AUTHOR INFORMATION

Section 1 of 11

Authored by Aamir Hashmat, MD, Consulting Staff, Neurology and Neurodiagnostics Lab, Department of Neurology, Jeff Anderson Regional Medical Center

Coauthored by Zaineb Daud, MD, Consulting Staff, Department of Neurology, Medical College of Pennsylvania Hahnemann University; Thomas H Brannagan III, MD, Associate Professor of Clinical Neurology, Weill Medical College of Cornell University; Director, Diabetic Neuropathy Research Center, Department of Neurology, New York-Presbyterian Hospital, Weill Cornell Medical Center

Aamir Hashmat, MD, is a member of the following medical societies: AO Foundation, American Academy of Neurology, American Epilepsy Society, and American Medical Association

Edited by Dianna Quan, MD, Director, Electromyography Laboratory, Assistant Professor, Department of Neurology, University of Colorado Health Sciences Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, University of Pittsburgh Medical Center - Shadyside, Clinical Associate Professor, Department of Neurology, University of Pittsburgh School of Medicine; Selim R Benbadis, MD, Professor of Neurology, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine, Tampa General Hospital; and Nicholas Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants

Author's Email:	Aamir Hashmat, MD
Editor's Email:	Dianna Quan, MD

eMedicine Journal, May 1 2006, VOLUME 7, Number 5

INTRODUCTION

Section 2 of 11

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

• HMSN types 1A and B (dominantly inherited hypertrophic neuropathies)

• HMSN type 2 (neuronal type of peroneal muscular atrophy)

• HMSN type 3 (hypertrophic neuropathy of infancy [Dejerine-Sottas])

• HMSN type 4 (hypertrophic neuropathy [Refsum] associated with phytanic acid excess)

• HMSN type 5 (associated with spatic paraplegia)

• HMSN type 6 (with optic atrophy)

• HMSN type 7

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

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

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

Frequency:

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

Mortality/Morbidity:

• Usually, life expectancy is normal.

• Disability is highly variable and difficult to predict in young individuals. This is related, at least in part, to the variable genetic penetrance of the disorders.

• In general, Charcot-Marie-Tooth disease is a slowly progressive condition. If progression accelerates, other causes, such as acquired neuropathies or other inherited neuromuscular conditions, should be sought.

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

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

Age:

• The onset of HMSN 1 in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.

• Patients with HMSN 2 are usually asymptomatic until later in life, and the symptoms most commonly begin in the second decade of life.

• The onset of HMSN 3 is in early childhood.

CLINICAL

Section 3 of 11

History:

• Hereditary motor and sensory neuropathy type 1


• • Because of its insidious onset, some patients are unaware of their disease or seek medical attention only late in life. In contrast to acquired neuropathies in which pain in a prominent feature, patients with HMSN1 experience a relative lack of pain.
  
  
  
  • Motor symptoms predominate over sensory symptoms.
  
  
  
  • Often, patients report loss of balance, muscle weakness, and foot deformities.
  
  
  
  • Onset in the first decade of life is typical, but disease develops in some patients in young or mid adulthood.
  
  
  
  • Patients report tripping over objects because of foot drop. Ankle sprains and fractures are frequent.
  
  
  
  • Because of hammertoes and high arches, patients have difficulty finding well-fitting shoes or experience painful calluses.
  
  
  
  • Cold feet, often associated with hair loss or leg edema, is common.
  
  
  
  • Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed.
  
  
  
• Hereditary motor and sensory neuropathy type 2: Not infrequently, asymptomatic individuals are discovered during screening of families after one relative has been diagnosed.



• Hereditary motor and sensory neuropathy type 3 (Dejerine-Sottas syndrome)


• • This is a rare hypertrophic neuropathy of infancy inherited as an autosomal recessive trait.
  
  
  
  • The clinical features are those of a severe neuropathy with onset in early childhood.
  
  
  
  • Motor development is delayed.
  
  
  
  • Jumping and running are impaired.
  
  
  
  • Muscular weakness is progressive, affecting legs and arms.
  
  
  

Physical:

• Hereditary motor and sensory neuropathy type 1


• • Roughly half of patients with CMT could be grouped into a classic phenotype associated with distal weakness, decreased tendon reflexes, foot deformities, with or without sensory loss. Weakness and muscle atrophy, which is dominant distally, affect the legs more severely and earlier than the arms.
  
  
  
  • Sensation may be normal until adulthood, but mild diffuse sensory loss is common.
  
  
  
  • Hyporeflexia or areflexia is the rule.
  
  
  
  • Foot deformities include high arches or flat feet, hammertoes, and tight Achilles tendons.
  
  
  
  • Enlargement and excessive firmness are found in the nerves of more than 25% of patients and are often visible in the superficial cervical nerves and palpable in the arms.
  
  
  
  • Tremor occurs in up to 25% of patients.
  
  
  
• Hereditary motor and sensory neuropathy type 2


• • Peripheral nerves are not enlarged clinically, and weakness of feet and leg muscles predominates; hands are less severely affected than the legs.
  
  
  
  • Patients experience sensory loss in the distal extremities, and foot deformities (ie, pes cavus) tend to be less marked than those of HMSN 1.
  
  
  
• Hereditary motor and sensory neuropathy type 3


• • General areflexia with prominent enlarged peripheral or cranial nerves is typical.
  
  
  
  • Patients experience a definite sensory loss, and some patients have marked sensory ataxia.
  
  
  

Causes:

• Genetic defects in inherited demyelinating neuropathies. Current estimates indicate that up to 60% of patients with CMT1 have the chromosome 17 duplication.


• • HMSN type 1A - Duplication on chromosome 17 (region containing human peripheral myelin protein 22 [PMP22] gene), point mutation in PMP22 gene, autosomal dominant inheritance, with the HMSN 1 locus mapped on the short arm of chromosome 17 (p11.2-p12 band)
  
  
  
  • HMSN type 1B - Point mutation in the P0 gene (an important structural protein of peripheral nerve myelin) on the long arm of chromosome 1, linked to the Duffy blood group
  
  
  
  • HMSN type 2 - Gene localized to chromosome 1
  
  
  
  • HMSN type 3 (Dejerine-Sottas disease) - Missense and point mutation in PMP22 (recent genetic studies) and the P0 gene, other undetermined causes
  
  
  
  • HMSN type X
    • X-linked dominant HMSN is phenotypically similar to HMSN type 1. Male subjects tend to be more severely affected, whereas female subjects may have a mild neuropathy or be asymptomatic.

    • No male-to-male transmission occurs.

    • Linkage analysis localized the locus to the proximal long arm of the X chromosome; a recent study isolated a gap junction protein, connexin 32, as the candidate gene, which, if abnormal, can cause HMSN X.
  
  
  
• Lupski and coworkers reported that a segment band of chromosome 17 (17p11.2-p12) was duplicated in affected members of families with HMSN 1A. The PMP22 gene is found in the region of the duplication. PMP22 encodes for the synthesis of a peripheral nervous system myelin protein. Most patients with genetically defined HMSN 1A have either a gene dose effect (ie, duplication of 17p11.2-p12) or a mutation affecting the PMP22 gene on chromosome 17. Interestingly, the human PMP22 gene is deleted in patients with HSMN with liability to pressure palsies.

DIFFERENTIALS

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Other Problems to be Considered:

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

WORKUP

Section 5 of 11

Lab Studies:

• The workup should include tests that address causes of neuropathies, such as endocrinologic, infectious, and immunologic abnormalities; vitamin and nutritional deficiencies; and nerve compression.



• On cerebrospinal fluid (CSF) analysis, CSF protein levels usually are within the reference range in patients with Charcot-Marie-Tooth disease type 1B, but they may be elevated above 100 mg/dL. By contrast, CSF protein is elevated in most but not all cases of Dejerine-Sottas syndrome.

Other Tests:

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

Procedures:

• Electrodiagnostic studies


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

TREATMENT

Section 6 of 11

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

• Physical therapy is often required to prevent and treat joint deformities. Prosthetic devices, such as ankle-foot orthoses, can prevent Achilles tendon shortening and prolong near-normal ambulation. At times, boots can delay the need for such ankle braces. Thick-handled tools and cutlery can render certain activities of daily living easier.



• Pain may result from joint deformities or compensatory overuse of certain muscle groups. Some types of pain may respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Dysesthetic pain may occur but is not typical; it responds to antidepressants, such as amitriptyline, desipramine, or paroxetine, and to anticonvulsants, such as gabapentin or carbamazepine.



• Recent research and updates proposed that the most common form of inherited peripheral neuropathy results from overexpression of a single gene. Simple application of an antiprogesterone drug can reduce gene expression and alleviate symptoms in a rat model. Sereda et al described the first successful treatment strategy in a rat model of Charcot-Marie-Tooth subtype 1A (CMT-1A), the most common variant of the inherited peripheral neuropathies. Their observations offer a glimpse of hope for patients, provided their strategy can be translated into clinical trials in humans.

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

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

MEDICATION

Section 7 of 11

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

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

Drug Name	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.
Adult Dose	400-800 mg PO tid with food
Pediatric Dose	Not recommended
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency; 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 coagulation abnormalities or during anticoagulant therapy

Drug Name	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.
Adult Dose	500 mg PO bid with food
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
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; 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: Antidepressants -- These drugs increase the synaptic concentration of serotonin and/or norepinephrine in CNS by inhibiting their reuptake at the presynaptic neuronal membrane. These mechanisms may play a role in the analgesic effects of these medications.

Drug Name	Nortriptyline (Pamelor, Aventyl HCl) -- Has demonstrated effectiveness in treatment of pain.
Adult Dose	25-100 mg PO hs; not to exceed 200 mg/d
Pediatric Dose	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
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; MAOIs within 14 d
Interactions	Cimetidine may increase nortriptyline levels; may increase effects of warfarin (monitor INR)
Pregnancy	D - Unsafe in pregnancy
Precautions	Patients with cardiac conduction disturbances and a history of hyperthyroidism; those with renal or hepatic impairment; avoid using in elderly patients

Drug Name	Amitriptyline (Elavil) -- Has demonstrated effectiveness in treatment of pain.
Adult Dose	25-100 mg PO hs; not to exceed 150 mg/d
Pediatric Dose	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
Contraindications	Documented hypersensitivity; narrow-angle glaucoma; MAOIs within 14 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
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in cardiac conduction disturbances, history of hyperthyroidism, and renal or hepatic impairment; avoid using in elderly patients

Drug Category: Serotonin reuptake inhibitors -- Serotoninergic antidepressants have had mixed reviews in the literature. Some of them have been reported to relieve painful sensory symptoms.

Drug Name	Paroxetine (Paxil) -- Considered an alternative to TCAs, with fewer adverse anticholinergic and cardiovascular effects.
Adult Dose	10 mg/d PO initially; titrate to maximum 50 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; pregnancy and lactation; severe renal or hepatic disease
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Drug Category: Anticonvulsants -- These medications reduce neuronal excitability and prevent neuronal discharges associated with pain sensation.

Drug Name	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.
Adult Dose	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 Dose	Not established
Contraindications	Documented hypersensitivity; bone marrow depression; sensitivity to tricyclics; MAOIs within last 14 d
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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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.
Adult Dose	900-2700 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
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
Pregnancy	C - Safety for use during pregnancy has not been established.
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

Section 8 of 11

Complications:

• Rare complications include radiculopathies due to enlarged nerve roots.

Prognosis:

• Life expectancy is normal.



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

MISCELLANEOUS

Section 9 of 11

Medical/Legal Pitfalls:

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



• Associated conditions must be excluded and treated appropriately.

Special Concerns:

• No particular complications are associated with pregnant women with Charcot-Marie-Tooth disease type 1B.



• As with surgical procedures, prolonged positioning of the body and limbs in particular postures can result in nerve compression, which could make any underlying neuropathy worse.



• Regional anesthesia is contraindicated in Charcot-Marie-Tooth disease.



• Because of the variability of clinical manifestations, couples who have symptomatic or asymptomatic Charcot-Marie-Tooth disease type 1B may have homozygous offspring with Dejerine-Sottas syndrome or congenital hypomyelination neuropathy.

TEST QUESTIONS

Section 10 of 11

CME Question 1: A 23-year-old woman presents with chief symptoms of bilateral ankle weakness and decreased sensation in her feet. On examination, she has high-arched feet and distal lower extremity muscle atrophy. Mild plantar weakness and dorsiflexion weakness are present. Temperature, vibration, and proprioception are impaired in lower extremities. Reflexes are absent in both lower extremities. Nerve conduction study reveals mildly prolonged distal latency and uniform slowing of motor conduction velocities. Sensory responses are absent in the lower extremities. What is the most likely diagnosis?

A: Diabetic neuropathy
B: Chronic inflammatory demyelinating polyneuropathy
C: Charcot-Marie-Tooth disease
D: Guillain-Barré syndrome
E: Mononeuritis multiplex

The correct answer is C: The patient has typical history and electrophysiologic features of a hereditary primary demyelinating neuropathy, such as Charcot-Marie-Tooth disease type 1A. The young age of the patient and the uniform distribution of conduction abnormalities are typical of inherited neuropathies.

CME Question 2: Which of the following is not a subtype of hereditary motor sensory neuropathies?

A: Charcot-Marie-Tooth disease type 1A
B: Charcot-Marie-Tooth disease type 1B
C: Charcot-Marie-Tooth disease type 2
D: Charcot-Marie-Tooth disease type 10
E: Chronic inflammatory demyelinating polyneuropathy

The correct answer is E: Charcot-Marie-Tooth disease types IA, IB, 2, and 10 are all subcategories of hereditary sensory motor neuropathies. Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired condition. The precise mechanism of CIDP is unknown, but an immunologic mechanism plays a major role.

Pearl Question 1 (T/F): Charcot-Marie-Tooth disease type 1 is the result of a systemic metabolic defect.

The correct answer is False: Charcot-Marie-Tooth disease type 1 is an inherited disorder. In most families, the mode of inheritance is autosomal dominant and the defective gene is localized to the short arm of chromosome 17.

Pearl Question 2 (T/F): The most common inherited peripheral neuropathy is Charcot-Marie-Tooth disease.

The correct answer is True: Among all inherited neuropathies, Charcot-Marie-Tooth disease type 1 is the most common. In the last few years, advances in genetic science have provided new ways to classify and understand these disorders.

Pearl Question 3 (T/F): Patients with hereditary motor sensory neuropathy type 2 are disabled severely early in life.

The correct answer is False: Patients with hereditary motor sensory neuropathy type 2 are usually asymptomatic until later in life. Peripheral nerves are not usually enlarged clinically, and weakness of feet and leg muscles predominates.

Pearl Question 4 (T/F): The pathologic hallmark of the Charcot-Marie-Tooth disease is the onion bulb formation.

The correct answer is True: Onion bulb formation is the classic pathologic marker of the hypertrophic neuropathies in which repeated segmental demyelination and remyelination occur. Onion bulb formations are frequently observed in the Charcot-Marie-Tooth disease, Dejerine-Sottas syndrome, Refsum disease, and chronic relapsing idiopathic (inflammatory) demyelinating neuropathy.

BIBLIOGRAPHY

Section 11 of 11

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

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