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CHARCOT MARIE TOOTH DISEASE

Introduction

Charcot-Marie-Tooth (CMT) disease is a common, inherited neuromuscular disorder. More recently, the term has come to represent a heterogenous group of hereditary disorders that all involve chronic motor and sensory polyneuropathy. CMT is characterized by the gradual development of motor weakness and sensory impairment, typically starting in childhood and initially affecting only the lower extremity. In ~50-67% of patients, CMT progresses to also involve the hands, where it often leads to significant clinical morbidity and reduced quality of life. Patients with CMT often require a multidisciplinary management team, and the condition is usually approached conservatively with some combination of hand rehabilitation and/or pharmacological intervention. Although surgery is commonly used to address lower limb involvement, it is performed rarely for the hands, when there is significant disability after several years of disease progression.1-5

Pathophysiology

  • More than 90 genes have been associated with CMT, which encode for proteins that may play a role in maintaining the myelin sheath of the peripheral nervous system, in the function of related axons function, or in the mitochondrial metabolism. Thus, mutations of different genes can elicit demyelination, axonal loss, or both.5
  • The etiology and pathophysiology of CMT varies depending on which type is present, as the disease is typically classified into the following groups:
    • CMT1 (demyelinating CMT): most common type, accounting for about 67% of all cases; caused by genetic defects that damage the myelin sheath; further divided into subtypes A–F
      • CMT1A: most common CMT subtype (accounting for 60–70% of CMT1 and 40–50% of all CMT cases; caused by duplication of the PMP22 gene
      • CMT1B: second most common CMT1 subtype; caused by mutations in the MPZ gene, which encodes for the myelin protein zero
  • CMT2 (axonal CMT): accounts for ~20% of all cases; caused by defects in genes that code for the structure and function of the axons of peripheral nerves; typically inherited in an autosomal dominant manner but may be autosomal recessive in some cases
    • CMT2A: most common of the CMT2 subtypes; caused by defects in the MFN2 gene
  • CMT3 (Dejerine-Sottas disease): rare and severe type of CMT that starts in early childhood and involves myelin sheath disruption that leads to significant motor impairments
  • CMT4: another rare type of CMT beginning in early childhood that affects the myelin sheath; usually inherited in an autosomal recessive manner
  • CMTX (X-linked CMT): another demyelinating type of CMT caused by mutations of the GJB1 or PRPS1 genes
  • DI-CMT (dominant intermediate CMT): involves both demyelination and axonal degeneration; mutations of the DNM2, MPZ, and YARS genes have all been associated with various DI-CMT subtypes1,6,7
  • Several studies have shown that ~90% of patients with CMT confirmed by genetic testing had a mutation in one of these genes: PMP22, GJB1, MPZ, or either MFN2 or GDAP1.6
  • The release of calcium ions from Schwann cell mitochondria by the voltage-dependent anion channel-1 may be another contributing factor in the pathophysiology of demyelinating forms of CMT.6

Related Anatomy

  • Myelin sheath
  • Peripheral nervous system
  • Mitochondrial metabolism
  • Thenar muscles
  • Hypothenar muscles
  • Interosseous muscles

Incidence 

Assessing the exact prevalence of CMT is difficult due to the heterogeneity of the disease and a lack of relevant epidemiological studies, which has led to some reported variation in different geographic populations.4

  • The estimated prevalence of CMT most commonly cited is 1/2,500.4-6
  • One systematic review found the prevalence of CMT in Europe to range from 9.7/100,000 in Serbia to 82.3/100,000 in Norway.4 Another systematic review revealed similar estimates, with a CMT prevalence in Ireland of 10.5/100,000.8
  • CMT does not appear to have an ethnic predisposition and occurs fairly evenly in men and women.6

Related Conditions

  • Chronic inflammatory demyelinating polyneuropathies
  • Distal myopathies 
  • Hereditary neuralgic amyotrophy
  • Motor neuropathies
  • Refsum disease 
  • Sensory neuropathies

Differential Diagnosis

  • Adrenomyeloneuropathy
  • Amyloid neuropathies
  • Autosomal recessive genetic disorders
  • Chronic inflammatory demyelinating polyneuropathy
  • Distal myopathies 
  • Familial brachial plexus neuropathy
  • Friedreich ataxia
  • Hereditary neuropathies
  • Krabbe disease
  • Leprosy
  • Lowe syndrome
  • Metachromatic leukodystrophy
  • Neurosyphilis
  • Pelizaeus-Merzbacher disease
  • Transthyretin-associated amyloidosis 
  • Troyer syndrome
  • Vasculitis
  • X-linked recessive genetic disorders
ICD-10 Codes

  • CHARCOT MARIE TOOTH DISEASE

    Diagnostic Guide Name

    CHARCOT MARIE TOOTH DISEASE

    ICD 10 Diagnosis, Single Code, Left Code, Right Code and Bilateral Code

    DIAGNOSISSINGLE CODE ONLYLEFTRIGHTBILATERAL (If Available)
    CHARCOT MARIE TOOTH DISEASE (HEREDITARY NEUROPATHY)G60.0   
    CHARCOT'S JOINT, ELBOW M14.622M14.621 
    CHARCOT'S JOINT, WRIST M14.632M14.631 
    CHARCOT'S JOINT, HAND M14.642M14.641 

    ICD-10 Reference

    Reproduced from the International statistical classification of diseases and related health problems, 10th revision, Fifth edition, 2016. Geneva, World Health Organization, 2016 https://apps.who.int/iris/handle/10665/246208

Clinical Presentation Photos and Related Diagrams
  • Bilateral hands of a middle aged male with advanced CMT disease. Note the severe intrinsic atrophy (arrows).
    Bilateral hands of a middle aged male with advanced CMT disease. Note the severe intrinsic atrophy (arrows).
  • Bilateral hands (palmar view) of a middle aged male with advanced CMT disease. Note the severe thenar atrophy (arrows).
    Bilateral hands (palmar view) of a middle aged male with advanced CMT disease. Note the severe thenar atrophy (arrows).
Symptoms
Mixed ulnar and median nerve palsies with a positive family history for neurologic disease
Distal sensory loss, muscle weakness and functional disability
Neurological pain
Sensorineural hearing loss
Impaired intrinsic hand muscle function
Typical History

A typical patient is a 15-year-old boy with a family history of CMT. He initially experienced minor difficulties walking and began tripping frequently due to progressive foot and distal leg weakness.  His increasing impairments went on to prevent him from being able to participate in sports. Over time, he began to notice issues with his hand function, and his muscles felt weak, and he struggled to grip small objects. This soon led to a hand-claw deformity, and his combination of symptoms had gone on to severely impact his ability to perform daily activities, which led him to seek out treatment.

Positive Tests, Exams or Signs
Work-up Options
Treatment Options
Treatment Goals
  • Diagnosis CMT early and accurately
  • Provide optimum conservative management with a team approach
  • Provide appropriate surgical treatment when indicated
Conservative
  • There is no cure for CMT, and as such, management strategies should instead focus on addressing symptoms to preserve function for as long as possible.
  • Patients with CMT should be managed by a multidisciplinary team that may include neurologists, physiatrists, orthopedic surgeons, and physical and/or occupational therapists.1,9
  • Most cases of CMT are managed conservatively, and treatment options for patients with hand involvement typically consist of hand rehabilitation and pharmacological intervention.1,3,5
  • Hand rehabilitation
    • Hand rehabilitation is one of the more commonly used therapeutic tactics for CMT, but there is no standardized protocol dedicated specifically to the hands. 
    • A typical rehabilitation program may include some combination of muscle recruitment, stretching exercises, proprioceptive exercises, and strengthening exercises—especially those used to improve gripping movements—for hand weakness.1,5
    • Exercise
      • Regular exercise is typically recommended for most patients with CMT to maintain mobility and function.1
      • Drug Treatment in CMT
        • Modafinil for fatigue1
        • Acetaminophen/nonsteroidal anti-inflammatory drugs for musculoskeletal pain1
        • Tricyclic antidepressants for neuropathic pain1
        • Ascorbic acid3
        • Neurotrophin3
Operative
  • Surgery2,3,9,10  is rarely needed to address hand involvement in CMT, but some surgeons may recommend it as a palliative treatment to address patients with severe hand weakness, clawing, and/or functional limitations.2
  • When surgical procedures are performed, the procedures are usually directed at thumb stabilization and pinch strengthening, improving opposition of the thumb, and correcting clawing of the fingers.  Finger clawing is caused by denervated intrinsic muscles.  When thenar atrophy is present, the primary stabilization procedure is usually a thumb MP joint fusion.  IP joint and CMC joint fusions may also be needed in some CMT patients. 
  • Pinch transfers and opponensplasties can also be used to improve thumb opposition and pinch.  Extensor carpi ulnaris transfer to extensor pollicis brevis is commonly used to improve thumb opposition.  This specific transfer is recommended because the radial nerve innervated motor is typically the last nerve in the upper extremity to be damaged by CMT.  
  • Finger clawing can be addressed with tenodesis procedures, volar plate advancement at the MP joints (Zancolli capsulodesis), or dynamic procedures like the Zancolli lasso technique.  These tenodesis procedures have been described by Riordan, Fowler, Smith and Sirinivasan.  These procedures may or may not include tendon grafting.  The Zancolli volar plate MP advancement procedure provides a capsulodesis of the MP joint in flexion to correct finger clawing.  The Zancolli lasso technique is a dynamic procedure that can be used for finger clawing but it is not ideal because the flexor muscles may become dysfunctional early in the course of the CMT.
  • It often difficult to determine the optimal time to perform surgery, but most patients that visit a hand surgeon do so many years after their CMT diagnosis, often due to severe thenar, intrinsic wasting, and decreased sensibility.10
  • One study proposed categorizing surgical candidates into two groups: 
    • Patients with active forearm muscles (usually younger patients)
      • Muscle transfers should be proposed initially, and when the effect this surgery dissipates, static procedures may help to reduce clawing deformation and prolong dexterity
    • Patients with no active muscles (older patients)
      • Only static hand procedures should be used3
Complications
  • Infection
  • Long-term disability
  • Late tendon transfer failure secondary to CMT disease progression in the originally transferred muscles.
Outcomes
  • In one study of nine patients with CMT, a rehabilitative protocol primarily based on stretching and proprioceptive exercises led to improvements in the performance of both hands, with more significant gains in the dominant hand.5
  • Studies on the use of ascorbic acid and neurotrophin have been inconclusive.3
  • There are few studies that evaluate surgery to address hand involvement in CMT.3
  • Reconstructive surgery has been associated with positive outcomes, with some research showing that tendon transfers can lead to many years of improved function.3,9,10
    • In one study, good restoration of opposition was reported in five patients after the ring flexor superficialis tendon was routed around the proximal portion of the flexor retinaculum as a pulley.11
    • In another study, two patients experienced restored satisfactory function in with an extensor pollicis longus opponensplasty transferred subcutaneously.12
    • Various surgical procedures led to satisfactory outcomes in five patients that underwent eight operations, including a bilateral carpal tunnel release, Zancolli lasso technique, and Zancolli capsulodesis.3
Video
Charcot-Marie-Tooth (CMT) Disease - note the complete lack of opposition and the marked first dorsal interosseous muscle weakness.
Key Educational Points
  • CMT was first described in 1886 by Charcot and Marie in Paris, and Tooth in London. The original term given to this condition was peroneal muscular atrophy.4
  • Careful monitoring and earlier surgical intervention may help patients avoid late salvage procedures like soft tissue releases and joint fusions.10
  • The clinical presentation of CMT is non-specific and similar to many other conditions involving intrinsic muscle wasting, but a distal-to-proximal progression pattern can be considered a hallmark sign that CMT is likely present.3
  • Although lower limb surgery is generally accepted as a palliative treatment for foot deformities in CMT, upper extremity surgery has not gained the same recognition and is less frequently performed.3
  • Hand involvement in CMT usually begins with intrinsic paralysis, which leads to thumb thenar atrophy and other thumb mobility impairments, as well as finger clawing, abduction and adduction weakness, and loss of synchronistic finger flexion. Forearm muscle wasting occurs next, primarily with weakness of median- and ulnar-nerve innervated muscles. Subsequent hand sensory function loss and neurological pain may also develop when large-diameter axons are damaged.3
  • Symptomatology can vary drastically in CMT1, with some patients barely detecting symptoms and others eventually becoming wheelchair-dependent due to severe limb involvement.2
  • The nerve conduction velocity of the median nerve of the affected side should be compared with the contralateral side or the homolateral ulnar nerve.3
  • Nerve biopsy is often indicated in CMT
  • Molecular genetic testing is indicated in CMT
References

Cited

  1. Bird TD. Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews((R)). Seattle (WA) 1993. PMID: 20301532
  2. Wood VE, Huene D, Nguyen J. Treatment of the upper limb in Charcot-Marie-Tooth disease. J Hand Surg Br 1995;20(4):511-518. PMID: 7594996
  3. Georgiou S, Gay A, Legré, R. Hand Treatment in Charcot–Marie–Tooth Disease. J Hand Surg Am 2013;38(12):2482–2484.
  4. Barreto LC, Oliveira FS, Nunes PS, et al. Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review. Neuroepidemiology 2016;46(3):157-165. PMID: 26849231
  5. 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;9(4):465. PMID: 30305981
  6. Pareyson D, Saveri P, Pisciotta C. New developments in Charcot-Marie-Tooth neuropathy and related diseases. Curr Opin Neurol 2017;30(5):471-480. PMID: 28678038
  7. Charcot-Marie-Tooth News. Types of Charcot-Marie-Tooth Disease. https://charcot-marie-toothnews.com/types-of-charcot-marie-tooth-disease/. Accessed 5 December 2019.
  8. Lefter S, Hardiman O, Ryan AM. A population-based epidemiologic study of adult neuromuscular disease in the Republic of Ireland. Neurology 2017;88(3):304-313. PMID: 27927941
  9. Miller MJ, Williams LL, Slack SL, Nappi JF. The hand in Charcot-Marie-Tooth disease. J Hand Surg Br 1991;16(2):191-196. PMID: 2061663
  10. Brown RE, Zamboni WA, Zook EG, Russell RC. Evaluation and management of upper extremity neuropathies in Charcot-Marie-Tooth disease. J Hand Surg Am 1992;17(3):523-530. PMID: 1319438
  11. Michelinakis E, Vourexakis H. Tendon transfer for intrinsic-muscle paralysis of the thumb in Charcot-Marie Tooth neuropathy. Hand 1981;13(3):276-278. PMID: 7319330
  12. Riley WB, Jr., Mann RJ, Burkhalter WE. Extensor pollicis longus opponensplasty. J Hand Surg Am 1980;5(3):217-220. PMID: 7400558

New Articles

  1. 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;9(4):465. PMID: 30305981
  2. Pareyson D, Saveri P, Pisciotta C. New developments in Charcot-Marie-Tooth neuropathy and related diseases. Curr Opin Neurol 2017;30(5):471-480. PMID: 28678038

Reviews

  1. Morena J, Gupta A, Hoyle JC. Charcot-Marie-Tooth: From Molecules to Therapy. Int J Mol Sci 2019;20(14). pii: E3419. PMID: 31336816

Classics

  1. Guthrie L. Two Cases of Muscular Atrophy of the Peroneal Type (Charcot, Marie, Tooth) in Father and Son. Proc R Soc Med 1911;4(Clin Sect):126-8. PMID: 19974884
  2. Lidge RT, Chandler FA. Charcot-Marie-Tooth disease. J Pediatr 1953;43(2):152-63. PMID: 13070127
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