eMedicine Specialties > Neurology > Neuromuscular Diseases

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

Author: Aamir Hashmat, MD, Consulting Staff, Neurology and Neurodiagnostics Lab, Department of Neurology, Jeff Anderson Regional Medical Center
Coauthor(s): 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
Contributor Information and Disclosures

Updated: Apr 20, 2006

Introduction

Background

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

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

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

Pathophysiology

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

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

Frequency

United States

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

Mortality/Morbidity

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

Race

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

Sex

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

Age

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

Clinical

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.

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