AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Charcot-Marie-Tooth (CMT) disease was first recognized independently in France and Great Britain (Charcot and Marie, 1886; Tooth, 1886). A few years later, a more severe form of inherited neuropathy was described (Dejerine and Sottas, 1893). More recent nomenclature designated Charcot-Marie-Tooth disease as a hereditary motor and sensory neuropathy (HMSN). Recent advances in genetic research have identified several types of HMSN, which correspond with specific genetic mutations. In 1968, Dyck and Lambert created a broader classification system, which is as follows:

• HMSN types 1A and B (dominantly inherited hypertrophic neuropathies)
• HMSN type 2 (neuronal type of peroneal muscular atrophy)
• HMSN type 3 (hypertrophic neuropathy of infancy [Dejerine-Sottas])
• HMSN type 4 (hypertrophic neuropathy [Refsum] associated with phytanic acid excess)
• HMSN type 5 (associated with spatic paraplegia)
• HMSN type 6 (with optic atrophy)
• HMSN type 7

This article discusses only HMSN types 1, 2, and 3 because these are the most commonly occurring hereditary neuropathies. Other forms of HMSN are extremely rare.

Pathophysiology

HMSN 1 is the most common form of hereditary neuropathy. Severely and uniformly slowed nerve conduction velocities (NCVs) and primary hypertrophic myelin pathology with prominent onion bulbs and secondary axonal changes are the hallmarks of the disease.

HMSN 2, on the other hand, represents the nondemyelinating neuronal type with relatively normal NCVs and primary axonal pathology. Although nerves are not enlarged in the neuronal form, weakness often is less marked and onset of this neuropathy is delayed.

Frequency

United States

Estimates of the frequency of Charcot-Marie-Tooth disease vary widely. In 1974, Skre and colleagues reported a prevalence of 1 case per 2500 individuals, whereas another worldwide meta-analysis estimated a prevalence of 1 per 10,000 individuals (Emery, 1991). Charcot-Marie-Tooth disease type 1 accounts for about two thirds of cases and Charcot-Marie-Tooth disease type 2 accounts for about one third of cases, while other forms of Charcot-Marie-Tooth disease are very rare.

Mortality/Morbidity

• Usually, life expectancy is normal.
• Disability is highly variable and difficult to predict in young individuals. This is related, at least in part, to the variable genetic penetrance of the disorders.
• In general, Charcot-Marie-Tooth disease is a slowly progressive condition. If progression accelerates, other causes, such as acquired neuropathies or other inherited neuromuscular conditions, should be sought.

Race

No racial predilection is reported for Charcot-Marie-Tooth disease.

Sex

The male-to-female ratio is not established. Often, males are affected slightly more than females; however, this is possibly due to an increased likelihood of nerve trauma.

Age

• The onset of HMSN 1 in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.
• Patients with HMSN 2 are usually asymptomatic until later in life, and the symptoms most commonly begin in the second decade of life.
• The onset of HMSN 3 is in early childhood.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Hereditary motor and sensory neuropathy type 1
• • Because of its insidious onset, some patients are unaware of their disease or seek medical attention only late in life. In contrast to acquired neuropathies in which pain in a prominent feature, patients with HMSN1 experience a relative lack of pain.
  • Motor symptoms predominate over sensory symptoms.
  • Often, patients report loss of balance, muscle weakness, and foot deformities.
  • Onset in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.
  • Patients report tripping over objects because of foot drop. Ankle sprains and fractures are frequent.
  • Because of hammertoes and high arches, patients have difficulty finding well-fitting shoes or experience painful calluses.
  • Cold feet, often associated with hair loss or leg edema, is common.
  • Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed.
• Hereditary motor and sensory neuropathy type 2: Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed.
• Hereditary motor and sensory neuropathy type 3 (Dejerine-Sottas syndrome)
• • This is a rare hypertrophic neuropathy of infancy inherited as an autosomal recessive trait.
  • The clinical features are those of a severe neuropathy with onset in early childhood.
  • Motor development is delayed.
  • Jumping and running are impaired.
  • Muscular weakness is progressive, affecting legs and arms.

Physical

• Hereditary motor and sensory neuropathy type 1
• • Roughly half of patients with CMT could be grouped into a classic phenotype associated with distal weakness, decreased tendon reflexes, foot deformities, with or without sensory loss. Weakness and muscle atrophy, which is dominant distally, affect the legs more severely and earlier than the arms.
  • Sensation may be normal until adulthood, but mild diffuse sensory loss is common.
  • Hyporeflexia or areflexia is the rule.
  • Foot deformities include high arches or flat feet, hammertoes, and tight Achilles tendons.
  • Enlargement and excessive firmness are found in the nerves of more than 25% of patients and are often visible in the superficial cervical nerves and palpable in the arms.
  • Tremor occurs in up to 25% of patients.
• Hereditary motor and sensory neuropathy type 2
• • Peripheral nerves are not enlarged clinically, and weakness of feet and leg muscles predominates; hands are less severely affected than the legs.
  • Patients experience sensory loss in the distal extremities, and foot deformities (ie, pes cavus) tend to be less marked than those of HMSN 1.
• Hereditary motor and sensory neuropathy type 3
• • General areflexia with prominent enlarged peripheral or cranial nerves is typical.
  • Patients experience a definite sensory loss, and some patients have marked sensory ataxia.

Causes

• Genetic defects in inherited demyelinating neuropathies. Current estimates indicate that up to 60% of patients with CMT1 have the chromosome 17 duplication.
• • HMSN type 1A - Duplication on chromosome 17 (region containing human peripheral myelin protein 22 [PMP22] gene), point mutation in PMP22 gene, autosomal dominant inheritance, with the HMSN 1 locus mapped on the short arm of chromosome 17 (p11.2-p12 band)
  • HMSN type 1B - Point mutation in the P0 gene (an important structural protein of peripheral nerve myelin) on the long arm of chromosome 1, linked to the Duffy blood group
  • HMSN type 2 - Gene localized to chromosome 1
  • HMSN type 3 (Dejerine-Sottas disease) - Missense and point mutation in PMP22 (recent genetic studies) and the P0 gene, other undetermined causes
  • HMSN type X
    • X-linked dominant HMSN is phenotypically similar to HMSN type 1. Male subjects tend to be more severely affected, whereas female subjects may have a mild neuropathy or be asymptomatic.
    • No male-to-male transmission occurs.
    • Linkage analysis localized the locus to the proximal long arm of the X chromosome; a recent study isolated a gap junction protein, connexin 32, as the candidate gene, which, if abnormal, can cause HMSN X.
• Lupski and coworkers reported that a segment band of chromosome 17 (17p11.2-p12) was duplicated in affected members of families with HMSN 1A. The PMP22 gene is found in the region of the duplication. PMP22 encodes for the synthesis of a peripheral nervous system myelin protein. Most patients with genetically defined HMSN 1A have either a gene dose effect (ie, duplication of 17p11.2-p12) or a mutation affecting the PMP22 gene on chromosome 17. Interestingly, the human PMP22 gene is deleted in patients with HSMN with liability to pressure palsies.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Charcot-Marie-Tooth disease type 1B
Charcot-Marie-Tooth disease type 1A
Charcot-Marie-Tooth disease type 10
Charcot-Marie-Tooth disease type 2
Dejerine-Sottas syndrome
Congenital hypomyelination neuropathy
Acquired neuropathies
Chronic inflammatory demyelinating polyneuropathy (CIDP)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The workup should include tests that address causes of neuropathies, such as endocrinologic, infectious, and immunologic abnormalities; vitamin and nutritional deficiencies; and nerve compression.
• On cerebrospinal fluid (CSF) analysis, CSF protein levels usually are within the reference range in patients with Charcot-Marie-Tooth disease type 1B, but they may be elevated above 100 mg/dL. By contrast, CSF protein is elevated in most but not all cases of Dejerine-Sottas syndrome.

Other Tests

• Genetic testing: Patients in whom the clinical phenotype, family history, and findings on electrodiagnostic studies suggest an inherited neuropathy should undergo genetic testing. Genotyping permits sound genetic and prognostic counseling and advances the scientific understanding of phenotypes.

Procedures

• Electrodiagnostic studies
• • Charcot-Marie-Tooth disease type 1 is characterized typically by diffuse and uniform motor conduction velocity slowing in virtually all the nerves tested. In 1980, Harding and Thomas proposed a criterion that motor conduction velocity less than 38 m/s be used as the cutoff value for HMSN 1, provided the compound muscle action potential (CMAP) is at least 0.5 mV in the nerve where the conduction velocity is tested. Recent multiple studies have shown that neurophysiologic testing on the median and peroneal nerves revealed mean motor NCVs of 20 m/s (range, 5 m/s to 34 m/s) and 17 m/s (range, 10 m/s to 22 m/s), respectively. If temporal dispersion of the CMAP or conduction block is found, an alternative diagnosis, such as CIDP, should be considered.
  • Motor NCVs are near normal or normal in patients with HMSN 2. Sensory nerve action potentials (SNAPs) are reduced uniformly or are absent.
  • Motor conduction velocities are reduced markedly, usually below 10 m/s in patients with HMSN 3 (ie, Dejerine-Sottas syndrome).

Histologic Findings

Most nerve biopsies from patients with Charcot-Marie-Tooth disease show evidence of a hypertrophic demyelinating neuropathy, with onion bulbs as evidence of chronic remyelination and loss of myelinated fibers, preferentially those of large diameter. Focally sausagelike thickenings of myelin sheath (tomacula) have been described in patients with Charcot-Marie-Tooth disease. Note that tomaculous neuropathy also is a hallmark of hereditary neuropathy with liability to pressure palsy resulting from a deletion of PMP22 at band 17p11.2 and rare PMP22 nonsense mutations. Dejerine-Sottas syndrome and congenital hypomyelination neuropathy are characterized by more severe hypomyelination and demyelination and axonal loss.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Prevention, recognition, and treatment of acquired neuropathies are particularly important if compression neuropathies are to be avoided. This may require adjustments in lifestyle and avoidance of job-related nerve injury. Patients, family members, and physicians must be aware of drugs that can affect the peripheral nervous system.

• Physical therapy is often required to prevent and treat joint deformities. Prosthetic devices, such as ankle-foot orthoses, can prevent Achilles tendon shortening and prolong near-normal ambulation. At times, boots can delay the need for such ankle braces. Thick-handled tools and cutlery can render certain activities of daily living easier.
• Pain may result from joint deformities or compensatory overuse of certain muscle groups. Some types of pain may respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Dysesthetic pain may occur but is not typical; it responds to antidepressants, such as amitriptyline, desipramine, or paroxetine, and to anticonvulsants, such as gabapentin or carbamazepine.
• Recent research and updates proposed that the most common form of inherited peripheral neuropathy results from overexpression of a single gene. Simple application of an antiprogesterone drug can reduce gene expression and alleviate symptoms in a rat model. Sereda et al described the first successful treatment strategy in a rat model of Charcot-Marie-Tooth subtype 1A (CMT-1A), the most common variant of the inherited peripheral neuropathies. Their observations offer a glimpse of hope for patients, provided their strategy can be translated into clinical trials in humans.

Surgical Care

Depending on the degree of foot deformities, patients may benefit from Achilles tendon lengthening, tendon transfers, hammertoe correction, and release of the plantar fascia.

Diet

Patients should maintain a well-balanced diet and avoid obesity, which can contribute to spinal root diseases and certain entrapment neuropathies (eg, meralgia paresthetica).

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Drug Category: Nonsteroidal anti-inflammatory drugs (NSAIDS)

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Drug Category: Antidepressants

These drugs increase the synaptic concentration of serotonin and/or norepinephrine in CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These mechanisms may play a role in the analgesic effects of these medications.

Drug Category: Serotonin reuptake inhibitors

Serotoninergic antidepressants have had mixed reviews in the literature. Some of them have been reported to relieve painful sensory symptoms.

Drug Category: Anticonvulsants

These medications reduce neuronal excitability and prevent neuronal discharges associated with pain sensation.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Complications

• Rare complications include radiculopathies due to enlarged nerve roots.

Prognosis

• Life expectancy is normal.
• Disability is highly variable and difficult to predict in young individuals, even among siblings.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• HMSN and its variants are uncommon disorders and can be difficult to diagnose and treat. Frequently, patients with this disorder require referral to a medical center specializing in neuropathic disorders.
• Associated conditions must be excluded and treated appropriately.

Special Concerns

• No particular complications are associated with pregnant women with Charcot-Marie-Tooth disease type 1B.
• As with surgical procedures, prolonged positioning of the body and limbs in particular postures can result in nerve compression, which could make any underlying neuropathy worse.
• Regional anesthesia is contraindicated in Charcot-Marie-Tooth disease.
• Because of the variability of clinical manifestations, couples who have symptomatic or asymptomatic Charcot-Marie-Tooth disease type 1B may have homozygous offspring with Dejerine-Sottas syndrome or congenital hypomyelination neuropathy.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Antonellis A, Ellsworth RE, Sambuughin N, et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet. May 2003;72(5):1293-9. [Medline].
• Auer-Grumbach M, Strasser-Fuchs S, Wagner K, et al. Roussy-Levy syndrome is a phenotypic variant of Charcot-Marie-Tooth syndrome IA associated with a duplication on chromosome 17p11.2. J Neurol Sci. Jan 21 1998;154(1):72-5. [Medline].
• Bird TD, Kraft GH, Lipe HP, et al. Clinical and pathological phenotype of the original family with Charcot-Marie-Tooth type 1B: a 20-year study. Ann Neurol. Apr 1997;41(4):463-9. [Medline].
• Birouk N, Gouider R, Le Guern E, et al. Charcot-Marie-Tooth disease type 1A with 17p11.2 duplication. Clinical and electrophysiological phenotype study and factors influencing disease severity in 119 cases. Brain. May 1997;120 ( Pt 5):813-23. [Medline].
• Blanquet-Grossard F, Pham-Dinh D, Dautigny A, et al. Charcot-Marie-Tooth type 1B neuropathy: a mutation at the single glycosylation site in the major peripheral myelin glycoprotein Po. Hum Mutat. 1996;8(2):185-6. [Medline].
• Chapon F, Latour P, Diraison P, et al. Axonal phenotype of Charcot-Marie-Tooth disease associated with a mutation in the myelin protein zero gene. J Neurol Neurosurg Psychiatry. Jun 1999;66(6):779-82. [Medline].
• D'Urso D, Ehrhardt P, Muller HW. Peripheral myelin protein 22 and protein zero: a novel association in peripheral nervous system myelin. J Neurosci. May 1 1999;19(9):3396-403. [Medline].
• Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol. Jun 1968;18(6):603-18. [Medline].
• Gabreels-Festen AA, Hoogendijk JE, Meijerink PH, et al. Two divergent types of nerve pathology in patients with different P0 mutations in Charcot-Marie-Tooth disease. Neurology. Sep 1996;47(3):761-5. [Medline].
• Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain. Jun 1980;103(2):259-80. [Medline].
• Lagueny A, Latour P, Vital A, et al. Peripheral myelin modification in CMT1B correlates with MPZ gene mutations. Neuromuscul Disord. Oct 1999;9(6-7):361-7. [Medline].
• Lebo RV, Chance PF, Dyck PJ, et al. Chromosome 1 Charcot-Marie-Tooth disease (CMT1B) locus in the Fc gamma receptor gene region. Hum Genet. Nov 1991;88(1):1-12. [Medline].
• Marrosu MG, Vaccargiu S, Marrosu G, et al. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology. May 1998;50(5):1397-401. [Medline].
• Paulson HL, Garbern JY, Hoban TF. Transient central nervous system white matter abnormality in X-linked Charcot-Marie-Tooth disease. Ann Neurol. Oct 2002;52(4):429-34. [Medline].
• Simonati A, Fabrizi GM, Taioli F. Dejerine-Sottas neuropathy with multiple nerve roots enlargement and hypomyelination associated with a missense mutation of the transmembrane domain of MPZ/P0. J Neurol. Sep 2002;249(9):1298-302. [Medline].

Article Last Updated: Apr 20, 2006