Charcot Marie Tooth Disease

7 Interesting Facts of Charcot Marie Tooth Disease

1. Charcot-Marie-Tooth disease is a spectrum of disorders caused by specific genetic mutations leading to metabolic or structural defects involving the myelin or axons of peripheral motor and sensory nerves 
2. Classified as types 1 to 7, X, and intermediate, with many subtypes (comprising distinct genetic disorders involving more than 40 loci) 
3. Classic presentation is of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed or absent tendon reflexes 
4. Diagnosis is based on history, physical examination findings, family history, electrodiagnostic test results, and genetic test results; nerve biopsy is no longer necessary in most cases 
5. Clinical features such as age of onset, disease severity, presence of associated abnormalities, and mode of inheritance help guide genetic testing
6. Treatment is supportive and includes physical/occupational therapy, orthotics and assistive devices, pain management, and surgical treatment of severe skeletal deformities and soft tissue abnormalities 
7. Severity of symptoms and disease progression are variable, and most patients have a normal life expectancy 

Pitfalls

• Owing to risk of disease exacerbation, avoid medications that are neurotoxic or potentially neurotoxic
  • Potential exists with chemotherapy agents (eg, vinca alkaloids, taxoids, platins), amiodarone, suramin, thalidomide, leflunomide, nitrofurantoin, and others 
• Take into consideration the theoretical risk associated with regional anesthesia in patients with Charcot-Marie-Tooth disease when considering options for anesthesia or pain management 

• Charcot-Marie-Tooth disease is a spectrum of disorders caused by specific genetic mutations leading to metabolic or structural defects involving the myelin or axons of peripheral motor and sensory nerves 
  • Usually classified as synonymous with hereditary motor and sensory neuropathy
  • Classified as types 1 to 7, X, and intermediate, with many subtypes
  • Genetically heterogeneous, comprising distinct genetic disorders involving more than 40 loci, but with a relatively homogenous clinical phenotype consisting of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed or absent tendon reflexes 
• Charcot-Marie-Tooth disease is the most common inherited neurologic disorder, with an estimated prevalence of 1 in 2500 

Classification

• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 1: demyelinating form
  • 50% to 80% of all cases 
  • Usually has typical clinical phenotype 
  • Uniform and diffuse motor and sensory slowing of nerve conduction velocity (slower than 38 m/second in median or ulnar nerve) 
  • Nerve biopsy, if performed, demonstrates onion bulbs or other myelin abnormalities and secondary axonal degeneration 
  • Autosomal dominant inheritance is the most common pattern
  • Sporadic mutations are also possible but are rare
  • Type 1 can be further divided into subtypes based on the affected gene, as follows: 1A, 1B, 1C, 1D, 1E, and 1F/2E
  • Most common form of Charcot-Marie-Tooth disease overall is type 1A 
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 2: axonal form
  • 10% to 15% of all cases 
  • Usually has typical clinical phenotype 
  • Normal or slightly reduced nerve conduction velocity (faster than 38 m/second in median or ulnar nerve) and significantly diminished amplitudes 
  • Nerve biopsy, if performed, demonstrates chronic axonal neuropathy 
  • Inheritance pattern is usually autosomal dominant, but it can be autosomal recessive in some cases 
  • Type 2 can be further divided into subtypes based on the affected gene, as follows: 2A1, 2A2, 2B, 2B1, 2B2, 2C, 2D, 2E/1F, 2F, 2G, 2H/2K, 2I/2J, 2L, 2M, 2N, 2O, 2P, 2S, 2T, and 2U 
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 3 (Dejerine-Sottas neuropathy and congenital hypomyelinating neuropathy)
  • Earlier onset (usually at birth or in infancy) than in other forms and often very severe 
    • Often leads to wheelchair dependency at an early age
  • Very slow nerve conduction velocities (slower than 12 m/second) 
  • Autosomal dominant inheritance, autosomal recessive inheritance, and sporadic cases have been reported
  • Nerve biopsy, if performed, demonstrates demyelination and onion bulbs 
• Intermediate Charcot-Marie-Tooth disease
  • Less than 4% of all cases 
  • Mild to moderate severity with motor nerve conduction velocity between 25 and 45 m/second 
  • Nerve biopsy, if performed, finds axonal and myelinopathic characteristics of type 1 and type 2 Charcot-Marie-Tooth disease 
  • Inheritance pattern is autosomal dominant
  • Can be further divided into subtypes: dominant intermediate Charcot-Marie-Tooth disease subtypes A, B, C, D, and F 
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 4
  • Rare disease 
  • Earlier onset and more severe course than type 1; may include vocal cord paresis, sensorineural deafness, and facial and diaphragmatic weakness 
  • Variable motor nerve conduction velocity; tends to be slower than 38 m/second 
  • Nerve biopsy, if performed, demonstrates demyelination
  • Inheritance pattern is autosomal recessive
  • Subtypes include 4A, 4B1, 4B2, 4B3, 4C, 4D, 4E, 4F, 4G, 4H, and 4J 
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type X
  • 10% to 15% of all cases 
  • Nerve conduction slowing can be nonuniform and asymmetrical; commonly 30 to 45 m/second 
  • Nerve biopsy, if performed, finds axonal loss, some demyelination, and a few onion bulbs 
  • Inheritance pattern is X-linked
  • Subtypes include X1 to X6
  • Subtype X1 affects males more than females; other subtypes affect only males 
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 5 (spastic paresis with sensory neuropathy) 
  • Has pyramidal involvement ranging from increased deep tendon reflexes to spastic paraplegia
  • Electrophysiologic findings indicate axonal loss and reduced sensory action potential amplitudes
  • Autosomal dominant inheritance
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 6 (optic atrophy with motor sensory neuropathy); now referred to as type 2A2 
  • Associated with optic atrophy causing severe visual loss
  • Early onset
  • Nerve conduction velocities are normal or mildly slowed
  • Autosomal dominant inheritance
• Charcot-Marie-Tooth or hereditary motor and sensory neuropathy type 7 (retinitis pigmentosa with motor sensory neuropathy) 

Clinical Presentation

History

• Age of onset, rate of progression, specific characteristics, and overall severity vary according to specific type of disease, causative gene, and type of mutation 
• Type 1 is the most common and well characterized form of the disease and results in the usual phenotype described here; presentation is similar in other forms but may occur at earlier age or in association with cranial nerve involvement, speech abnormalities, deafness, and visual loss 
• Symptoms usually appear in childhood, adolescence, or early adulthood
  • Symptoms typically develop between ages 5 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 
  • Onset is commonly earlier in autosomal recessive neuropathies than in autosomal dominant forms
• Clinical presentation is variable, ranging from undetectable mild symptoms to significant disability 
• Initial manifestation is weakness in feet, which progressively affects ankles and legs 
  • Subsequently hands and then forearms may be involved
• Patients may describe difficulty in running or walking, twisting ankles or tripping, or difficulty in manipulating objects by hand; if symptoms occur in infancy, the result is delayed walking 
• Sensory loss progresses in the same manner; however, paresthesias are rare
• Other symptoms include: 
  • Hand tremors
  • Muscle cramps in legs or feet
  • Cold feet
  • Acrocyanosis
  • Foot callosities
  • Painful feet, lower limbs, and lumbar spine

Physical examination

• Foot deformities
  • Pes cavus 
  • Hammer toe 
  • Pes planus (less common) 
  • Foot calluses
• Muscle wasting and weakness initially in distal segments of lower, then upper limbs 
  • Distal calf atrophy results in characteristic stork leg appearance
  • Atrophy of intrinsic muscles of hands may result in clawhand appearance 
• Decreased vibration, pain, and touch sensation initially in distal segments of lower, then upper limbs; sometimes proprioception is also involved 
• Reduced or absent deep tendon reflexes in upper and lower extremities
  • Palpable nerve hypertrophy may be present in 25% to 66% of type 1 cases, particularly in ulnar nerve at olecranon groove in elbow and in greater auricular nerve along neck 
• Gait abnormalities
  • Bilateral foot drop
  • Steppage gait 
  • Toe walking (in early childhood) 
• Scoliosis 
• Hypotonia (in infants) 
• Some types of the disease may be associated with characteristic type-specific features (eg, cranial nerve involvement, vocal cord palsy, deafness, pupillary abnormalities, optic atrophy, predominantly upper limb or sensory abnormalities) 

Causes

• Caused by specific genetic mutations leading to metabolic or structural defects involving myelin or axons of peripheral motor and sensory nerves 

Risk factors and/or associations

Age

• Age of symptom onset most commonly falls between ages 5 and 25 years, although onset in infancy or in middle age can occur 

Sex

• Males with X-linked form of disease are typically more symptomatic than females 

Genetics

• In approximately 90% of cases in the United Kingdom, northern Europe, and the United States, the inheritance pattern is either autosomal dominant or X-linked 
• In consanguineous populations, the autosomal recessive inheritance pattern accounts for 40% of cases 
• Over 50 relevant gene defects have been identified
  • In over 90% of cases in the United States, the United Kingdom, and France in which a genetic diagnosis is made, the mutation involves PMP22 (peripheral myelin protein 22), MPZ (myelin protein zero), GJB1 (gap junction protein β1), or MFN2 (mitofusin 2) 
    • Type 1A is caused by a duplication in chromosomal bands 17p11.2 to 17p12 (which contain PMP22), a point mutation of PMP22, or sporadic mutations 
      • Type 1A is the most common form of Charcot-Marie-Tooth disease in Western countries, comprising 70% to 80% of type 1 cases 
      • Duplication mutation accounts for 89% of cases of paternal origin, 11% of cases of maternal origin, and 5% to 24% of random cases 
      • Point mutations have been reported as an infrequent cause of type 1A (2%-5% of cases) 
    • Type 1B is caused by mutations in MPZ (on chromosomal band 1q22) 
      • This type is the second most common cause of the autosomal dominant inheritance pattern, comprising 10% of cases 
      • Point mutations in exons 2 and 3 are the primary cause of type 1B 
    • Type X1 is caused by mutation of GJB1 on chromosomal band Xq13.1, representing 90% of X-linked cases 

Ethnicity/race

• Some types have been reported to predominate in certain nationalities; epidemiologic study reveals unexplained differences 

Diagnostic Procedures

Primary diagnostic tools

• Diagnose on basis of history, physical examination, family history, electrophysiologic test results, and genetic test results 
  • Clinical features such as age of onset, disease severity, presence of associated abnormalities, and mode of inheritance help guide the genetic testing
    • Ascertain mode of inheritance with family history; in situations where the symptoms are variable within the same family, clinical and electrophysiologic testing of first-degree relatives may be necessary 
  • Obtain nerve conduction tests to assess presence, degree, and pattern of nerve conduction slowing 
  • Molecular genetic analysis, guided by clinical features, mode of inheritance, and nerve conduction velocities, usually confirms specific diagnosis 
• Nerve biopsy is unnecessary in most cases; however, it may be useful when primary diagnostic tests are inconclusive 
  • May be used when genetic test results are negative in familial cases or when necessary to rule out inflammatory neuropathy
  • Do not perform routinely, owing to associated risk of permanent paresthesias
• Laboratory tests are not required to make diagnosis but may be obtained to exclude infectious, nutritional, endocrine, or immunologic causes of neuropathy

Laboratory

• Genetic testing
  • May be performed to identify specific genetic cause of disease, which may aid in determining inheritance pattern and, to some extent, prognosis (although individual prognosis is difficult to predict even with precise genetic results) 
  • Use focused approach based on clinical phenotype, physiology, mode of inheritance, and prevalence of various mutations 
  • Suggested initial strategy for demyelinating (type 1 and X-linked) forms consists of testing for PMP22 duplication and GJB1 mutation, followed by PMP22 mutation and MPZ mutation 
  • Initial strategy for axonal (type 2) disease involves testing for mutations in MFN2, MPZ, and GJB1 
  • If initial testing does not identify a pathologic variant, a genetic neuropathy screening panel followed by whole exome sequencing may be considered 
  • Failure to identify a genetic cause does not exclude the disease, because undetected variants may be responsible 

Functional testing

• Electrophysiologic testing
  • Nerve conduction tests and EMG allow classification of disease into demyelinating, axonal, or intermediate groups based on motor nerve conduction velocities and compound muscle action potentials
  • Demyelinating form (type 1) has slow nerve conduction velocity; the cutoff value is slower than 38 m/second, but even slower values are common (eg, 20-25 m/second, or less than 15 m/second in severe cases) 
  • Axonal form (type 2) cases usually exhibit nerve conduction velocities within the reference range (ie, faster than 40-45 m/second) with greatly reduced compound motor action potentials 
    • However, occasional mildly abnormal velocities have been identified (in the range of 30-40 m/second) 
  • Nerve conduction velocity reference range is usually defined as at least 38 m/second or at least 40 to 45 m/second; mildly to intermediately slowed velocities are usually defined in ranges of 30 to 40 m/second or 35 to 45 m/second 
  • Conduction velocities are obtained in upper limbs

Procedures

• Collection of a sural nerve sample for pathologic examination
• Not usually necessary since advent of molecular genetic testing 
• May have role in confirming diagnosis when genetic test results are negative in familial cases and in excluding inflammatory neuropathy 
• No absolute contraindications
• Permanent paresthesias
• Findings for type 1 include appearance of onion bulbs or other myelin abnormalities and secondary axonal degradation
• Findings for type 2 include evidence of chronic axonal neuropathy without specific diagnostic features
• Intermediate form has features of both types 1 and 2
• Findings for X-linked form include evidence of axonal loss, some demyelination, and a few onion bulbs
• Findings for motor-only variants are normal or near-normal

Differential Diagnosis

Most common

• Other inherited neuropathies
  • Hereditary sensory neuropathy (most common is type 1A)
    • Autosomal dominant motor and sensory neuropathy with axonal pathology
    • Like Charcot-Marie-Tooth disease, may present with distal sensory loss and later also have distal muscle wasting and weakness
    • Differentiated on basis of history, physical examination findings, and results of electrophysiologic and genetic testing
  • Friedrich ataxia
    • Autosomal recessive disease characterized by slowly progressive ataxia
    • Like Charcot-Marie-Tooth disease, may present with distal muscle weakness, sensory loss, and pes cavus deformity
    • Unlike Charcot-Marie-Tooth disease, typically involves ataxia of gait and limbs, dysarthria, and dysphagia; often associated with hypertrophic cardiomyopathy, diabetes, or deafness
    • Differentiated on basis of history, physical examination findings, electrophysiologic testing, and genetic testing
  • Hereditary neuropathy with liability to pressure palsies
    • Recurrent episodic demyelinating neuropathy 
    • Atypical presentations may be similar to presentation of Charcot-Marie-Tooth disease, with generalized weakness and muscle cramps
    • However, typically presents with a temporary isolated nerve palsy in area affected by compression or trauma, with weakness or loss of sensation
    • Differentiated on basis of history, physical examination findings, and results of electrophysiologic testing, nerve biopsy, and genetic testing
  • Hereditary motor neuropathy
    • Like Charcot-Marie-Tooth disease, results in distal muscle weakness and wasting
    • Unlike Charcot-Marie-Tooth disease, has no associated sensory loss
    • Differentiated on basis of history, physical examination findings, electrophysiologic testing, and genetic testing
  • Various other hereditary disorders are associated with peripheral neuropathy (eg, Refsum disease, Krabbe disease, several mitochondrial disorders, and distal myopathies) 
    • These may be differentiated on basis of history, physical examination findings, laboratory and electrophysiologic testing, and genetic testing
• Acquired peripheral neuropathies
  • Causes of acquired peripheral neuropathy include vitamin B₁₂ deficiency, diabetes, thyroid disease, uremia, neurosyphilis, drugs (especially chemotherapy agents), heavy metals, alcoholism, and Guillain-Barré syndrome 
    • Differentiated on basis of history, physical examination findings, and laboratory and electrodiagnostic testing

Treatment Goals

• Maintain function and quality of life

Admission criteria

• Admit patients who require surgical treatment of deformities

Recommendations for specialist referral

• Refer to neurologist for diagnosis and ongoing care and monitoring 
• Refer as needed to:
  • Physical/occupational therapist
  • Orthopedic surgeon
  • Genetic counselor
  • Mental health specialist

Treatment Options

There is no specific therapy for Charcot-Marie-Tooth disease; treatment is supportive and consists of:

• Physical/occupational therapy to protect joint range of motion, avoid contractures, and maximize function of upper and lower extremities 
  • Mild to moderate exercise is safe and improves walking ability and distal leg strength
  • Passive stretching is recommended to prevent and counteract tendon retractions
• Shoe modifications, orthotics, braces, and assistive devices may help overcome foot abnormalities and improve walking 
• Surgical treatment of skeletal deformities and soft tissue abnormalities
  • Various approaches are used, as follows:
    • Plantar fasciotomy to reduce cavus deformity
    • Various types of tendon releases and/or transfers in upper and lower limbs
    • Arthrodesis to fuse talocalcaneal, talonavicular, and calcaneocuboid joints in severe foot deformities
    • Various types of osteotomies for fixed or severe equinocavovarus deformity
    • Spinal surgery to correct scoliosis
• Symptomatic therapy for neuropathic and musculoskeletal pain using agents such as NSAIDs, antidepressants, anticonvulsants, and muscle relaxants 
• Psychosocial support
• Advise to avoid medications associated with peripheral nerve toxicity (particularly certain chemotherapy agents) because they may exacerbate symptoms
  • Potential exists with chemotherapy agents (eg, vinca alkaloids, taxoids, platins), amiodarone, suramin, thalidomide, leflunomide, nitrofurantoin, and others 
• Take into consideration the theoretical risk associated with regional anesthesia in patients with Charcot-Marie-Tooth disease when considering options for anesthesia or pain management 

To date, no data support the use of specific drug therapy; however, studies involving ascorbic acid, progesterone antagonists, and curcumin have shown some promise 

Offer genetic counseling to patients and their families

Nondrug and supportive care

• Physical therapy and orthoses
  • Formal individualized physical therapy sessions increase upper and lower extremity muscular strength and improve ability to perform activities of daily living
  • Orthoses appear to improve balance and ability to ambulate, although further study is necessary to be conclusive

Special populations

• Pregnant women
  • Possible increased muscle weakness during pregnancy 
  • Surgical delivery may be necessary 

Monitoring

• Regular follow-up by a multidisciplinary team is recommended to evaluate the following:
  • Neurologic status
  • Disease progression
  • Functional disability and need for orthoses and/or surgery
  • Mental health status

Complications

• Reduced ability to perform activities of daily living owing to muscle weakness, muscle atrophy, and sensory loss 
• Impaired walking and susceptibility to falls 
• Depression, anxiety, and decrease in quality of life owing to progressive disability 
• Breathing difficulty caused by muscle weakness 
• Skin breakdown due to use of orthoses 
• Susceptibility to burns and wounds owing to loss of sensory perception
• Hip dysplasia as a result of strategies to compensate for muscle weakness and sensory loss 
• Scoliosis, secondary to neuromuscular weakness, in 20% of cases 

Prognosis

• Life span is normal for patients with type 1, type 2, intermediate, and X-linked Charcot-Marie-Tooth disease
  • These patients rarely become wheelchair dependent, and disease progression is slow
• Type 4 has a more severe clinical course
  • Patients with type 4A or 4B become wheelchair dependent by ages 30 years and 20 years, respectively 
  • Disease duration is 27 to 39 years, with death in the fourth or fifth decade for patients with type 4B

Screening

At-risk populations

• At-risk, asymptomatic adult relatives of an affected person 
• In accordance with ethical consensus, do not perform genetic screening tests in at-risk, asymptomatic children and adolescents (younger than 18 years) 

Screening tests

• Genetic testing
  • Testing is only for personal decision making with genetic counseling
    • No treatment is available for early disease stages 
    • Testing is not useful for predicting onset of symptoms, symptom severity, symptom type, or rate of progression; substantial phenotypic variability occurs even within the same type of disease 

References

Pareyson D et al: Diagnosis, natural history, and management of Charcot-Marie-Tooth disease. Lancet Neurol. 8(7):654-67, 2009