WORKUP	Section 5 of 11
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Lab Studies:

• All routine laboratory tests are normal in individuals with CMT.

Imaging Studies:

• High-resolution ultrasonography of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis in CMT 1A.

Other Tests:

• Special genetic tests are available for some types of CMT.

• CMT 1A: Pulsed field gel electrophoresis and a specialized fluorescent in situ hybridization (FISH) assay are the most reliable genetic tests, but they are 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 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 CMT 1 cases are designated CMT 1A, caused by alteration of the PMP-22 gene (chromosome band 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 cases are designated CMT 1B and are caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosome band 1q22).

• CMT 1C and CMT 1D: Very rarely, mutations occur in the EGR2 (early growth response 2) gene or the LITAF gene, causing CMT 1D and CMT 1C, respectively, for which molecular genetic testing is also available clinically.

• The 4 subtypes of CMT 2 are indistinguishable clinically and are distinguished solely based on genetic linkage findings. Relative proportions of CMT 2A, 2B, 2C, and 2D have not been determined yet. 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 for CMT 2A, 2B1, 2E, and 2F only.

• CMT X: Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases. Such testing is clinically available.

• Genetic testing currently is not available for other types of CMTs.

• Nerve biopsy rarely is indicated to diagnose CMT, especially since genetic testing has become available. Biopsies sometimes are performed in cases of diagnostic dilemmas. Findings vary in different types of CMT.

• In CMT type 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 is frequently observed and is made of circumferentially directed Schwann cells and their processes.

• In CMT type 2, axon loss with wallerian degeneration is generally found.

• In CMT type 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

• Perform these studies first if CMT is suggested. Findings vary depending on the type of CMT.

• In demyelinating types such as CMT 1, diffuse and uniform slowing of nerve conduction velocities is observed (see Image 3).

• Harding and Thomas criteria for diagnosing CMT 1 include median motor nerve conduction velocity less than 38 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 nerves tested, both sensory and motor, 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 m/s in Dejerine-Sottas disease and congenital hypomyelination. Slowing of nerve conduction also can be found in asymptomatic individuals.

• In neuronal (ie, axonal) types, nerve conduction velocity is usually normal, but markedly low amplitudes are noted in both sensory (ie, sensory nerve action potential [SNAP]) and motor nerve (ie, CMAP) studies.

• In neuronal (ie, axonal) types, increased insertional activity is evident as fibrillation potentials and positive sharp waves are observed. Motor unit potentials show decreased recruitment patterns and neuropathic changes in morphology.

• In CMT type 1, peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by a rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. Concentric hypertrophy of the lamellar sheaths is seen. Formation of the typical onion bulb is noted and is made of circumferentially directed Schwann cells and their processes.

• In CMT type 2, axonal degeneration is observed.

• In CMT type 3 and Dejerine-Sottas disease, demyelination with thinning of the myelin sheath can be seen.

• No inflammatory infiltrate should be present, indicating autoimmune demyelinating process.

	TREATMENT	Section 6 of 11
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Medical Care:

• Currently, no treatment exists to reverse or slow the natural disease process for the underlying disorder. Nothing can correct the abnormal myelin, prevent its degeneration, or prevent axonal degeneration.

• Improved understanding of the genetics and biochemistry of the disorder offers hope for an eventual treatment.

• Patients often are evaluated and treated symptomatically by a team that includes a neurologist, physiatrist, orthopedic surgeon, physical therapist, and occupational therapist.

Surgical Care: Orthopedic surgery is required to correct severe pes cavus deformities, scoliosis, and other joint deformities. Treatment is determined by the age of the patient and the cause and severity of the deformity.

• Surgical procedures consist of the following 3 types:
  • Soft tissue (plantar fascia release, tendon release or transfer)

  • Osteotomy (metatarsal, midfoot, calcaneal)

  • Joint stabilizing (triple arthrodesis)

• Surgical procedures are usually staged. The initial procedure is a radical plantar or plantar-medial release, with a dorsal closing-wedge osteotomy of the first metatarsal base if necessary. Tendo calcaneus lengthening should not be performed as part of the initial procedure because the force used to dorsiflex the forefoot causes the calcaneus to dorsiflex into an unacceptable position. If the hindfoot is flexible and a posterior release is not necessary, posterior tibial tendon transfer can be done as part of the initial procedure for severe anterior tibial weakness.

• When the hindfoot is flexible, early aggressive treatment with soft-tissue releases can delay the need for more extensive reconstructive procedures. The Jones procedure includes transfer of the extensor hallucis longus and arthrodesis of the interphalangeal joint of the great toe.

• The Coleman Block Test is sometimes used to help decide what type of surgery is best. In cases of cavovarus deformity, this test evaluates hindfoot flexibility. The Coleman Block test is performed by placing the patient's foot on a wood block that is 2.5-4 cm thick, with the heel and lateral border of foot on the block and bearing full weight while the first, second, and third metatarsals are allowed to hang freely into plantar flexion and pronation. If heel varus corrects while the patient is standing on the block, the hindfoot is considered flexible. If the subtalar joint is supple and corrects with the block test, then surgical procedures may be directed to correcting forefoot pronation, which is usually due to plantar flexion of the first metatarsal. If the hindfoot is rigid, then surgical correction of both the forefoot and hindfoot are required.

• Triple arthrodesis serves as a salvage procedure for patients in whom other procedures were unsuccessful or in patients with untreated fixed deformities.

• Children younger than 8 years with supple hindfeet usually respond to plantar releases and appropriate tendon transfers. A first metatarsal osteotomy may be needed in some cases.

• Children younger than 12 years with rigid hindfoot deformities may need radical plantar-medial release, first metatarsal osteotomy, and Dwyer lateral closing-wedge osteotomy of the calcaneus to correct the deformities.

• Wukich and Bowen (1989) reported that only 14% of patients with CMT disease required triple arthrodesis. They also reported hindfoot stability with triple arthrodesis; and when transferring the posterior tibial tendon anteriorly, this eliminated the need for a postoperative drop-foot brace. They reported good or excellent results in 88% of their patients treated with this method.

• Generally, spinal deformities in children with CMT disease can be treated with the same techniques used for idiopathic scoliosis.

Consultations:

• Consult specialists in neurogenetics to order specific genetic tests and proper genetic counseling.

Activity:

• No specific activity limitation is recommended.

	MEDICATION	Section 7 of 11
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Avoid drugs and medications known to cause nerve damage (eg, vincristine, 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 et al (1982) and Ginsberg et al (2004) have described a few individuals with CMT 1 and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin produced variable levels of improvement. Sahenk et al (2003) are studying the effects of neurotrophin-3 on individuals with CMT 1A. Passage et al (2004) reported benefit from ascorbic acid (vitamin C) in a mouse model of CMT 1.

Drug Category: Nonsteroidal anti-inflammatory drugs -- Have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Drug Name	Ibuprofen (Motrin, Ibuprin) -- DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.
Adult Dose	200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d
Pediatric Dose	<6 months: Not established 6 months to 12 years: 4-10 mg/kg/dose PO tid/qid >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; peptic ulcer disease, recent GI bleeding or perforation, renal insufficiency, or high risk of bleeding
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; caution in congestive heart failure, hypertension, and decreased renal and hepatic function; caution in anticoagulation abnormalities or during anticoagulant therapy

Drug Name	Naproxen (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.
Adult Dose	500 mg PO followed by 250 mg q6-8h; not to exceed 1.25 g/d
Pediatric Dose	<2 years: Not established >2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
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
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Category D in third trimester of pregnancy; 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

Drug Category: 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.

Drug Name	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.
Adult Dose	200 mg/d PO qd; alternatively, 100 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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 LFT results

Drug Category: Tricyclic antidepressants -- A complex group of drugs that has central and peripheral anticholinergic effects, as well as sedative effects. Tricyclic antidepressants have central effects on pain transmission, blocking the active reuptake of norepinephrine and serotonin.

Drug Name	Amitriptyline (Elavil) -- Analgesic for certain chronic and neuropathic pain. Inhibits membrane pump responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neuron.
Adult Dose	30-100 mg/d PO qhs
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity; patient has taken MAO inhibitors in past 14 d; has history of seizures, cardiac arrhythmias, glaucoma, and urinary retention
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
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in cardiac conduction disturbances and history of hyperthyroidism, renal or hepatic impairment; avoid using in elderly patients

Drug Name	Nortriptyline (Pamelor) -- Has demonstrated effectiveness in the treatment of chronic pain. By inhibiting the re-uptake 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.
Adult Dose	25 mg PO tid/qid, up to 150 mg/d
Pediatric Dose	<12 years: Not established >12 years 25-35 kg: 10-20 mg/d PO 35-54 kg: 25-35 mg/d PO
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; do not administer to patients who have taken MAO inhibitors in past 14 d
Interactions	Cimetidine may increase nortriptyline levels when used concurrently; nortriptyline may increase prothrombin time in patients stabilized with warfarin
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	Doxepin (Sinequan) -- Inhibits histamine and acetylcholine activity and has proven useful in treatment of various forms of depression associated with chronic and neuropathic pain.
Adult Dose	10-150 mg/d PO hs or divided bid/tid
Pediatric Dose	<12 years: Not recommended >12 years: 25-50 mg/d PO hs or bid/tid and increase gradually to 100 mg/d
Contraindications	Documented hypersensitivity; urinary retention; acute recovery phase following myocardial infarction; glaucoma
Interactions	Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement

Drug Name	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.
Adult Dose	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 Dose	<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
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
Interactions	Decreases antihypertensive effects of clonidine but increases effects of sympathomimetics and benzodiazepines; effects of desipramine increase with phenytoin, carbamazepine, and barbiturates
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in cardiovascular disease, conduction disturbances, seizure disorders, urinary retention, hyperthyroidism, and patients receiving thyroid replacement

Drug Category: Anticonvulsants -- Used to manage pain and provide sedation in neuropathic pain.

Drug Name	Gabapentin (Neurontin) -- Membrane stabilizer, a structural analogue of the inhibitory neurotransmitter gamma-amino butyric 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 sub unit of the calcium channel.
Adult Dose	300-3600 mg PO in 3-4 divided doses
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Antacids may reduce bioavailability of gabapentin significantly (administer at least 2 h following antacids); may increase norethindrone levels significantly
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Adjust dose in patients with renal insufficiency; if CrCl 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

Drug Category: 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.

Drug Name	Acetaminophen (Tylenol) -- DOC for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.
Adult Dose	325-650 mg PO q4-6h or 1000 mg tid/qid; not to exceed 4 g/d
Pediatric Dose	<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
Contraindications	Documented hypersensitivity; known G-6-P deficiency
Interactions	Rifampin can reduce analgesic effects of acetaminophen; coadministration with barbiturates, carbamazepine, hydantoins, and isoniazid may increase hepatotoxicity
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Hepatotoxicity possible in those with chronic alcoholism 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

	FOLLOW-UP	Section 8 of 11
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Further Outpatient Care:

• Patients should have regular follow-up visits to check for deterioration in function and 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.

Deterrence/Prevention:

• Regular and proper follow-up and therapeutic interventions are necessary to avoid joint contractures and deformities.

• Proper genetic counseling helps parents understand the risk of having children with this disorder and gives them a chance to make informed decisions on pregnancy.

Complications:

• Due to loss of protective sensation distally in all 4 limbs, patients with CMT are susceptible to skin breakdown or burns, nonhealing foot ulcers, and, in severe cases, bony deformities of bilateral feet. As mentioned previously, orthoses are required for 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, which is linked to a higher occurrence of emergency interventions during birth.

Prognosis:

• Prognosis for the different types of CMT varies and depends on clinical severity (see Table).

• Generally, CMT is a slowly progressive neuropathy that causes eventual disability secondary to distal muscle weakness and deformities.

• CMT does not usually shorten the expected life span.

• Shy et al (2005) developed the CMT neuropathy score, which is a modification of total neuropathy score. 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 to help them make informed medical and personal decisions. Offer patients with CMT genetic counseling so that they can make informed decisions regarding potential risk of passing the disease to their children.

• Drugs and medications such as vincristine, 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	Section 9 of 11
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Medical/Legal Pitfalls:

• Failure to make the proper diagnosis, including the genetic pattern, has significant medicolegal concerns.

• Informing parents about the genetic nature of the disease and the possibility of having a baby with the disorder is medicolegally important.

	PICTURES	Section 10 of 11
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Caption: Picture 1. Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
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Picture Type: Photo

Caption: Picture 2. Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared to normal (B).
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Picture Type: Photo

Caption: Picture 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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Picture Type: Graph

	BIBLIOGRAPHY	Section 11 of 11
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Pictures Bibliography

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Charcot-Marie-Tooth Disease excerpt