eMedicine Specialties > Physical Medicine and Rehabilitation > Peripheral Neuropathy

Charcot-Marie-Tooth Disease

Divakara Kedlaya, MBBS, Clinical Associate Professor, Department of Physical Medicine and Rehabilitation, Loma Linda University School of Medicine

Updated: Feb 16, 2009

Introduction

Background

Charcot-Marie-Tooth disease (CMT) is the most common inherited neurologic disorder. CMT is characterized by inherited neuropathies without known metabolic derangements. In 1886, Professor Jean Martin Charcot of France (1825-1893) and his student Pierre Marie (1853-1940) published the first description of distal muscle weakness and wasting beginning in the legs, calling it peroneal muscular atrophy.

Howard Henry Tooth (1856-1926) described the same disease in his Cambridge dissertation in 1886, calling the condition peroneal progressive muscular atrophy. Tooth was the first to correctly attribute the disorder's symptoms to neuropathy rather than to myelopathy, as physicians had done before him. In 1912, Hoffman identified a case of peroneal muscular atrophy with thickened nerves. This disease was referred to as Hoffman disease and later was known as Charcot-Marie-Tooth-Hoffman disease.

In 1968, CMT was subdivided into 2 types, CMT-1 and CMT-2, based on pathologic and physiologic criteria. CMT has been further subdivided, based on the genetic cause of the disease. With the advent of genetic testing, all of the different diseases that fall under the heading of CMT syndrome eventually are likely to become distinguishable.

Related eMedicine topics:
Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies
Charcot-Marie-Tooth Disease [Orthopedic Surgery]
Hereditary Neuropathies of the Charcot-Marie-Tooth Disease Type

Pathophysiology

Charcot-Marie-Tooth disease (CMT) is actually a heterogeneous group of genetically distinct disorders with a similar clinical presentation. CMT-1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP-22) gene. Mutations in the gene encoding the major peripheral nervous system myelin protein, myelin protein zero (MPZ), account for 5% of patients with CMT. The mutation results in abnormal myelin that is unstable and spontaneously breaks down. This process results in demyelination, leading to uniform slowing of conduction velocity.

Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. A study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT-1A are caused by loss or damage to large-diameter motor and sensory axons.¹ Pain and temperature sensations usually are not affected, because they are carried by unmyelinated (type C) nerve fibers.

In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons. These changes cause what is referred to as an onion bulb appearance.

CMT-2 is primarily a neuronal (ie, axonal) disorder, not a demyelinating disorder. Type 2 results in peripheral neuropathy through direct axonal death and wallerian degeneration. CMT-3 (also known as Dejerine-Sottas disease) is characterized by infantile onset. Type 3 results in severe demyelination with delayed motor skills and is a much more severe form than type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination. CMT-X (X-linked CMT) and CMT-4 are also demyelinating neuropathies.

Frequency

United States

The prevalence of Charcot-Marie-Tooth disease (CMT) is 1 person per 2500 population, or about 125,000 patients in the US. CMT-1 incidence is 15 persons per 100,000 population. CMT-1A incidence is 10.5 persons per 100,000 population, or 70% of CMT-1 cases. CMT-2 incidence is 7 persons per 100,000 population. CMT-X represents at least 10-20% of persons with the CMT syndrome.

International

In Japan, the prevalence of Charcot-Marie-Tooth disease is reportedly 10.8 cases per 100,000 population. In Italy, the prevalence is reported to be 17.5 cases per 100,000 population, and in Spain, it is 28.2 cases per 100,000 population.

Mortality/Morbidity

Morbidity in Charcot-Marie-Tooth disease is mainly secondary to distal muscle weakness and foot deformities.^2,3 In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties.

Race

No race predilection is recognized in Charcot-Marie-Tooth disease.

Sex

There is no known sex predilection in Charcot-Marie-Tooth disease.

Age

The age of presentation for Charcot-Marie-Tooth disease (CMT) varies depending on the type of CMT. Please refer to the table under Causes.

Clinical

History

• Patients usually have a significant family history of Charcot-Marie-Tooth disease (CMT). This history varies, depending on the inheritance and penetrance pattern of the particular disorder. Spontaneous mutations also have been reported.
• Slow progressing weakness beginning in the distal limb muscles, typically in the lower extremities before the upper extremities, generally is noted.³ A subgroup of patients with CMT-1A can present with proximal muscle wasting and weakness.
• Onset usually is in the first 2 decades of life.
• Patients' initial complaints may be difficulty walking and frequent tripping because of foot and distal leg weakness. Frequent ankle sprains and falls are characteristic.³
• Parents may report that a child is clumsy or simply not very athletic.
• As weakness becomes more severe, foot drop commonly occurs. Steppage (ie, gait in which patient must lift the leg in an exaggerated fashion to clear the foot off the ground) also is common.³
• Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavus.^2,3 Symptoms related to structural foot abnormalities include calluses, ulcers, cellulitis, or lymphangitis.
• Hand weakness results in complaints of poor finger control, poor handwriting, difficulty using zippers and buttons, and clumsiness in manipulating small objects.^4,5
• Patients usually do not complain of numbness. This phenomenon may be due to the fact that CMT patients will have never had normal sensation and therefore, simply do not perceive their lack of sensation.
• Musculoskeletal and neuropathic types of pain may be present. Muscle cramping is a common complaint.
• Autonomic symptoms usually are absent, but a few men with CMT have reported impotence.

Physical

• In patients with Charcot-Marie-Tooth disease (CMT), distal muscle wasting may be noted in the legs, resulting in the characteristic stork leg or inverted champagne bottle appearance.
• Bony abnormalities commonly seen in long-standing CMT include the following:
  • In 25% of cases, pes cavus (high-arch foot), which is probably analogous to the development of claw hand in ulnar nerve lesion, occurs in the first decade of life; in 67% of cases it arises in later decades. Other foot deformities also can occur (see image below and Image 1).^2,3
  • Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT-1.
• Deep tendon reflexes (DTRs) are markedly diminished or absent.
• Vibration sensation and proprioception are decreased significantly, although patients usually have no sensory symptoms.
• Patients may have sensory gait ataxia, and Romberg test is usually positive.
• Sensation of pain and temperature usually is intact.
• Essential tremor is present in 30-50% of CMT patients.
• Sensory neuronal hearing loss is observed in 5% of patients.^6,7
• Enlarged and palpable peripheral nerves are common.
• Phrenic nerve involvement with diaphragmatic weakness is rare, but it has been described.
• Vocal cord involvement and hearing loss can occur in rare forms of CMT.^6,7

Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.

Causes

Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM).Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

*Autosomal dominant

†Autosomal recessive

‡X-linked dominant

§Nerve conduction velocities

||Hereditary neuropathy with liability to pressure palsy

¶Peripheral myelin protein

#Early growth response

**Myelin protein zero

††Normal

The above classification is the most specific, up-to-date, and comprehensive classification for Charcot-Marie-Tooth disease (CMT). In the past, CMT was classified as hereditary motor and sensory neuropathy (HMSN). Hereditary neuropathy with diffusely slow nerve conduction velocity (hypertrophic neuropathy) is HMSN-I.

• HMSN-I (CMT-1) with different subclassifications
• HMSN-III (Dejerine-Sottas disease, hypertrophic neuropathy of infancy, congenital hypomyelinated neuropathy) - Autosomal recessive inheritance
• HMSN-IV (Refsum syndrome - phytanic acid excess) - Autosomal recessive inheritance — tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebrospinal fluid (CSF) protein
• Hereditary motor and sensory neuropathy with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)
  • HMSN-II (CMT-2)
    • CMT-2A - Chromosome 1(p35-36) - Typical type, no enlarged nerves, later onset of symptoms, feet more severely affected than hands
    • CMT-2B - Chromosome 3(q13-22) - Typical type with axonal spheroids
    • CMT-2C - Not linked to any known loci; diaphragm and vocal cord weakness
    • CMT-2D - Chromosome 7(p14) - Muscle weakness and atrophy is more severe in hands than feet
    • Autosomal recessive CMT-2
  • HMSN-V (ie, spastic paraplegia) - Normal upper limbs and no sensory symptoms
• Roussy-Levy syndrome - Autosomal dominant with essential tremor
• HMSN-VI - With optic atrophy
• HMSN-VII - With retinitis pigmentosa
• Prednisone-responsive hereditary neuropathy

Differential Diagnoses

Alcoholism
HIV Infection
Leprosy
Neurosyphilis
Thyroid Disease

Other Problems to Be Considered

Acquired nongenetic causes of peripheral neuropathies
Vitamin B-12 deficiency
Diabetes mellitus
Vasculitis
Amyloid associated with chronic inflammation
Occult malignancy
Heavy-metal intoxication
Chronic inflammatory demyelinating polyneuropathy
Motor neuropathy with multiple conduction block
Other genetic neuropathies
Familial brachial plexus neuropathy (ie, hereditary neuralgic amyotrophy)
Autosomal recessive genetic disorders, such as Refsum disease or metachromatic leukodystrophy
X-linked recessive genetic disorders, such as adrenomyeloneuropathy or Pelizaeus-Merzbacher disease
Amyloid neuropathies
Hereditary ataxias with neuropathy (eg, Friedreich ataxia)

Blindness, seizures, dementia, and mental retardation are not part of Charcot-Marie-Tooth syndrome.

Workup

Laboratory Studies

• Results of all routine laboratory tests are within the reference range in Charcot-Marie-Tooth disease (CMT). Special genetic tests are available for some types of CMT.
  • CMT-1A - Pulsed-field gel electrophoresis or a specialized fluorescent in situ hybridization (FISH) assay is the most reliable genetic test, but it is not widely available. DNA-based testing for the PMP-22 duplication (CMT-1A) is widely available and detects more than 98% of patients with CMT-1A (see image below and Image 2). Point mutations in the PMP-22 gene cause fewer than 2% of cases of CMT-1A and are identified by this technique. Approximately 70-80% of cases of CMT-1 are designated as CMT-1A, caused by alteration of the PMP-22 gene (chromosomal locus 17p11).
  • CMT-1B - Genetic testing is performed primarily on a research basis, but it is available from a few commercial laboratories. Approximately 5-10% of CMT-1 is designated CMT-1B and is caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosomal locus 1q22).
  • CMT-1C and CMT-1D - Very rarely, mutations occur in the EGR-2 (early growth response 2) gene or in the LITAF gene, causing CMT-1D and CMT-1C, respectively, for which molecular genetic testing also is clinically available.
  • CMT-2 - Clinically indistinguishable, the 4 subtypes of CMT-2 are distinguished solely from genetic linkage findings. The relative proportions of CMT-2A, CMT-2B, CMT-2C, and CMT-2D have not yet been determined. The chromosomal loci for CMT-2A, CMT-2B, CMT-2C, CMT-2D, CMT-2E, CMT-2F, CMT-2G, and CMT-2L have been mapped, but the genes have not been identified. Molecular genetic testing is clinically available only for CMT-2A, CMT-2B1, CMT-2E, and CMT-2F.
  • CMT-X - Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases. Such testing is clinically available.
  • Genetic testing is not currently available for other types of CMT.

Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).

Imaging Studies

• High-resolution ultrasonography of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis in Charcot-Marie-Tooth disease type 1A.^{8,9,10,11,12,13}

Other Tests

• Nerve biopsy rarely is indicated for the diagnosis of Charcot-Marie-Tooth disease (CMT), especially because genetic testing is available. Biopsies sometimes are performed in cases of diagnostic dilemmas. Findings vary in different types of CMT, as follows:
  • In CMT-1, peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. Concentric hypertrophy of the lamellar sheaths is seen. Onion bulb formation, made up of circumferentially directed Schwann cells and their processes, frequently is observed.
  • In CMT-2, axon loss with wallerian degeneration generally is found.
  • In CMT-3, or Dejerine-Sottas disease, demyelination with thinning of the myelin sheath is observed.
  • Inflammatory infiltrate, indicating an autoimmune demyelinating process, should not be present.

Procedures

• Electromyography/nerve conduction study (EMG/NCS)^{8,9,10,11,12,13}
  • If Charcot-Marie-Tooth disease (CMT) is suggested, perform an EMG/NCS first. Findings vary depending on the type of CMT.
  • In demyelinating types of CMT, such as CMT-1, diffuse and uniform slowing of nerve conduction velocities is observed (see image below and Image 3).
  • Harding and Thomas criteria for diagnosing CMT-1 include median motor nerve conduction velocity of less than 38 meters per second (m/s), with compound motor action potential (CMAP) and amplitude of at least 0.5 millivolts (mV). No focal conduction block or slowing should be present unless associated with other focal demyelinating processes.
  • All sensory and motor nerves that are tested show the same degree of marked slowing.
  • Absolute values vary, but they are approximately 20-25 m/s in CMT-1 and less than 10 in Dejerine-Sottas disease and congenital hypomyelination. Slowing of nerve conduction can also be found in asymptomatic individuals.
  • In neuronal (ie, axonal) types of CMT, nerve conduction velocity usually is normal, but markedly low amplitudes are noted in sensory (ie, sensory nerve action potential [SNAP]) and motor (ie, CMAP) nerve studies.
  • In neuronal (ie, axonal) types of CMT, increased insertional activity is evident, with fibrillation potentials and positive sharp waves seen. Motor unit potentials show decreased recruitment patterns and neuropathic changes in morphology.

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

Histologic Findings

• In Charcot-Marie-Tooth disease type 2 (CMT-1), peripheral nerves contain few myelinated fibers, intramuscular nerves are surrounded by a rich connective tissue and hyperplastic neurilemma, and lengths of myelin are atrophic along the fibers.
• Concentric hypertrophy of the lamellar sheaths is seen. Formation of the typical onion bulb, made up of circumferentially directed Schwann cells and their processes, is noted.
• In CMT-2, axonal degeneration is observed.
• In CMT-3, Dejerine-Sottas disease, demyelination with thinning of the myelin sheath can be seen.
• No inflammatory infiltrate should be present, indicating an autoimmune demyelinating process.

Treatment

Rehabilitation Program

Physical Therapy

Daily heel-cord stretching exercises are desirable to prevent Achilles tendon shortening. Special shoes with good ankle support may be needed. Physical therapy can assist with ambulation and provide necessary evaluation and training with orthoses, such as an ankle-foot orthosis (AFO). Patients often require an AFO to correct foot drop and to aid walking.¹⁴

Some patients require the use of forearm crutches or a cane for improved gait stability, but fewer than 5% of patients need wheelchairs. Advise patients with Charcot-Marie-Tooth disease (CMT) about weight management, because obesity makes ambulation more difficult. Encourage exercise within each individual patient's capability. Most patients with CMT usually remain physically active.

Related eMedicine topics:
Foot Drop
Rehabilitation Management of Neuromuscular Disease

Occupational Therapy

An occupational therapist may recommend the use of adaptive equipment for activities of daily living (ADL) and self-care. Fitting of a proper orthosis and keeping the wrist and hand in functional position may be required. Vocational and avocational training regarding the importance of career and employment implications may be needed because of persistent weakness of the hands and/or feet.^4,5

Medical Issues/Complications

• In Charcot-Marie-Tooth disease (CMT), no treatment currently exists to reverse or slow the natural disease process for the underlying disorder. Nothing can correct the abnormal myelin, prevent the myelin's degeneration, or prevent axonal degeneration.
• Stem-cell and gene-transfer therapies are the most promising forms of treatment for the cure of CMT. Some promising results have been reported for antiprogesterone therapy and ascorbic acid treatment for CMT-1A in animal CMT-1A models. Progesterone-receptor antagonists have reduced PMP-22 overexpression and clinical severity in a CMT-1A rat model. Furthermore, ascorbic acid treatment reduced premature death and demyelination in a CMT-1A mouse model. There is also the prospect of developing drugs to reduce the effects of PMP-22 overexpression in gene duplications by down-regulation via the promoter. Improved understanding of the genetics and biochemistry of the disorder offers hope for an eventual treatment.
• Patients often are evaluated and managed symptomatically by a team that includes a physiatrist, a neurologist, an orthopedic surgeon, and physical and occupational therapists.

Surgical Intervention

Orthopedic surgery may be required to correct severe pes cavus deformities, scoliosis, and other joint deformities.^2,15

Related eMedicine topics:
Neuromuscular Scoliosis
Neuropathic Arthropathy (Charcot Joint)
Pes Cavus

Consultations

Consult a specialist in neurogenetics to order specific genetic tests and proper genetic counseling.

Medication

Avoid drugs and medications known to cause nerve damage (eg, vincristine,^16,17 isoniazid, nitrofurantoin). Identify the cause of any pain as accurately as possible. Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). Neuropathic pain may respond to tricyclic antidepressants or antiepileptic drugs, such as carbamazepine or gabapentin.

Dyck and colleagues¹⁸ and Ginsberg and coauthors¹⁹ described a few individuals with Charcot-Marie-Tooth disease type 1 (CMT-1) and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin produced variable levels of improvement. Sahenk and colleagues have been studying the effects of neurotrophin-3 on individuals with CMT-1A. Passage and coauthors²⁰ reported therapeutic benefits from the administration of ascorbic acid (vitamin C) in a mouse model of CMT-1.

Nonsteroidal anti-inflammatory drugs

Have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase (COX) 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.

Dosing

Adult

200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d

Pediatric

<6 months: Not established
6 months to 12 years: 4-10 mg/kg/dose PO tid/qid
>12 years: Administer as in adults

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, or 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 anticoagulation abnormalities or during anticoagulant therapy

Naproxen (Naprelan, Naprosyn, Anaprox)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease in prostaglandin synthesis.

Dosing

Adult

500 mg PO followed by 250 mg q6-8h; not to exceed 1.25 g/d

Pediatric

<2 years: Not established
>2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d

Interactions

Coadministration with aspirin increases risk of inducing serious NSAID-related side 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

D - Fetal risk shown in humans; use only 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

Cyclooxygenase-2 inhibitors

Although increased cost can be a negative factor, the incidence of costly and potentially fatal GI bleeds is clearly less with COX-2 inhibitors than with traditional NSAIDs. Ongoing analysis of cost avoidance of GI bleeds will further define the populations that will find COX-2 inhibitors the most beneficial.

Celecoxib (Celebrex)

Inhibits primarily COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, GI toxicity may be decreased. Seek lowest dose of celecoxib for each patient.

Dosing

Adult

200 mg/d PO qd; alternatively, 100 mg PO bid

Pediatric

Not established

Interactions

Coadministration with fluconazole may cause increase in celecoxib plasma concentrations because of inhibition of celecoxib metabolism; coadministration of celecoxib with rifampin may decrease celecoxib plasma concentrations

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

May cause fluid retention and peripheral edema; caution in compromised cardiac function, hypertension, conditions predisposing to fluid retention; severe heart failure and hyponatremia, because may deteriorate circulatory hemodynamics; NSAIDs may mask usual signs of infection; caution in the presence of existing controlled infections; evaluate symptoms and signs suggesting liver dysfunction or in cases of abnormal liver lab results

Analgesics

Pain control is essential to quality patient care. Analgesics ensure patient comfort and have sedating properties, which are beneficial for patients who experience pain.

Acetaminophen (Tylenol)

DOC for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.

Dosing

Adult

325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d

Pediatric

<12 years: 10-15 mg/kg/dose PO q4-6h prn; not to exceed 2.6 g/d
>12 years: 325-650 mg PO q4h; not to exceed 5 doses in 24 h

Interactions

Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity

Contraindications

Documented hypersensitivity; known G-6-P deficiency

Precautions

Pregnancy

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

Precautions

Hepatotoxicity possible in chronic alcoholics following various dose levels; severe or recurrent pain or high or continued fever may indicate a serious illness; APAP is contained in many OTC products and combined use with these products may result in cumulative APAP doses exceeding recommended maximum dose

Tricyclic antidepressants

A complex group of drugs that has central and peripheral anticholinergic effects, as well as sedative effects. They have central effects on pain transmission, blocking the active reuptake of norepinephrine and serotonin.

Amitriptyline (Elavil)

Analgesic for certain chronic and neuropathic pain. Inhibits membrane pump responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neuron.

Dosing

Adult

30-100 mg/d PO qhs

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

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

Contraindications

Documented hypersensitivity; patient has taken MAO inhibitors in past 14 d; has history of seizures, cardiac arrhythmias, glaucoma, and urinary retention

Precautions

Pregnancy

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

Precautions

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

Nortriptyline (Pamelor)

Has demonstrated effectiveness in the treatment of chronic pain. By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the central nervous system.
Pharmacodynamic effects, such as the desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors, also appear to play a role in its mechanisms of action.

Dosing

Adult

25 mg PO tid/qid, up to 150 mg/d

Pediatric

<12 years: Not established
>12 years:
25-35 kg: 10-20 mg/d PO
35-54 kg: 25-35 mg/d PO

Interactions

Cimetidine may increase nortriptyline levels when used concurrently; nortriptyline may increase prothrombin time in patients stabilized with warfarin

Contraindications

Documented hypersensitivity; narrow-angle glaucoma; do not administer to patients who have taken MAO inhibitors in past 14 d

Precautions

Pregnancy

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

Precautions

Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; due to pronounced effects in cardiovascular system, best to avoid in elderly patients

Doxepin (Sinequan)

Inhibits histamine and acetylcholine activity and has proven useful in treatment of various forms of depression associated with chronic and neuropathic pain.

Dosing

Adult

10-150 mg/d PO hs or divided bid/tid

Pediatric

<12 years: Not recommended
>12 years: 25-50 mg/d PO hs or bid/tid and increase gradually to 100 mg/d

Interactions

Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates

Contraindications

Documented hypersensitivity; urinary retention; acute recovery phase following myocardial infarction; glaucoma

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 cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement

Desipramine (Norpramin)

May increase synaptic concentration of norepinephrine in CNS by inhibiting reuptake by presynaptic neuronal membrane. May have effects in the desensitization of adenyl cyclase, down-regulation of beta-adrenergic receptors, and down-regulation or serotonin receptors.

Dosing

Adult

75 mg/d PO initially in equally divided doses and increase gradually prn; not to exceed 300 mg/d
Elderly patients: 25-100 mg/d PO; not to exceed 150 mg/d

Pediatric

<6 years: Not established
6-12 years: 1-5 mg/kg/d PO in equally divided doses; not to exceed 5 mg/kg qd
>12 years: 25-50 mg/d PO, initially and increase gradually to 100 mg/d prn; not to exceed 150 mg/d; give in single or equally divided doses

Interactions

Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates

Contraindications

Documented hypersensitivity; narrow-angle glaucoma, recent postmyocardial infarction; patients currently receiving MAO inhibitors or fluoxetine or who have taken them in the previous 2 wk

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 cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement

Anticonvulsants

Used to manage pain and provide sedation in neuropathic pain.

Gabapentin (Neurontin)

Membrane stabilizer, a structural analogue of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), which paradoxically is thought not to exert effect on GABA receptors. Appears to exert action via the alpha(2)delta1 and alpha(2)delta2 subunit of the calcium channel.

Dosing

Adult

300-3600 mg PO in 3-4 divided doses

Pediatric

<12 years: Not established
>12 years: Administer as in adults

Interactions

Antacids may significantly reduce bioavailability of gabapentin (administer at least 2 h following antacids); may increase norethindrone levels significantly

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

Adjust dose in patients with renal insufficiency
If creatinine clearance is 30-60 mL/min, dose should be 300 mg bid; if 15-30 mL/min, 300 mg qd; if <15 mL/min, 300 mg qod; in hemodialysis patients, administer 200-300 mg after each dialysis

Follow-up

Further Outpatient Care

• Patients should have regular follow-up visits to check for deterioration in function and the development of contractures. This follow-up allows early detection of complications. Proper interventions early in the disease course help to avoid significant and permanent functional limitations.¹⁴

Deterrence

• Regular and proper follow-up and therapeutic interventions are necessary to avoid joint contractures and deformities.¹⁴
• Proper genetic counseling helps parents to understand the risk of having a child with this disorder and gives them a chance to make informed decisions about having children.

Complications

• Due to a loss of protective sensation distally in all 4 limbs, patients with Charcot-Marie-Tooth disease (CMT) are susceptible to skin breakdown, burns, nonhealing foot ulcers, and in severe cases, bony, bilateral foot deformities. As mentioned previously, orthoses are required for the treatment of foot drop or to accommodate bony foot deformities. If not fit properly, the orthoses themselves become a source of skin breakdown secondary to associated distal sensory impairment.
• Maternal CMT increases the risk for complications during delivery; this risk is linked to a higher occurrence, in such cases, of emergency interventions during birth.

Prognosis

• The prognosis for the different types of Charcot-Marie-Tooth disease (CMT) varies; it depends on the condition's clinical severity (see the table under Causes).
• Generally, CMT is a slowly progressive neuropathy, with eventual disability occurring secondary to distal muscle weakness and deformities.
• CMT usually does not shorten a patient's expected life span.
• Shy and colleagues developed the CMT neuropathy score, which is a modification of the total neuropathy score.²¹ This has been shown to be a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies and clinical trials of CMT.

Patient Education

• Genetic counseling is the process of providing individuals and families with information on the nature, inheritance patterns, and implications of genetic disorders in order to help them make informed medical and personal decisions. Offer patients with Charcot-Marie-Tooth disease (CMT) genetic counseling so that they can make informed decisions regarding the potential risk of passing the disease to their children.
• Certain drugs and medications, such as vincristine,^16,17 isoniazid, paclitaxel, cisplatin, and nitrofurantoin, are known to cause nerve damage and should be avoided.
• Routine exercise within the individual's capability is encouraged; many individuals remain physically active.
• Obesity should be avoided, because it makes walking more difficult.
• Daily heel-cord stretching exercises are warranted to prevent Achilles tendon shortening.

Miscellaneous

Medicolegal Pitfalls

• Failure to make a proper diagnosis in cases of Charcot-Marie-Tooth disease, including the genetic pattern, brings with it significant medicolegal concerns.
• Informing parents about the genetic nature of the disease and the possibility of having a child with the disorder is medicolegally important.

Multimedia

Media file 1: Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.

Media file 2: Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).

Media file 3: Nerve conduction study showing decreased nerve conduction velocity in the median nerve in an 18-year-old woman with Charcot-Marie-Tooth disease type 1.

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Keywords

Charcot-Marie-Tooth disease, Charcot Marie Tooth, Charcot Marie Tooth disease, neuropathy, Charcot, Charcot Marie, pes cavus, connexin, Charcot Marie Tooth syndrome, hereditary motor sensory neuropathy, HMSN, peroneal muscular atrophy, PMA, CMT

Contributor Information and Disclosures

Author

Divakara Kedlaya, MBBS, Clinical Associate Professor, Department of Physical Medicine and Rehabilitation, Loma Linda University School of Medicine
Divakara Kedlaya, MBBS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, and Colorado Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Milton J Klein, DO, MBA, Consulting Physiatrist, Sewickley Valley Hospital, Allegheny General Hospital, Harmarville Rehabilitation Center, Ohio Valley General Hospital, and Aliquippa Community Hospital
Milton J Klein, DO, MBA is a member of the following medical societies: American Academy of Disability Evaluating Physicians, American Academy of Medical Acupuncture, American Academy of Osteopathy, American Academy of Physical Medicine and Rehabilitation, American Medical Association, American Osteopathic Association, American Osteopathic College of Physical Medicine and Rehabilitation, American Pain Society, and Pennsylvania Medical Society
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Michael T Andary, MD, MS, Residency Program Director, Professor, Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine
Michael T Andary, MD, MS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Association of Academic Physiatrists
Disclosure: allergan Honoraria Speaking and teaching

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Kelly L Allen, MD, Regional Medical Director, IMX-Medical Management Services
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Chief Editor

Robert H Meier III, MD, Director, Amputee Services of America; Active Medical Staff, Presbyterian/St Luke's Hospital, Spalding Rehabilitation Hospital, Select Specialty Hospital; Consulting Staff, Kindred Hospital
Robert H Meier III, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation and Association of Academic Physiatrists
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