eMedicine Specialties > Neurology > Neuromuscular Diseases

Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies

Timothy C Parsons, MD, Fellow in EMG and Neuromuscular Disease, Department of Neurology, Columbia University Medical Center, New York
Thomas H Brannagan III, MD, Associate Professor of Clinical Neurology and Director, Peripheral Neuropathy Center, Columbia University, College of Physicians and Surgeons; Co-Director, EMG Laboratory, New York-Presbyterian Hospital, Columbia Campus, New York

Updated: Nov 5, 2009

Introduction

Background

Slowly progressive distal weakness, muscle atrophy, and sensory loss due to an inherited peripheral neuropathy was described independently in 1886 by Charcot and Marie in France and by Tooth in England.^1,2 A few years later, Dejerine and Sottas recognized and described a more severe, infantile form of inherited neuropathy.³  
 
As more heterogeneity and overlap in clinical appearance, pathological features, and forms of inheritance were recognized in the following decades, an improved classification system was needed to avoid confusion. Starting in the 1950s, the clinical use of nerve conduction studies combined with pathological information allowed patients to be divided into 2 major groups.

• Group 1 was characterized by slow nerve conduction velocities and evidence of hypertrophic demyelinating neuropathy.
• Group 2 was characterized by relatively normal nerve conduction velocities and axonal degeneration.

• HMSN types 1A and 1B (dominantly inherited hypertrophic demyelinating neuropathies)
• HMSN type 2 (dominantly inherited neuronal neuropathies)
• 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 spastic paraplegia)
• HMSN type 6 (with optic atrophy)
• HMSN type 7 (with retinitis pigmentosa)

• CMT1 is a dominantly inherited, hypertrophic, predominantly demyelinating form.
• CMT2 is a dominantly inherited predominantly axonal form.
• Dejerine-Sottas is a severe form with onset in infancy.
• CMTX is inherited in an X-linked manner.
• CMT4 includes the various demyelinating autosomal recessive forms of Charcot-Marie-Tooth disease.

Pathophysiology

CMT1A

The extra PMP22 gene copy within the 1.5 mB duplication on chromosome 17 is believed to cause most cases.¹² PMP22 is a 160 amino acid integral membrane protein that is expressed at high levels in myelinating Schwann cells, localizing to compact myelin and making up 2–5% of total myelin protein.^30,31 PMP22 expression in CMT1A nerve biopsies is increased³² , but the process by which protein overexpression actually causes the Charcot-Marie-Tooth phenotype remains unclear.
 
Abnormal expression of PMP22 seems to alter Schwann cell growth and differentiation both in vivo and in vitro, and may impair the ability of the Schwann cell to maintain normal myelin stability and turnover. A putative interaction between PMP22 and MPZ could play a role in maintaining myelin compaction and stability, and an imbalance in one could explain why changes in expression in either gene can lead to the clinically and pathologically indistinguishable CMT1A and CMT1B phenotypes.³³
 
Despite the evidence of demyelination found on pathological and electrophysiological studies and the more recent implication of myelin proteins, the signs and symptoms of weakness and sensory loss are likely the result of axonal degeneration rather than demyelination. Anatomical evidence of progressive length-dependent axonal loss following demyelination in CMT1 exists.³⁴ Children with CMT1A have slow nerve conduction velocities in the first years of life, generally preceding the development of signs and symptoms.³⁵ Krajewski and colleagues demonstrated that compound motor action potential amplitudes correlate best with weakness in CMT1A rather than nerve conduction velocities.³⁶
 
In vivo studies of CMT1A patients have demonstrated altered axonal excitability, in the form of elevated stimulation thresholds and a markedly abnormal threshold electrotonus. These findings suggested that demyelination causes exposure of fast K+ channels, which are normally sequestered under the myelin.³⁷
 
CMT1B

Myelin protein zero is an integral type I membrane protein, and is the most abundant structural protein of compact peripheral nerve myelin.^38,15  
 
More than 80 mutations in myelin protein zero have been described. Most are associated with
the typical CMT1B phenotype, but correlations have been found with other clinical phenotypes including CMT2, Dejerine Sottas syndrome, and congenital hypomyelination neuropathy.^39,40
 
Predominantly axonal and predominantly demyelinating forms appear to be due to different mutations in the same gene. Mutations that introduce a charged amino acid, removed or added a cysteine residue, or altered an evolutionarily conserved amino acid alter the tertiary structure of the MPZ protein as a result and lead to the more severe early onset phenotype. As with diseases of PMP22 expression, the mechanism for either demyelinating or axonal forms remains unclear, but may be due to impaired myelin-axon interaction.^41,42,43
 
CMTX

CMTX is caused by mutations in connexin32/Gap Junction Beta 1 (Cx32 or GJB1), which maps to chromosome Xq13. Connexins assemble to form intercellular gap junctions, which allow the diffusion of ions and small molecules across apposed cell membranes. Connexin 32 is expressed in many tissues, but is localized in the myelin sheath of large diameter fibers near the nodes of Ranvier.^18,44
 
Axonal and demyelinating changes are mixed in CMTX. Men are clinically and electrophysiologically more severely affected than affected women. Interestingly, nerve conduction velocities in affected women can vary markedly within the same limb, in contrast to men whose conduction velocities tend to resemble the diffusely slow velocities seen in CMT1. This may be partly explained by X-inactivation of Schwann cell precursors during development. The mechanisms by which different Cx32 mutations cause CMT1X are not fully understood. Phenotype-genotype correlations in CMT1X will be difficult to establish because of phenotypic variability both within and between kindreds.^45,46,47
 
CMT2

The most common mutation responsible for CMT2 has been found in the mitochondrial GTPase mitofusin 2 (MFN2) gene.⁴⁸ This is referred to as CMT2A.
 
MFN2 is a dynamin family GTPase that spans the outer mitochondrial membrane and is believed to primarily be involved in mitochondrial docking, tethering, and fusion. Recent data were supportive of a mitochondrial trafficking insult as a possible mechanism of length-dependent axonal neuropathy.^49,50

CMT4

The causes of CMT4 are diverse and very rare and will not be reviewed here.

Frequency

International

CMT is the most common inherited neuromuscular disorder. Estimates of the frequency of Charcot-Marie-Tooth disease vary widely. In 1974, Skre and colleagues reported a prevalence of 1 case per 2,500 individuals. A worldwide meta-analysis estimated a prevalence of 1 per 10,000 individuals, and a prevalence of 10.8 per 100,000 was found in western Japan.^51,52  
 
Charcot-Marie-Tooth disease type 1 accounts for about two thirds of CMT cases. Of these, 70% are due to duplications in PMP22. Duplications in PMP22 therefore account for roughly half of all combined CMT subtypes.^13,53 CMT1B makes up about 5% of CMT1 and about 1.6% of all CMT cases.^53,54
 
Charcot-Marie-Tooth disease type 2 accounts for about 22% of CMT cases.⁵³ CMT2A (MFN2 mutation) has been estimated to account for 11-23% of all CMT2 cases.⁵⁵

Charcot-Marie-Tooth disease type X accounts for about 16% of CMT cases.⁵³ CMTX1 (Cx32 mutation) accounts for most CMTX cases and may be the second most common cause of CMT overall, at 7-20%.^41,42

Mortality/Morbidity

Most people with CMT have a normal life expectancy, the exceptions being patients with respiratory involvement or severe disability. Disability varies greatly both between and within families, and can range from asymptomatic with minimal examination findings to severe. Marked differences in clinical severity have even been reported in monozygotic twins with CMT1A (despite similar nerve conduction velocities)⁵⁶ and myelin protein zero mutations⁵⁷ . 
 
A 2001 study showed that 44% of CMT1A patients were significantly disabled, and 18% were depressed. It was estimated that CMT1 patients suffer emotional stress similar to patients with stroke and comparable disability.⁵⁸

CMT is nearly always slowly progressive. A longitudinal study showed steady progression in nerve conduction velocity and disability, and severity could be predicted based on nerve conduction velocity abnormalities in childhood.⁵⁹ Killian and colleagues studied nerve conduction velocities and neurologic examinations in 8 members of a single family over 22 years and found minimal progression of disability.⁶⁰ Another study of 43 patients with CMT2 over 5 years documented slow progression of weakness and disability, and most patients remained ambulatory.⁶¹

As CMT is relatively common, it can occur with other inherited or acquired neuromuscular conditions. If progression accelerates, these possibilities should be pursued.⁶²

Race

No racial predilection is recognized in the common forms of CMT. Rare, recessively inherited forms (CMT4) cluster in particular ethnic groups.

Sex

As expected, CMTX affects males earlier, more frequently, and more severely than females. Other forms of CMT do not show predilection for either sex.

Age

Onset is usually in childhood. Thomas and colleagues found that 75% of patients with CMT1A developed clinical evidence of disease before age 10, and 85% before age 20.⁶³ Some patients experience very slow progression of mild, lifelong symptoms, and may seek medical attention only late in life.
 
There are patients and families in which CMT has a late onset, as late as the fifth or sixth decade in some MPZ mutations, and even as late as the seventh decade in CMT2.^40,64

Clinical

History

Despite wide genetic heterogeneity, the phenotypes of the different CMT subtypes are relatively similar. Dysfunction of all mutated proteins, even those involved in myelin formation, leads to the common end point of length-dependent axonal degeneration. Most patients present in the first 2 decades of life with some combination of distal muscle wasting and weakness (especially in the peroneal-innervated muscles) and distal sensory loss in the legs. History and examination alone are not sufficient to distinguish between predominantly demyelinating and predominantly axonal forms.^65,64 Inheritance is usually dominant, but may also be X-linked or sporadic. 

Patients with CMT can present with many symptoms and signs, although motor symptoms predominate over sensory symptoms in all age groups. Onset may occur in infancy, with a delay in motor milestones, a gait or running impairment with otherwise normal rate of development, or with toe walking. Adolescents may present with steppage gait, ankle injuries, or deformities like pes cavus or thin lower legs. Family members familiar with other affected relatives may bring children to medical attention based on other nonspecific motor problems.⁶³ Some patients with lifelong mild symptoms may not seek medical care until they experience frequent tripping or imbalance in late life, and only close questioning will reveal any evidence of prior impairment.⁶⁴ Asymptomatic patients can be detected during screening after a relative has been diagnosed.

• Sensation is often experienced as normal, and positive sensory symptoms such as dysesthetic pain are not as common as with acquired peripheral neuropathies. Pain of musculoskeletal origin or from entrapped nerves or compressed nerve roots is more common.^66,63  
• Gait is impaired by distal weakness but usually remains independent; proximal weakness only affects a minority of patients.^67,64  
• As mentioned earlier, clinical progression is slow and any acceleration should lead to a workup for superimposed conditions.⁶²
• Family history is usually suggestive of autosomal dominant inheritance, but the complete lack of a family history does not rule out any of the CMT subtypes. Recessively inherited mutations may have little to no family history, and sporadic patients due to de novo mutations are common.^68,41

Some features of different subtypes that deviate from the standard history given above are listed below.
 
CMT1B

Rather than presenting with a classical Charcot-Marie-Tooth phenotype, patients seem to manifest signs and symptoms according to 1 of 2 phenotypes: either prior to walking or around age 40.⁴⁰

CMT2

As with other forms of CMT, clinical variation is common between and within CMT2 families, but in general, weakness is often less marked and onset is later.⁶⁴ CMT2 with later onset can be difficult to distinguish from acquired axonal neuropathies, especially when the family history is unclear, because of the lack of distinctive physical examination and electrophysiologic findings.

Dejerine-Sottas

Onset of upper and lower extremity weakness and sensory loss occurs in infancy and tends to be not only earlier than other forms of CMT, but more severe. Dominantly inherited, recessively inherited, and sporadic cases exist.

CMTX

Symptoms due to distal weakness typically begin in childhood, as in CMT1. Weakness and atrophy of hand muscles and positive sensory phenomena are more prominent in CMTX. Female carriers may be asymptomatic. Those affected have a later onset and are less severely affected than males.⁴⁶ There is enough clinical overlap with CMT1 that the diagnosis should be considered in all patients who have a typical CMT story, especially if the family history lacks clear male-to-male transmission.

CMT4

Autosomal recessive forms are rare, often confined to small ethnic groups, and are clinically heterogeneous. Not only are other organ systems frequently involved, but as with many recessive conditions, clinical manifestations are often severe by comparison to the dominantly inherited forms.

Atypical

In a series of 61 patients with CMT1A, 34 patients presented with the classic Charcot-Marie-Tooth phenotype, and 27 patients had additional features such as CNS signs, prominent muscle cramps, tremor, or focal peripheral neuropathies.⁶³ CNS features should not be assumed to be due to CMT and always warrant further investigation.

Physical

Nerves
 
Enlarged and excessively firm nerves were found in 17 of 67 patients in Dyck and Lambert’s original series⁴ and are often visible in the superficial cervical nerves and palpable in the arms in patients with hypertrophic, demyelinating forms of CMT.
 
Motor
 
Motor signs tend to develop before sensory signs. Due to length dependent axonal degeneration, weakness and atrophy is first seen in intrinsic foot muscles, followed by ankle and toe dorsiflexors. This mismatch between strength in the affected peroneal-innervated muscles and the less affected tibial-innervated muscles leads to the typical high arched feet, hammer toes, and difficulty with heel walking seen early on physical examination.^4,69

Muscle atrophy and weakness progress proximally over time, and as distal leg muscle bulk is lost, the legs assume a characteristic “inverted champagne bottle” appearance. The distal thighs and hands can become involved, and weakness of intrinsic hand muscles gives rise to the typical “claw hand” deformity seen in CMT. Areflexia is frequent, especially distally. Proximal weakness only affects a small minority of patients.^67,64 Gait is impaired by muscle weakness, foot deformities that result from weakness, and proprioceptive loss. Despite these obstacles, most patients remain ambulatory.⁶¹

Bienfait and colleagues found that CMT2 had later disease onset and had a lower incidence of areflexia, foot deformities, and weakness of foot dorsiflexors, but concluded that there were no robust clinical signs to differentiate CMT1 from CMT2.⁷⁰ Men affected by CMTX are more likely to show hand weakness with early thenar atrophy and relative preservation of tendon reflexes.⁴⁶
 
Sensory
 
Sensory impairment tends to follow motor impairment, and remains less severe. Patients may remain asymptomatic despite substantial sensory loss on examination. Dyck and Lambert found large-fiber modalities like proprioception and vibratory sense to be affected out of proportion to other modalities, but Harding and Thomas found pansensory loss.^4,64
 
Orthopedic

Foot deformities are common in CMT but vary even among relatives in the same family, and are not specific. High arches, flat feet, hammer toes, and tight Achilles tendons can be seen. These deformities become more prevalent with age.⁴

Other

Some of the CMT2 subtypes have unusual associated clinical features that are of interest and may help with diagnosis.

• CMT2B - Poorly healing foot ulcers⁷¹
• CMT2C - Diaphragm weakness and vocal cord paralysis⁷²
• CMT2D - Weakness and atrophy that is more severe in the hands than in the feet⁵³
• CMT2 associated with MPZ mutation - Late-onset axonal polyneuropathy with prominent sensory involvement, pupillary abnormalities, and hearing loss⁷³

Causes

Please see the Pathophysiology section for a more thorough overview. 

• CMT1A -PMP22 duplication on chromosome 17
• CMT1B -MPZ mutation on chromosome 1
• CMT2A - MFN2 mutation on chromosome 1 (most common cause)
• CMTX1 -Cx32 on the X chromosome
• Dejerine-Sottas - Linked to mutations in MPZ, PMP22, Cx32, or EGR2 on chromosome 10
• Dominantly inherited intermediate CMT - Genetically heterogeneous (Specific Cx32, MPZ, GDAP1, tyrosyl-tRNA synthetase (YARS), and neurofilament light chain (NF-L) mutations can cause velocities and morphologic changes that fall between CMT1 and CMT2.^{74,75,76,77,78} )

Many mutations are not found with current genetic testing. Out of 153 patients with inherited neuropathies, a mutation was not found in 50 (32.7%).⁴¹ A more recent study of 6 families with late-onset axonal neuropathies showed no mutations in an extensive screen of 9 genes known to cause CMT.⁷⁹

Differential Diagnoses

Other Problems to Be Considered

The differential diagnosis of neuropathy is wide. A positive family history makes CMT likely, and a pedigree can help elucidate the inheritance pattern, which can narrow the differential diagnosis between CMT subtypes. Nerve conduction velocities, in most cases, can separate CMT1 (very slow) from CMT2 (mildly slow to normal).
 
It is essential to separate the demyelinating forms of CMT from acquired, potentially treatable demyelinating neuropathies. Uniform conduction slowing is seen in CMT1, whereas in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and other immune-mediated neuropathies, conduction velocity varies between segments in the same nerve and different nerves. The Guillain-Barre syndrome has similar electrodiagnostic findings to CIDP but the rapidity of onset that defines the disease should prevent confusion.
 
Other inherited neuropathic syndromes, such as Friedreich Ataxia and Spinal Muscular Atrophy, can be confused with CMT or have overlapping features.
 
Other causes of acquired neuropathy should not be overlooked. Neuropathy may be due to diabetes mellitus or other metabolic/nutritional causes, drugs of abuse such as alcohol, neurotoxic medications, infections (including leprosy, which may cause thickened, palpable nerves), compression, or vasculitis, among others.

Myopathies and muscular dystrophies can be clinically confused with CMT in some cases.

Workup

Laboratory Studies

The workup should be primarily geared toward the identification or exclusion of a treatable neuropathy, including tests that address the causes of neuropathy. If a clear family history is identified and CMT has not been confirmed genetically, genotyping is warranted. Ascertaining the presence of a demyelinating or axonal form with nerve conduction studies, and establishing inheritance pattern with a pedigree can narrow the differential diagnosis and reduce the number of needed tests. De novo mutations are not rare, and genetic counseling can be pursued even in the absence of a family history of neuropathy.
 
Despite the lack of available treatments, genotyping is useful in providing information for prognosis and genetic counseling.
 
A negative genetic test does not exclude the diagnosis, especially in axonal forms. Beinfait and colleagues found mutations in only 3 out of 18 families (61 patients) with CMT2, and Bennett and colleagues found no mutations in 6 families with late-onset (median age 57), predominantly axonal neuropathies.^67,79

Imaging Studies

Nerve root hypertrophy can be directly imaged with an MRI of the spine, which may help in distinguishing hereditary from acquired demyelinating neuropathy.⁸⁰ Sonography of peripheral nerves can play a similar role.⁸¹

Other Tests

Examination of the CSF is usually normal except for an elevated CSF protein. More marked elevations of protein are routinely seen in Dejerine-Sottas syndrome and may be more common in forms of CMT with MPZ mutations.^4,82,42

Procedures

Electrodiagnostic studies are critical to narrow the differential diagnosis.
 
Harding and Thomas found median nerve conduction velocities below 38 m/s in patients with CMT1 and above 38 m/s in patients with CMT2.⁶⁴ Thomas and colleagues found median nerve conduction velocities averaged 19.9 m/s and ranged from 5-34 m/s in patients with CMT1. Values in the lower limb nerves were more difficult to obtain because of denervation of small foot muscles, but peroneal and tibial nerve conduction velocity averaged 17 m/sec and ranged between 10-22 m/sec. Sensory nerve action potentials were usually absent or severely reduced in amplitude, but when present, showed similar reductions in velocity (mean 22.9 m/sec).⁶³ Dyck and Lambert had previously shown that ulnar nerve conduction velocities were even more severely affected in patients with Dejerine-Sottas syndrome, consistently measuring less than 10 m/s.^4,82  
 
Lewis and Sumner compared 18 patients with CMT1 to 40 patients with chronic acquired demyelinating neuropathies, and found that slowing was uniform both along individual nerves and between different nerves in an individual patient with CMT1. There was no evidence of dispersion or conduction block in any of these patients. They concluded that this pattern serves to distinguish patients with CMT1 from patients with CIDP or AIDP, who demonstrate more multifocality. These findings were confirmed in a larger study of 129 patients with CMT1.^83,84

Female carriers with CMTX often demonstrate intermediate nerve conduction velocities, averaging 45 m/sec (ranging from 26-61 m/sec), which is significantly faster than CMT1A. Affected men, by comparison, have slower conduction velocities, averaging 31 m/sec, also significantly higher than those found in CMT1. The combination of intermediate conduction velocities and more rapid velocities in affected females suggests CMTX.⁷⁴ Interestingly, Dubourg and colleagues found that the difference between the median and ulnar motor nerve conduction velocities in affected female patients differed significantly when compared to the uniform velocities found in CMT1 and healthy subjects. Men with CMTX also demonstrated uniform slowing.⁴⁷

Histologic Findings

CMT1
 
Dyck and Lambert observed an abnormally large transverse fascicular area in biopsied nerves, but a reduction in the number of myelinated fibers both per unit of fascicular area and per nerve. Large onion bulbs were seen, and there was marked variation in length and diameter of myelinated fiber internodes on teased fiber preparations, indicating chronic demyelination and remyelination. There was additional evidence of Wallerian degeneration in some nerve fibers, indicating concurrent axonal injury.⁴
 
CMT1A
 
Sural nerve biopsies in patients with confirmed PMP22 duplications show nerve thickening and a reduction in myelinated fiber density even in the first year of life. As the first few years pass, active demyelination is prominent and onion bulbs are infrequent. By late childhood, active demyelination subsides and well-formed onion bulbs appear. There is loss of large fibers and a relative increase in small fibers as a result of regeneration of damaged axons.⁸⁵
 
CMT2
 
Behse and Buchthal demonstrated endoneurial areas to be normal. Onion bulbs were absent, and segmental demyelination was absent or rare on teased fiber analysis. The main abnormality was a reduction in the number of large fibers.⁸⁶
 
CMTX
 
Pathology of CMTX is mixed, as would be expected from electrophysiologic data. Hahn and colleagues found mild to moderate degeneration and loss of myelinated nerve fibers. Remaining fibers were surrounded by the thin myelin sheaths that would be expected with either repaired demyelination or regenerated nerve fibers. There were clusters of small fibers, indicating attempts at sprouting as part of the regenerative process. Teased fibers showed evidence of myelin instability in paranodal regions.⁴⁶

Treatment

Medical Care

Management of orthopedic complications is paramount.

• The common foot deformities of CMT can lead to discomfort, impaired ambulation, and disability and should be managed with physical therapy, which can be both preventive and therapeutic. Stretching, exercises, and adaptive maneuvers can all be helpful.
• Ankle weakness and instability can be treated with boots or orthoses, and can ease ambulation, keep patients active, and prevent potentially disabling injuries such as sprains or ankle fractures.
• While dysesthetic pain is not typical, it can occur, and responds to medications commonly used for neuropathic pain such as tricyclic antidepressants or anticonvulsants.
• More commonly, patients experience local musculoskeletal pain resulting from abnormal posture or overuse of certain muscle groups brought on by weakness or joint deformity. Joint deformity itself may be painful. NSAIDs and acetaminophen are first-line therapies.

There are no definitive medical therapies for CMT. Steroid responsive forms of Charcot-Marie-Tooth disease were originally recognized by Dyck in 1982. This finding has also been reported several times in patients with MPZ mutations and atypical features such as elevated CSF protein.^87,88 These may be patients with superimposed CIDP.⁸⁹ It is unlikely that immunomodulatory therapy will be effective in typical cases of CMT.

Surgical Care

If foot deformities are disabling, patients may benefit from tendon transfers or lengthening (especially the Achilles tendon), hammer toe correction, and release of the plantar fascia. The ankle can be fused to provide stability. Ideally, conservative measures such as those mentioned above, if instituted early, can prevent surgery.

Consultations

• Physiatrists
• Physical therapists
• Orthotics specialists
• Podiatrists
• Genetic counseling

Diet

A balanced diet is important to prevent obesity and diabetes, both of which can compound disability and pain and contribute to the development of certain entrapment neuropathies.

Activity

Activity as tolerated. Moderate activity is recommended. Overexertion should be avoided.

Medication

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

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.

Ibuprofen (Motrin, Ibuprin)

DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Supplied OTC in 200-mg dosing or prescribed as 400-, 600-, and 800-mg tabs.

Dosing

Adult

400-800 mg PO tid with food

Pediatric

Not recommended

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; high risk of bleeding

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in coagulation abnormalities or during anticoagulant therapy

Naproxen (Aleve, Naprelan, Naprosyn, Anaprox)

For relief of mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.

Dosing

Adult

500 mg PO bid with food

Pediatric

Not established

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently

Contraindications

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

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.

Nortriptyline (Pamelor, Aventyl HCl)

Has demonstrated effectiveness in treatment of pain.

Dosing

Adult

25-100 mg PO hs; not to exceed 200 mg/d

Pediatric

Children: 0.1 mg/kg PO hs; increase as tolerated; not to exceed 0.5-2 mg/d hs
Adolescents: 25-50 mg/d PO; increase gradually to 100 mg/d

Interactions

Cimetidine may increase nortriptyline levels; may increase effects of warfarin (monitor INR)

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; MAOIs within 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Patients with cardiac conduction disturbances and a history of hyperthyroidism; those with renal or hepatic impairment; avoid using in elderly patients

Amitriptyline (Elavil)

Has demonstrated effectiveness in treatment of pain.

Dosing

Adult

25-100 mg PO hs; not to exceed 150 mg/d

Pediatric

Children: 0.1 mg/kg PO hs; increase as tolerated; not to exceed 0.5-2 mg/d qhs
Adolescents: 25-50 mg/d PO; increase gradually to 100 mg/d

Interactions

Phenobarbital may decrease effects; coadministration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase amitriptyline levels; amitriptyline inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; MAOIs within 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in cardiac conduction disturbances, history of hyperthyroidism, and renal or hepatic impairment; avoid using in elderly patients

Serotonin reuptake inhibitors

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

Paroxetine (Paxil)

Considered an alternative to TCAs, with fewer adverse anticholinergic and cardiovascular effects.

Dosing

Adult

10 mg/d PO initially; titrate to maximum 50 mg/d

Pediatric

Not established

Interactions

Phenobarbital and phenytoin decrease effects of paroxetine; alcohol, cimetidine, sertraline, phenothiazines, and warfarin increase toxicity of paroxetine; serotonin syndrome (ie, myoclonus, rigidity, confusion, nausea, hyperthermia, autonomic instability, coma, eventual death) occurs with simultaneous use of other serotonergic agents (eg, anorectic agents, tramadol, buspirone, trazodone, clomipramine, nefazodone, tryptophan), discontinue other serotonergic agents at least 2 wk prior to using other SSRIs

Contraindications

Documented hypersensitivity; pregnancy and lactation; severe renal or hepatic disease

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Anxiety, insomnia or drowsiness, tremor, anorexia, anorgasmia, and other sexual dysfunctions have been reported; nausea, flu-like symptoms, and agitation that resolve within 1-2 wk also noted

Anticonvulsants

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

Carbamazepine (Tegretol)

A sodium channel blocker that typically provides substantial or complete relief of pain in 80% of individuals with both idiopathic and MS-associated TN within 24-48 h. Adverse effect profile for older patients is more onerous than with newer anticonvulsants, thereby limiting usefulness in this group. As more published data on long-term efficacy of agents such as lamotrigine and gabapentin become available, these medications may soon become drugs of choice.

Dosing

Adult

100 mg PO bid initially; may be increased qd by 200 mg until adequate relief is obtained
For maximum effect, dosage can be administered in divided doses 1 h before each meal
Maintenance dose: 100-600 mg PO bid; not to exceed 1200 mg; may continue for several wk depending on disease course
Patients may require maintenance dosage as low as 200 mg/d to prevent recurrences

Pediatric

Not established

Interactions

Levels are increased by CYP3A4 inhibitors (eg, cimetidine, macrolides, diltiazem, fluoxetine, ketoconazole, verapamil, valproate); levels are decreased by CYP3A4 inducers (eg, cisplatin, doxorubicin, felbamate, phenobarbital, phenytoin, primidone, rifampin, theophylline); may increase levels of clomipramine, phenytoin, and primidone and lithium toxicity; may decrease levels of phenytoin, warfarin, PO contraceptives, doxycycline, theophylline, haloperidol, alprazolam, clozapine, ethosuximide, and valproate; may interfere with other anticonvulsants, thyroid function, and pregnancy and TFTs

Contraindications

Documented hypersensitivity; bone marrow depression; sensitivity to tricyclics; MAOIs within last 14 d

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with history of cardiac, hepatic, renal, or hematologic dysfunction, latent psychosis, glaucoma, or adverse hematologic reaction to other drugs; may be converted to ER formulation on a mg/mg basis; common adverse reactions include ataxia, nausea, vomiting, sedation, and vertigo; because of risk of persistent leukopenia and aplastic anemia, patients should undergo CBC before starting and at 1, 3, and 6 mo; non–dose-dependent and idiosyncratic suppression of bone marrow may occur mandating vigilance early in therapy

Gabapentin (Neurontin)

Uncontrolled studies have indicated possible effectiveness in patients whose pain has become refractory to carbamazepine. Often is tolerated better than carbamazepine by elderly patients. No placebo-controlled studies have been published.

Dosing

Adult

900-2700 mg/d PO

Pediatric

Not established

Interactions

Potentiates CNS depression due to acute alcohol ingestion or other CNS depressants; antacids may reduce absorption, so separate administration by at least 2 h; may interfere with Multistix-SC urine protein tests

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal dysfunction; dosage in renal insufficiency is as follows:
CrCl >60 mL/min: 400 mg tid
CrCl 30-60 mL/min: 300 mg bid
CrCl 15-30 mL/min: 300 mg qid
CrCl <15 mL/min: 300 mg qid
Hemodialysis: 200-300 mg after 4 h of each hemodialysis

Follow-up

Deterrence/Prevention

Even if patients and carriers were to abstain from having children, CMT mutations occur de novo with some regularity and the disease would remain prevalent. Boerkoel and colleagues found that one third (6 of 16) of the point mutations detected in their series of 159 patients represent de novo events.⁴¹ As examined by Hoogendijk and colleagues, of 10 patients with CMT1 and no family history, 9 of them had PMP22 duplications.⁶⁸
 
Prevention should focus on avoiding conditions that can cause or worsen generalized or focal neuropathy, such as diabetes mellitus, vitamin deficiency, medication toxicity, and prolonged immobilization of limbs during surgery.

Complications

Patients with CMT are more susceptible to compression neuropathies and radiculopathies. Sprains and fractures are disabling and avoidable.
 
Medication toxicity is important to recognize when it occurs so that the offending agent can be discontinued. Preventing exposure to neurotoxic medications when possible is preferable. Weimer and Podwall found 26 case reports of CMT and toxic medication effects; 22 of these reports pertained to vincristine, 2 implicated nucleoside analogs, 2 cisplatin, 1 carboplatin, and 1 taxoids. The 22 reports about vincristine included 30 patients, and 26 of these patients had undiagnosed CMT. Only 10 had overt clinical signs or a known close relative with CMT, and many of them developed symptoms after only 1 or 2 doses.⁹⁴

Vinca alkaloid (Vincristine) is considered a definite high-risk medication for the development of CMT (including asymptomatic CMT). Prior to use, all patients should be asked about a family history of neuropathy and joint deformity and examined for clinical signs of a chronic neuropathy.

Commonly used medications that pose moderate to significant risk include the following:

• Amiodarone (Cordarone)
• Bortezomib (Velcade)
• Cisplatin and Oxaliplatin
• Colchicine (extended use)
• Metronidazole (extended use)
• Nitrofurantoin
• Pyridoxine (mega dose of Vitamin B-6)
• Taxols (paclitaxel, docetaxel)

Prognosis

Life expectancy is not altered in all but the most severe cases. Disability is highly variable within and between kindreds and cannot be predicted with any certainty, even among siblings. More marked disability does seem to be linked to earlier onset.

Patient Education

The CMT Association is a nonprofit organization concerned with patient support, public education, and promotion and support of research into the cause and treatment of CMT.

Miscellaneous

Special Concerns

Anesthesia

• Prolonged body and limb immobilization can result in focal compressive mononeuropathies.
• Regional anesthesia is contraindicated in Charcot-Marie-Tooth disease.
• In a series of 161 surgical procedures on 86 patients with Charcot-Marie-Tooth disease, the patients were found to have no difficulties tolerating anesthetics, even with succinylcholine, which is generally considered to be relatively contraindicated.⁹⁵

References

1. Charcot JM. Sur une forme particulaire d'atrophie musculaire progressive souvent familial debutant par les pieds et les jambes et atteingnant plus tard les mains. Rev Med. 1886;6:97-138.

2. Tooth HH. The peroneal type of progressive muscular atrophy. London: Lewis. 1886.

3. Dejerine H, Sottas J. Sur la nevrite interstitielle, hypertrophique et progressive de l'enfance. CR Soc Biol (Paris). 1893;45:63-96.

4. 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].

5. Thomas PK, Calne DB. Motor nerve conduction velocity in peroneal muscular atrophy: evidence for genetic heterogeneity. J Neurol Neurosurg Psychiatry. Jan 1974;37(1):68-75. [Medline].

6. Buchthal F, Behse F. Peroneal muscular atrophy (PMA) and related disorders. I. Clinical manifestations as related to biopsy findings, nerve conduction and electromyography. Brain. Mar 1977;100 Pt 1:41-66. [Medline].

7. Dyck PJ. Inherited neuronal degeneration and atrophy affecting peripheral motor, sensory and autonomic neurons. In: Dyck PJ, Thomas PK, and Lambert EH. Peripheral Neuropathy. 2. 1. Philadelphia: Saunders; 1975:825-867.

8. Bird TD, Ott J, Giblett ER. Evidence for linkage of Charcot-Marie-Tooth neuropathy to the Duffy locus on chromosome 1. Am J Hum Genet. May 1982;34(3):388-94. [Medline].

9. Vance JM, Nicholson GA, Yamaoka LH, Stajich J, Stewart CS, Speer MC, et al. Linkage of Charcot-Marie-Tooth neuropathy type 1a to chromosome 17. Exp Neurol. May 1989;104(2):186-9. [Medline].

10. Lupski JR, de Oca-Luna RM, Slaugenhaupt S. DNA duplication associated with Charcot-Marie-Tooth Disease Type 1A. Cell. 1991;66:219-32.

11. Raeymaekers P, Timmerman V, Nelis E, et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). Neuromuscul Disord. 1991;1:93-7.

12. Lupski JR, Wise CA, Kuwano A, Pentao L, Parke JT, Glaze DG. Gene dosage is a mechanism for Charcot-Marie-Tooth disease type 1A. Nat Genet. Apr 1992;1(1):29-33. [Medline].

13. Wise CA, Garcia CA, Davis SN, Heju Z, Pentao L, Patel PI. Molecular analyses of unrelated Charcot-Marie-Tooth (CMT) disease patients suggest a high frequency of the CMTIA duplication. Am J Hum Genet. Oct 1993;53(4):853-63. [Medline].

14. Fernandez-Torre JL, Otero B, Alvarez V, Hernando I, Fernandez-Toral J. De novo partial duplication of 17p associated with Charcot-Marie-Tooth disease type 1A. J Neurol Neurosurg Psychiatry. 2001;70:703-4.

15. Hayasaka K, Himoro M, Sato W, et al. CMT neuropathy 1B is associated with mutations of the myelin P0 gene. Nat Genet. 1993;5:31-4.

16. Kulkens T, Bolhuis PA, Wolterman RA, Kemp S, te Nijenhuis S, Valentijn LJ. Deletion of the serine 34 codon from the major peripheral myelin protein P0 gene in Charcot-Marie-Tooth disease type 1B. Nat Genet. Sep 1993;5(1):35-9. [Medline].

17. Su Y, Brooks DG, Li L, Lepercq J, Trofatter JA, Ravetch JV, et al. Myelin protein zero gene mutated in Charcot-Marie-tooth type 1B patients. Proc Natl Acad Sci U S A. Nov 15 1993;90(22):10856-60. [Medline].

18. Bergoffen J, Scherer SS, Wang S, Scott MO, Bone LJ, Paul DL. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science. Dec 24 1993;262(5142):2039-42. [Medline].

19. Chance PF, Alderson MK, Leppig KA, Lensch MW, Matsunami N, Smith B. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell. Jan 15 1993;72(1):143-51. [Medline].

20. Warner LE, Hilz MJ, Appel SH, et al. Clinical phenotypes of different MPZ (P-O) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelination. Neuron. 1996;17:451-60.

21. Marrosu MG, Vaccargiu S, Marrosu G, Vannelli A, Cianchetti C, Muntoni F. Charcot-Marie-Tooth disease type 2 associated with mutation of the myelin protein zero gene. Neurology. May 1998;50(5):1397-401. [Medline].

22. Numakura C, Shirahata E, Yamashita S, et al. Screening of the early growth response 2 gene in Japanese patients with Charcot–Marie–Tooth disease type 1. J Neurol Sci. 2003;210:61– 64.

23. Roa BB, Dyck PJ, Marks HG, Chance PF, Lupski JR. Dejerine –Sottas syndrome associated with point mutation in the peripheral myelin protein 22 (PMP22) gene. Nat Genet. 1993;5:269– 73.

24. Bradley WG, Madrid R, and Davis, CJF . The peroneal muscular atrophy syndrome. Clinical, genetic, electrophysiological, and nerve biopsy studies. III. Clinical, electrophysiological, and pathological correlations. J Neurol Sci. 1977;32:123-36.

25. Madrid R, Bradley WG, and Davis, CJF. The peroneal muscular atrophy syndrome. Clinical, genetic, electrophysiological, and nerve biopsy studies. II. Observations on pathological changes in sural nerve biopsies. J Neurol Sci. 1977;32:91-122.

26. Davis CJ, Bradley WG, Madrid R. The peroneal muscular atrophy syndrome: clinical, genetic, electrophysiological and nerve biopsy studies. I. Clinical, genetic and electrophysiological findings and classification. J Genet Hum. Dec 1978;26(4):311-49. [Medline].

27. Brust JCM, Lovelace RE, and Devi S. Clinical and electrodiagnostic features of Charcot-Marie-Tooth syndrome. Acta Neurologica Scandinavica. 1978;58:Supplement 68: 1-42.

28. Rossi A, Paradiso C, Cioni R, Rizzuto N, Guazzi G. Charcot-Marie-Tooth disease: study of a large kinship with an intermediate form. J Neurol. 1985;232(2):91-8. [Medline].

29. Villanova M, Timmerman V, De Jonghe P, Malandrini A, Rizzuto N, Van Broeckhoven C, et al. Charcot-Marie-Tooth disease: an intermediate form. Neuromuscul Disord. Aug 1998;8(6):392-3. [Medline].

30. Hai M, Bidichandani SI, Patel PI. Identification of a positive regulatory element in the myelin-specific promoter of the PMP22 gene. J Neurosci Res. Sep 15 2001;65(6):508-19. [Medline].

31. Snipes GJ, Suter U, Welcher A, Shooter E. Characterization of a Novel Peripheral Nervous System Myelin Protein (PMP22/SR13). J Cell Bio. 1992;117:225-238.

32. Vallat JM, Sindou P, Preux PM, Tabaraud F, Milor AM, Couratier P. Ultrastructural PMP22 expression in inherited demyelinating neuropathies. Ann Neurol. Jun 1996;39(6):813-7. [Medline].

33. Müller HW. New vistas on the pathomechanism of Charcot-Marie-Tooth and related peripheral neuropathies. Ann N Y Acad Sci. Sep 14 1999;883:152-9. [Medline].

34. Gabreëls-Festen AA, Joosten EM, Gabreëls FJ, Jennekens FG, Janssen-van Kempen TW. Early morphological features in dominantly inherited demyelinating motor and sensory neuropathy (HMSN type I). J Neurol Sci. Feb 1992;107(2):145-54. [Medline].

35. García A, Combarros O, Calleja J, Berciano J. Charcot-Marie-Tooth disease type 1A with 17p duplication in infancy and early childhood: a longitudinal clinical and electrophysiologic study. Neurology. Apr 1998;50(4):1061-7. [Medline].

36. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. Jul 2000;123 ( Pt 7):1516-27. [Medline].

37. Nodera H, Bostock H, Kuwabara S, Sakamoto T, Asanuma K, Jia-Ying S, et al. Nerve excitability properties in Charcot-Marie-Tooth disease type 1A. Brain. Jan 2004;127:203-11. [Medline].

38. Giese KP, Martini R, et al. Mouse PO Gene Disruption Leads to Hypomyelination, Abnormal Expression of Recognition Molecules, and Degeneration of Myelin and Axons. Cell. 1991;71:565-576.

39. Nelis E, Haites N, Van Broeckhoven C. Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies. Hum Mutat. 1999;13(1):11-28. [Medline].

40. Shy ME, Jáni A, Krajewski K, Grandis M, Lewis RA, Li J. Phenotypic clustering in MPZ mutations. Brain. Feb 2004;127(Pt 2):371-84. [Medline].

41. Boerkoel CF, Takashima H, Garcia CA, Olney RK, Johnson J, Berry K. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol. Feb 2002;51(2):190-201. [Medline].

42. Hattori N, Yamamoto M, Yoshihara T, Koike H, Nakagawa M, Yoshikawa H. Demyelinating and axonal features of Charcot-Marie-Tooth disease with mutations of myelin-related proteins (PMP22, MPZ and Cx32): a clinicopathological study of 205 Japanese patients. Brain. Jan 2003;126(Pt 1):134-51. [Medline].

43. Shy ME. Peripheral neuropathies caused by mutations in the myelin protein zero. J Neurol Sci. Mar 15 2006;242(1-2):55-66. [Medline].

44. Bruzzone R, White TW, Paul DL. Connections with connexins: the molecular basis of direct intercellular signaling. Eur J Biochem. May 15 1996;238(1):1-27. [Medline].

45. Birouk N, Le Guern E, Maisonobe T, et al. X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiological study. Neurology. 1998;50:1074-82.

46. Hahn AF, Bolton CF, White CM, Brown WF, Tuuha SE, Tan CC. Genotype/phenotype correlations in X-linked dominant Charcot-Marie-Tooth disease. Ann N Y Acad Sci. Sep 14 1999;883:366-82. [Medline].

47. Dubourg O, Tardieu S, Birouk N, Gouider R, Léger JM, Maisonobe T. Clinical, electrophysiological and molecular genetic characteristics of 93 patients with X-linked Charcot-Marie-Tooth disease. Brain. Oct 2001;124(Pt 10):1958-67. [Medline].

48. Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet. May 2004;36(5):449-51. [Medline].

49. Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM, Chan DC. Structural basis of mitochondrial tethering by mitofusin complexes. Science. Aug 6 2004;305(5685):858-62. [Medline].

50. Baloh RH, Schmidt RE, Pestronk A, Milbrandt J. Altered axonal mitochondrial transport in the pathogenesis of Charcot-Marie-Tooth disease from mitofusin 2 mutations. J Neurosci. Jan 10 2007;27(2):422-30. [Medline].

51. Emery AE. Population frequencies of inherited neuromuscular diseases--a world survey. Neuromuscul Disord. 1991;1(1):19-29. [Medline].

52. Kurihara S, Adachi Y, Wada K, Awaki E, Harada H, Nakashima K. An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan. Neuroepidemiology. Sep-Oct 2002;21(5):246-50. [Medline].

53. Ionasescu V, Searby C, Sheffield VC, Roklina T, Nishimura D, Ionasescu R. Autosomal dominant Charcot-Marie-Tooth axonal neuropathy mapped on chromosome 7p (CMT2D). Hum Mol Genet. Sep 1996;5(9):1373-5. [Medline].

54. Nelis E, Van Broeckhoven C, De Jonghe P, Löfgren A, Vandenberghe A, Latour P. Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet. 1996;4(1):25-33. [Medline].

55. Lawson VH, Graham BV, Flanigan KM. Clinical and electrophysiologic features of CMT2A with mutations in the mitofusin 2 gene. Neurology. Jul 26 2005;65(2):197-204. [Medline].

56. Garcia CA, Malamut RE, England JD, Parry GS, Liu P, Lupski JR. Clinical variability in two pairs of identical twins with the Charcot-Marie-Tooth disease type 1A duplication. Neurology. Nov 1995;45(11):2090-3. [Medline].

57. Marques W Jr, Hanna MG, Marques SR, Sweeney MG, Thomas PK, Wood NW. Phenotypic variation of a new P0 mutation in genetically identical twins. J Neurol. Jul 1999;246(7):596-9. [Medline].

58. Pfeiffer G, Wicklein EM, Ratusinski T, Schmitt L, Kunze K. Disability and quality of life in Charcot-Marie-Tooth disease type 1. J Neurol Neurosurg Psychiatry. Apr 2001;70(4):548-50. [Medline].

59. Dyck PJ, Karnes JL, Lambert EH. Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology. Oct 1989;39(10):1302-8. [Medline].

60. Killian JM, Tiwari PS, Jacobson S, Jackson RD, Lupski JR. Longitudinal studies of the duplication form of Charcot-Marie-Tooth polyneuropathy. Muscle Nerve. Jan 1996;19(1):74-8. [Medline].

61. Teunissen LL, Notermans NC, Franssen H, Van Engelen BG, Baas F, Wokke JH. Disease course of Charcot-Marie-Tooth disease type 2: a 5-year follow-up study. Arch Neurol. Jun 2003;60(6):823-8. [Medline].

62. Thomas FP, Geller TJ, Hahn AF, et al. Modification of CMT1A phenotypes by independent co-existing neurogenetic disorders, McArdle disease and chromosome 5p trisomy. Ann NY Acad Sci. 1999;883:472-6.

63. Thomas PK, Marques W Jr, Davis MB, Sweeney MG, King RH, Bradley JL, et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain. Mar 1997;120 ( Pt 3):465-78. [Medline].

64. 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].

65. Harding AE, Thomas PK. Genetic aspects of hereditary motor and sensory neuropathy (types I and II). J Med Genet. Oct 1980;17(5):329-36. [Medline].

66. Rosen SA, Wang H, Cornblath DR, Uematsu S, Hurko O. Compression syndromes due to hypertrophic nerve roots in hereditary motor sensory neuropathy type I. Neurology. Sep 1989;39(9):1173-7. [Medline].

67. Bienfait HM, Baas F, Koelman JH, de Haan RJ, van Engelen BG, Gabreëls-Festen AA. Phenotype of Charcot-Marie-Tooth disease Type 2. Neurology. May 15 2007;68(20):1658-67. [Medline].

68. Hoogendijk J. E., Hensels G. W., Gabrëels-Festen A. A., et al. De novo mutation in hereditary motor and sensory neuropathy type 1. Lancet. 1992;339:1081-2.

69. Berciano J, Garcia A, and Combarros O. Initial semiology in children with Charcot-Marie-Tooth disease 1A duplication. Muscle Nerve. 2003;27:34–39.

70. Bienfait HM, Verhamme C, van Schaik IN, et al. Comparison of CMT1A and CMT2: similarities and differences. J Neurology. 2006;253:1572-80.

71. Elliott JL, Kwon JM, Goodfellow PJ, Yee WC. Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics. Neurology. Jan 1997;48(1):23-8. [Medline].

72. Dyck PJ, Litchy WJ, Minnerath S, et al. Hereditary motor and sensory neuropathywith diaphragm and vocal cord paresis. Ann Neurol. 1994;35:608-15.

73. De Jonghe P, Timmerman V, Ceuterick C, et al. The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot–Marie–Tooth phenotype. Brain. 1999;122:281–290.

74. Nicholson G, Nash J. Intermediate nerve conduction velocities define X-linked Charcot-Marie-Tooth neuropathy families. Neurology. Dec 1993;43(12):2558-64. [Medline].

75. Mastaglia FL, Nowak KJ, Stell R, Phillips BA, Edmondston JE, Dorosz SM, et al. Novel mutation in the myelin protein zero gene in a family with intermediate hereditary motor and sensory neuropathy. J Neurol Neurosurg Psychiatry. Aug 1999;67(2):174-9. [Medline].

76. De Jonghe P, Mersivanova I, Nelis E, Del Favero J, Martin JJ, Van Broeckhoven C, et al. Further evidence that neurofilament light chain gene mutations can cause Charcot-Marie-Tooth disease type 2E. Ann Neurol. Feb 2001;49(2):245-9. [Medline].

77. Senderek J, Bergmann C, Ramaekers VT, Nelis E, Bernert G, Makowski A. Mutations in the ganglioside-induced differentiation-associated protein-1 (GDAP1) gene in intermediate type autosomal recessive Charcot-Marie-Tooth neuropathy. Brain. Mar 2003;126(Pt 3):642-9. [Medline].

78. Jordanova A, Irobi J, Thomas FP, Van Dijck P, Meerschaert K, Dewil M. Disrupted function and axonal distribution of mutant tyrosyl-tRNA synthetase in dominant intermediate Charcot-Marie-Tooth neuropathy. Nat Genet. Feb 2006;38(2):197-202. [Medline].

79. Bennett CL, Lawson VH, Brickell KL, Isaacs K, Seltzer W, Lipe HP. Late-onset hereditary axonal neuropathies. Neurology. Jul 1 2008;71(1):14-20. [Medline].

80. Liao JP, Waclawik AJ. Nerve root hypertrophy in CMT type 1A. Neurology. Mar 9 2004;62(5):783. [Medline].

81. Martinoli C, Schenone A, Bianchi S, Mandich P, Caponetto C, Abbruzzese M. Sonography of the median nerve in Charcot-Marie-Tooth disease. AJR Am J Roentgenol. Jun 2002;178(6):1553-6. [Medline].

82. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations. Arch Neurol. Jun 1968;18(6):619-25. [Medline].

83. Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. Jun 1982;32(6):592-6. [Medline].

84. Kaku DA, Parry GJ, Malamut R, Lupski JR, Garcia CA. Uniform slowing of conduction velocities in Charcot-Marie-Tooth polyneuropathy type 1. Neurology. Dec 1993;43(12):2664-7. [Medline].

85. Gabreëls-Festen A, Wetering RV. Human nerve pathology caused by different mutational mechanisms of the PMP22 gene. Ann N Y Acad Sci. Sep 14 1999;883:336-43. [Medline].

86. Behse F, Buchthal F. Peroneal muscular atrophy (PMA) and related disorders. II. Histological findings in sural nerves. Brain. Mar 1977;100 Pt 1:67-85. [Medline].

87. Donaghy M, Sisodiya SM, Kennett R, McDonald B, Haites N, Bell C. Steroid responsive polyneuropathy in a family with a novel myelin protein zero mutation. J Neurol Neurosurg Psychiatry. Dec 2000;69(6):799-805. [Medline].

88. Watanabe M, Yamamoto N, Ohkoshi N, Nagata H, Kohno Y, Hayashi A. Corticosteroid- responsive asymmetric neuropathy with a myelin protein zero gene mutation. Neurology. Sep 10 2002;59(5):767-9. [Medline].

89. Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB. Coexistent hereditary and inflammatory neuropathy. Brain. Jan 2004;127(Pt 1):193-202. [Medline].

90. Kaya F, Belin S, Bourgeois P, Micaleff J, Blin O, Fontés M. Ascorbic acid inhibits PMP22 expression by reducing cAMP levels. Neuromuscul Disord. Mar 2007;17(3):248-53. [Medline].

91. Pareyson D, Schenone A, Fabrizi GM, Santoro L, Padua L, Quattrone A. A multicenter, randomized, double-blind, placebo-controlled trial of long-term ascorbic acid treatment in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL): the study protocol [EudraCT no.: 2006-000032-27]. Pharmacol Res. Dec 2006;54(6):436-41. [Medline].

92. 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. Jan 2007;61(1):61-72. [Medline].

93. Shy ME, Chen L, Swan ER, Taube R, Krajewski KM, Herrmann D, et al. Neuropathy progression in Charcot-Marie-Tooth disease type 1A. Neurology. Jan 29 2008;70(5):378-83. [Medline].

94. Weimer LH, Podwall D. Medication-induced exacerbation of neuropathy in Charcot Marie Tooth disease. J Neurol Sci. Mar 15 2006;242(1-2):47-54. [Medline].

95. Antognini JF. Anaesthesia for Charcot-Marie-Tooth disease: a review of 86 cases. Can J Anaesth. Apr 1992;39(4):398-400. [Medline].

Keywords

Charcot-Marie-Tooth neuropathy, Charcot-Marie-Tooth disorder, Charcot-Marie-Tooth syndrome, CMT, Hereditary Motor and Sensory Neuropathy, HMSN, peroneal muscular atrophy, Dejerine-Sottas syndrome

Contributor Information and Disclosures

Author

Timothy C Parsons, MD, Fellow in EMG and Neuromuscular Disease, Department of Neurology, Columbia University Medical Center, New York
Timothy C Parsons, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas H Brannagan III, MD, Associate Professor of Clinical Neurology and Director, Peripheral Neuropathy Center, Columbia University, College of Physicians and Surgeons; Co-Director, EMG Laboratory, New York-Presbyterian Hospital, Columbia Campus, New York
Thomas H Brannagan III, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Peripheral Nerve Society
Disclosure: Nothing to disclose.

Medical Editor

Dianna Quan, MD, Associate Professor of Neurology, Director, Electromyography Laboratory, University of Colorado Health Sciences Center
Dianna Quan, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa
Disclosure: e-medicine Honoraria Other

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside
Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

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