different genotypes of Charcot- Marie-Tooth disease. Curr Opin Neurol. 1996 Oct. 9(5):338-42. [QxMD MEDLINE Link].
Gutierrez A, England JD, Sumner AJ, et al. Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease. Muscle Nerve. 2000 Feb. 23(2):182-8. [QxMD MEDLINE Link].
Lewis RA, Sumner AJ. Electrophysiologic features of inherited demyelinating neuropathies: a reappraisal. Ann N Y Acad Sci. 1999 Sep 14. 883:321-35. [QxMD MEDLINE Link].
Quattrone A, Gambardella A, Bono F, et al. Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. Neurology. 1996 May. 46(5):1318-24. [QxMD MEDLINE Link].
Guillebastre B, Calmels P, Rougier PR. Assessment of appropriate ankle-foot orthoses models for patients with Charcot-Marie-Tooth disease. Am J Phys Med Rehabil. 2011 Aug. 90(8):619-27. [QxMD MEDLINE Link].
Hassel B. Improvement of muscle function in Charcot-Marie-Tooth disease by transcutaneous electric nerve stimulation. Muscle Nerve. 1998 Feb. 21(2):267-8. [QxMD MEDLINE Link].
Holmes JR, Hansen ST Jr. Foot and ankle manifestations of Charcot-Marie-Tooth disease. Foot Ankle. 1993 Oct. 14(8):476-86. [QxMD MEDLINE Link].
Ward CM, Dolan LA, Bennett DL, et al. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease. J Bone Joint Surg Am. 2008 Dec. 90(12):2631-42. [QxMD MEDLINE Link]. [Full Text].
Wukich DK, Bowen JR. A long-term study of triple arthrodesis for correction of pes cavovarus in Charcot-Marie-Tooth disease. J Pediatr Orthop. 1989 Jul-Aug. 9(4):433-7. [QxMD MEDLINE Link].
Anderson TJ, Klugmann M, Thomson CE, et al. Distinct phenotypes associated with increasing dosage of the PLP gene: implications for CMT1A due to PMP22 gene duplication. Ann N Y Acad Sci. 1999 Sep 14. 883:234-46. [QxMD MEDLINE Link].
Marrosu MG, Vaccargiu S, Marrosu G, et al. A novel point mutation in the peripheral myelin protein 22 (PMP22) gene associated with Charcot-Marie-Tooth disease type 1A. Neurology. 1997 Feb. 48(2):489-93. [QxMD MEDLINE Link].
Suter U, Nave KA. Transgenic mouse models of CMT1A and HNPP. Ann N Y Acad Sci. 1999 Sep 14. 883:247-53. [QxMD MEDLINE Link].
Duchesne M, Danigo A, Richard L, et al. Skin Biopsy Findings in Patients With CMT1A: Baseline Data From the CLN-PXT3003-01 Study Provide New Insights Into the Pathophysiology of the Disorder. J Neuropathol Exp Neurol. 2018 Apr 1. 77 (4):274-81. [QxMD MEDLINE Link].
Chapon F, Latour P, Diraison P, Schaeffer S, Vandenberghe A. Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J Neurol Neurosurg Psychiatry. 1999 Jun. 66(6):779-82. [QxMD MEDLINE Link]. [Full Text].
Shy ME, Jani A, Krajewski K, et al. Phenotypic clustering in MPZ mutations. Brain. 2004 Feb. 127(Pt 2):371-84. [QxMD MEDLINE Link]. [Full Text].
Nicholson GA. The dominantly inherited motor and sensory neuropathies: clinical and molecular advances. Muscle Nerve. 2006 May. 33(5):589-97. [QxMD MEDLINE Link].
Krajewski KM, Lewis RA, Fuerst DR, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000 Jul. 123 Pt 7:1516-27. [QxMD MEDLINE Link]. [Full Text].
Vance JM. Charcot-Marie-Tooth disease type 2. Ann N Y Acad Sci. 1999 Sep 14. 883:42-6. [QxMD MEDLINE Link].
Marrosu MG, Vaccargiu S, Marrosu G, et al. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology. 1998 May. 50(5):1397-401. [QxMD MEDLINE Link].
Piscosquito G, Saveri P, Magri S, Ciano C, Gandioli C, Morbin M, et al. Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4). J Peripher Nerv Syst. 2016 Sep. 21 (3):142-9. [QxMD MEDLINE Link].
Jerath NU, Mankodi A, Crawford TO, Grunseich C, Baloui H, Nnamdi-Emeratom C, et al. Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges. Muscle Nerve. 2018 May. 57 (5):749-755. [QxMD MEDLINE Link].
A service of the U.S. National Library of Medicine. Genetics Home Reference: Your reference to understanding genetics conditions. Charcot-Marie-Tooth disease. Published: February 25, 2014. Available at http://ghr.nlm.nih.gov/condition/charcot-marie-tooth-disease.
Kurihara S, Adachi Y, Wada K, et al. An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan. Neuroepidemiology. 2002 Sep-Oct. 21(5):246-50. [QxMD MEDLINE Link].
Morocutti C, Colazza GB, Soldati G, et al. Charcot-Marie-Tooth disease in Molise, a central-southern region of Italy: an epidemiological study. Neuroepidemiology. 2002 Sep-Oct. 21(5):241-5. [QxMD MEDLINE Link].
Braathen GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol Scand Suppl. 2012. iv-22. [QxMD MEDLINE Link].
Carter GT, Jensen MP, Galer BS, et al. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998 Dec. 79(12):1560-4. [QxMD MEDLINE Link].
Garcia CA. A clinical review of Charcot-Marie-Tooth. Ann N Y Acad Sci. 1999 Sep 14. 883:69-76. [QxMD MEDLINE Link].
Auer-Grumbach M, Wagner K, Strasser-Fuchs S, et al. Clinical predominance of proximal upper limb weakness in CMT1A syndrome. Muscle Nerve. 2000 Aug. 23(8):1243-9. [QxMD MEDLINE Link].
Pareyson D, Taroni F, Botti S, et al. Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation. Neurology. 2000 Apr 25. 54(8):1696-8. [QxMD MEDLINE Link].
van Pomeren M, Selles RW, van Ginneken BT, et al. The hypothesis of overwork weakness in Charcot-Marie-Tooth: a critical evaluation. J Rehabil Med. 2009 Jan. 41(1):32-4. [QxMD MEDLINE Link].
Burns J, Bray P, Cross LA, et al. Hand involvement in children with Charcot-Marie-Tooth disease type 1A. Neuromuscul Disord. 2008 Dec. 18(12):970-3. [QxMD MEDLINE Link].
Prada V, Schizzi S, Poggi I, et al. Hand Rehabilitation Treatment for Charcot-Marie-Tooth Disease: An Open Label Pilot Study. J Neurol Neurophysiol. 2018 Jul 30. 9 (4):465. [QxMD MEDLINE Link]. [Full Text].
Pazzaglia C, Vollono C, Ferraro D, Virdis D, Lupi V, Le Pera D. Mechanisms of neuropathic pain in patients with Charcot-Marie-Tooth 1 A: a laser-evoked potential study. Pain. 2010 May. 149(2):379-85. [QxMD MEDLINE Link].
Ribiere C, Bernardin M, Sacconi S, Delmont E, Fournier-Mehouas M, Rauscent H. Pain assessment in Charcot-Marie-Tooth (CMT) disease. Ann Phys Rehabil Med. 2012 Apr. 55(3):160-73. [QxMD MEDLINE Link].
Bjelica B, Peric S, Basta I, et al. Neuropathic pain in patients with Charcot-Marie-Tooth type 1A. Neurol Sci. 2020 Mar. 41 (3):625-30. [QxMD MEDLINE Link].
Tozza S, Bruzzese D, Severi D, et al. The impact of symptoms on daily life as perceived by patients with Charcot-Marie-Tooth type 1A disease. Neurol Sci. 2021 Apr 26. [QxMD MEDLINE Link]. [Full Text].
Kennedy RA, Carroll K, Hepworth G, Paterson KL, Ryan MM, McGinley JL. Falls in paediatric Charcot-Marie-Tooth disease: a 6-month prospective cohort study. Arch Dis Child. 2018 Aug 13. [QxMD MEDLINE Link].
Pipis M, Feely SME, Polke JM, et al. Natural history of Charcot-Marie-Tooth disease type 2A: a large international multicentre study. Brain. 2020 Dec 1. 143 (12):3589-602. [QxMD MEDLINE Link]. [Full Text].
Kousseff BG, Hadro TA, Treiber DL, et al. Charcot-Marie-Tooth disease with sensorineural hearing loss--an autosomal dominant trait. Birth Defects Orig Artic Ser. 1982. 18(3B):223-8. [QxMD MEDLINE Link].
Stojkovic T, Latour P, Vandenberghe A, et al. Sensorineural deafness in X-linked Charcot-Marie-Tooth disease with connexin 32 mutation (R142Q). Neurology. 1999 Mar 23. 52(5):1010-4. [QxMD MEDLINE Link].
Reynaud V, Morel C, Givron P, et al. Walking Speed is Correlated with the Isokinetic Muscular Strength of the Knee in Patients with Charcot-Marie-Tooth Type 1A. Am J Phys Med Rehabil. 2018 Oct 26. [QxMD MEDLINE Link].
Cardoso J, de Baptista CRJA, Sartor CD, et al. Dynamic plantar pressure patterns in children and adolescents with Charcot-Marie-Tooth disease. Gait Posture. 2021 May. 86:112-9. [QxMD MEDLINE Link].
Nelis E, Timmerman V, De Jonghe P, et al. Molecular genetics and biology of inherited peripheral neuropathies: a fast-moving field. Neurogenetics. 1999 Sep. 2(3):137-48. [QxMD MEDLINE Link].
Pareyson D. Charcot-Marie-Tooth disease and related neuropathies: molecular basis for distinction and diagnosis. Muscle Nerve. 1999 Nov. 22(11):1498-509. [QxMD MEDLINE Link].
Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science. 1993 Dec 24. 262(5142):2039-42. [QxMD MEDLINE Link].
Bone LJ, Dahl N, Lensch MW, et al. New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease. Neurology. 1995 Oct. 45(10):1863-6. [QxMD MEDLINE Link].
Lewis RA. The challenge of CMTX and connexin 32 mutations. Muscle Nerve. 2000 Feb. 23(2):147-9. [QxMD MEDLINE Link].
Nicholson SM, Ressot C, Gomes D, et al. Connexin32 in the peripheral nervous system. Functional analysis of mutations associated with X-linked Charcot-Marie-Tooth syndrome and implications for the pathophysiology of the disease. Ann N Y Acad Sci. 1999 Sep 14. 883:168-85. [QxMD MEDLINE Link].
Chance PF. Overview of hereditary neuropathy with liability to pressure palsies. Ann N Y Acad Sci. 1999 Sep 14. 883:14-21. [QxMD MEDLINE Link].
Ionasescu VV, Ionasescu R, Searby C, et al. Dejerine-Sottas disease with de novo dominant point mutation of the PMP22 gene. Neurology. 1995 Sep. 45(9):1766-7. [QxMD MEDLINE Link].
Ben Othmane K, Hentati F, Lennon F, et al. Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet. 1993 Oct. 2(10):1625-8. [QxMD MEDLINE Link].
Bolino A, Muglia M, Conforti FL, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000 May. 25(1):17-9. [QxMD MEDLINE Link].
Gambardella A, Bolino A, Muglia M, et al. Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B). Neurology. 1998 Mar. 50(3):799-801. [QxMD MEDLINE Link].
Carter GT, Abresch RT, Fowler WM, et al. Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II. Am J Phys Med Rehabil. 1995 Sep-Oct. 74(5 Suppl):S140-9. [QxMD MEDLINE Link].
Keller MP, Chance PF. Inherited neuropathies: from gene to disease. Brain Pathol. 1999 Apr. 9(2):327-41. [QxMD MEDLINE Link].
Bird TD, Ott J, Giblett ER, et al. Genetic linkage evidence for heterogeneity in Charcot-Marie-Tooth neuropathy (HMSN type I). Ann Neurol. 1983 Dec. 14(6):679-84. [QxMD MEDLINE Link].
Berciano J, Combarros O, Figols J, et al. Hereditary motor and sensory neuropathy type II. Clinicopathological study of a family. Brain. 1986 Oct. 109 ( Pt 5):897-914. [QxMD MEDLINE Link].
Rose KJ, Hiller CE, Mandarakas M, Raymond J, Refshauge K, Burns J. Correlates of functional ankle instability in children and adolescents with Charcot-Marie-Tooth disease. J Foot Ankle Res. 2015. 8:61. [QxMD MEDLINE Link]. [Full Text].
Murphy SM, Laura M, Fawcett K, Pandraud A, Liu YT, Davidson GL. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry. 2012 Jul. 83(7):706-10. [QxMD MEDLINE Link].
Miller LJ, Saporta AS, Sottile SL, Siskind CE, Feely SM, Shy ME. Strategy for genetic testing in Charcot-Marie-disease. Acta Myol. 2011 Oct. 30(2):109-16. [QxMD MEDLINE Link]. [Full Text].
Shaffer LG, Kennedy GM, Spikes AS, et al. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet. 1997 Mar 31. 69(3):325-31. [QxMD MEDLINE Link].
Nicholson GA. Penetrance of the hereditary motor and sensory neuropathy Ia mutation: assessment by nerve conduction studies. Neurology. 1991 Apr. 41(4):547-52. [QxMD MEDLINE Link].
Hayasaka K, Himoro M, Sato W, et al. Charcot-Marie-Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nat Genet. 1993 Sep. 5(1):31-4. [QxMD MEDLINE Link].
Nicholson G, Nash J. Intermediate nerve conduction velocities define X-linked Charcot-Marie- Tooth neuropathy families. Neurology. 1993 Dec. 43(12):2558-64. [QxMD MEDLINE Link].
Bornemann A, Hansen FJ, Schmalbruch H. Nerve and muscle biopsy in a case of hereditary motor and sensory neuropathy type III with basal lamina onion bulbs. Neuropathol Appl Neurobiol. 1996 Feb. 22(1):77-81. [QxMD MEDLINE Link].
Nonnekes J, Hofstad C, de Greef-Rotteveel A, et al. Management of gait impairments in people with Charcot-Marie-Tooth disease: A treatment algorithm. J Rehabil Med. 2021 May 21. 53 (5):jrm00194. [QxMD MEDLINE Link]. [Full Text].
Njegovan ME, Leonard EI, Joseph FB. Rehabilitation medicine approach to Charcot-Marie-Tooth disease. Clin Podiatr Med Surg. 1997 Jan. 14(1):99-116. [QxMD MEDLINE Link].
Vinci P, Gargiulo P. Poor compliance with ankle-foot-orthoses in Charcot-Marie-Tooth disease. Eur J Phys Rehabil Med. 2008 Mar. 44(1):27-31. [QxMD MEDLINE Link].
Zuccarino R, Anderson KM, Shy ME, Wilken JM. Satisfaction with ankle foot orthoses in individuals with Charcot-Marie-Tooth disease. Muscle Nerve. 2021 Jan. 63 (1):40-5. [QxMD MEDLINE Link]. [Full Text].
Dufek JS, Neumann ES, Hawkins MC, O'Toole B. Functional and dynamic response characteristics of a custom composite ankle foot orthosis for Charcot-Marie-Tooth patients. Gait Posture. 2014 Jan. 39(1):308-13. [QxMD MEDLINE Link].
Guillebastre B, Calmels P, Rougier PR. Assessment of appropriate ankle-foot orthoses models for patients with Charcot-Marie-Tooth disease. Am J Phys Med Rehabil. 2011 Aug. 90(8):619-27. [QxMD MEDLINE Link].
Phillips MF, Robertson Z, Killen B, White B. A pilot study of a crossover trial with randomized use of ankle-foot orthoses for people with Charcot-Marie-tooth disease. Clin Rehabil. 2012 Jun. 26(6):534-44. [QxMD MEDLINE Link].
El Mhandi L, Pichot V, Calmels P, Gautheron V, Roche F, Féasson L. Exercise training improves autonomic profiles in patients with Charcot-Marie-Tooth disease. Muscle Nerve. 2011 Nov. 44(5):732-6. [QxMD MEDLINE Link].
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 May 22. [QxMD MEDLINE Link].
Mori L, Signori A, Prada V, et al. Treadmill training in patients affected by Charcot-Marie-Tooth neuropathy: results of a multicenter, prospective, randomized, single-blind, controlled study. Eur J Neurol. 2020 Feb. 27 (2):280-7. [QxMD MEDLINE Link]. [Full Text].
Kamholz J, Menichella D, Jani A, et al. Charcot-Marie-Tooth disease type 1: molecular pathogenesis to gene therapy. Brain. 2000 Feb. 123 ( Pt 2):222-33. [QxMD MEDLINE Link]. [Full Text].
Gess B, Baets J, De Jonghe P, Reilly MM, Pareyson D, Young P. Ascorbic acid for the treatment of Charcot-Marie-Tooth disease. Cochrane Database Syst Rev. 2015 Dec 11. 12:CD011952. [QxMD MEDLINE Link].
Hoff JM, Gilhus NE, Daltveit AK. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease. Neurology. 2005 Feb 8. 64(3):459-62. [QxMD MEDLINE Link].
Graf WD, Chance PF, Lensch MW, et al. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996 Apr 1. 77(7):1356-62. [QxMD MEDLINE Link].
Kuruvilla G, Perry S, Wilson B, et al. The natural history of vincristine-induced laryngeal paralysis in children. Arch Otolaryngol Head Neck Surg. 2009 Jan. 135(1):101-5. [QxMD MEDLINE Link].
Dyck PJ, Swanson CJ, Low PA, et al. Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc. 1982 Apr. 57(4):239-46. [QxMD MEDLINE Link].
Ginsberg L, Malik O, Kenton AR, et al. Coexistent hereditary and inflammatory neuropathy. Brain. 2004 Jan. 127:193-202. [QxMD MEDLINE Link]. [Full Text].
Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, et al. NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology. 2005 Sep 13. 65(5):681-9. [QxMD MEDLINE Link].
Pareyson D, Marchesi C. Natural history and treatment of peripheral inherited neuropathies. Adv Exp Med Biol. 2009. 652:207-24. [QxMD MEDLINE Link].
Passage E, Norreel JC, Noack-Fraissignes P, et al. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med. 2004 Apr. 10(4):396-401. [QxMD MEDLINE Link].
Burns J, Ouvrier RA, Yiu EM, Joseph PD, Kornberg AJ, Fahey MC, et al. Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial. Lancet Neurol. 2009 Jun. 8(6):537-44. [QxMD MEDLINE Link].
Micallef J, Attarian S, Dubourg O, Gonnaud PM, Hogrel JY, Stojkovic T, et al. Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2009 Dec. 8(12):1103-10. [QxMD MEDLINE Link].
Verhamme C, de Haan RJ, Vermeulen M, Baas F, de Visser M, van Schaik IN. Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial. BMC Med. 2009 Nov 12. 7:70. [QxMD MEDLINE Link]. [Full Text].
Pareyson D, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, et al. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. 2011 Apr. 10(4):320-8. [QxMD MEDLINE Link]. [Full Text].
Meyer zu Horste G, Prukop T, Liebetanz D, Mobius W, Nave KA, Sereda MW. Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy. Ann Neurol. 2007 Jan. 61(1):61-72. [QxMD MEDLINE Link].
Sereda MW, Meyer zu Hörste G, Suter U, Uzma N, Nave KA. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med. 2003 Dec. 9(12):1533-7. [QxMD MEDLINE Link].
Shy ME. Charcot-Marie-Tooth disease: an update. Curr Opin Neurol. 2004 Oct. 17(5):579-85. [QxMD MEDLINE Link].
Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci. 2006 Mar 15. 242(1-2):47-54. [QxMD MEDLINE Link].
Shy ME, Blake J, Krajewski K, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology. 2005 Apr 12. 64(7):1209-14. [QxMD MEDLINE Link].
Burns J, Ouvrier R, Estilow T, Shy R, Laurá M, Pallant JF, et al. Validation of the Charcot-Marie-Tooth disease pediatric scale as an outcome measure of disability. Ann Neurol. 2012 May. 71(5):642-52. [QxMD MEDLINE Link]. [Full Text].
Siskind CE, Panchal S, Smith CO, Feely SM, Dalton JC, Schindler AB, et al. A review of genetic counseling for Charcot Marie Tooth disease (CMT). J Genet Couns. 2013 Aug. 22(4):422-36. [QxMD MEDLINE Link].
Ramdharry GM, Pollard AJ, Marsden JF, Reilly MM. Comparing gait performance of people with Charcot-Marie-Tooth disease who do and do not wear ankle foot orthoses. Physiother Res Int. 2012 Dec. 17(4):191-9. [QxMD MEDLINE Link].

Media Gallery

Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).
Nerve conduction study showing decreased nerve conduction velocity in the median nerve in an 18-year-old woman with Charcot-Marie-Tooth disease type 1.
Foot of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
Hands of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
Right ulnar motor nerve conduction study in a 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
Left ulnar motor nerve conduction study in 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.

of 7

Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

CMT Type	Chromosome; Inheritance Pattern	Age of Onset	Clinical Features	Average NCVs^§
CMT-1A (PMP-22^¶ dupl.)	17p11.2; AD*	First decade	Distal weakness	15-20 m/s
CMT-1B (P₀ -MPZ)**	1q23.3; AD	First decade	Distal weakness	< 20 m/s
CMT-1C (non-A, non-B) (LITAF)	16p13.13;AD	Second decade	Distal weakness	26-42 m/s
CMT-1D (EGR-2)^#	10q21.3; AD	First decade	Distal weakness	15-20 m/s
CMT-1E (PMP22)	17p11.2; AD	First decade	Distal weakness, deafness	15-20 m/s
CMT-1F (NEFL)	8p21.2; AD	First decade	Distal weakness	15-20 m/s
CMT-X (connexin-32)^{[51, 52, 53, 54]}	Xq13; XD^‡	Second decade	Distal weakness	25-40 m/s
CMT-2A	1p36; AD	10 y	Distal weakness	>38 m/s
CMT-2B	3q21; AD	Second decade	Distal weakness, sensory loss, skin ulcers	Axon loss; Normal
CMT-2C	12q23-q24, AD	First decade	Vocal cord, diaphragm, and distal weakness	>50 m/s
CMT-2D	7p14; AD	16-30 y	Distal weakness, upper limb predominantly	Axon loss; N^††
CMT-2E	8p21; AD	10-30 y	Distal weakness, lower limb predominantly	Axon loss; N
CMT-2F	7q11-q21; AD	15-25 y	Distal weakness	Axon loss; N
CMT-2G	12q12-q13; AD	9-76 y	Distal weakness	Axon loss; N
CMT-2H	8q21; AD	15-25 y	Distal weakness, pyramidal features	Axon loss; N
CMT-2I	1q23; AD	47-60 y	Distal weakness	Axon loss; N
CMT-2J	1q23; AD	40-50 y	Distal weakness, hearing loss	Axon loss; N
CMT-2K	8q13-q21; AD	< 4 y	Distal weakness	Axon loss; N
CMT-2L	12q24; AD	15-25 y	Distal weakness	Axon loss; N
CMT–R-Ax (Ouvrier)	AR	First decade	Distal weakness	Axon loss; N
CMT–R-Ax (Moroccan)	1q21; AR	Second decade	Distal weakness	Axon loss; N
Cowchock syndrome	Xq24-q26	First decade	Distal weakness, deafness, intellectual disability	Axon loss; N
HNPP^\|\| (PMP-22 deletion)^[55] or tomaculous neuropathy	17p11; AD	All ages	Episodic weakness and numbness	Conduction Blocks
Dejerine-Sottas-syndrome (DSS) or HMSN-3^[56]	P₀; AR PMP-22; AD 8q23; AD	2 y	Severe weakness	< 10 m/s
Congenital hypomyelination (CH)	P₀, EGR-2 or PMP-22 AR	Birth	Severe weakness	< 10 m/s
CMT-4A^[57]	8q13; AR	Childhood	Distal weakness	Slow
CMT-4B (myotubularin- related protein 2)^{[58, 59]}	11q23; AR	2-4 y	Distal and proximal weakness	Slow
CMT-4C	5q23; AR	5-15 y	Delayed walking	14-32 m/s
CMT-4D (Lom) (N-myc downstream- regulated gene 1)	8q24; AR	1-10 y	Distal muscle wasting, foot and hand deformities	10-20 m/s
CMT-4E (EGR-2)	10q21; AR	Birth	Infant hypotonia	9-20 m/s
CMT-4G	10q23.2; AR	8-16 years	Distal weakness	9-20 m/s
CMT-4H	12p11.21-q13.11; AR	0-2 years	Delayed walking	9-20 m/s
CMT-4F	19q13; AR	1-3 y	Motor delay	Absent
Autosomal dominant †Autosomal recessive ‡X-linked dominant §Nerve conduction velocities \|\|Hereditary neuropathy with liability to pressure palsy ¶Peripheral myelin protein #Early growth response *Myelin protein zero ††Normal