History

Patients usually have a significant family history of Charcot-Marie-Tooth disease (CMT).^[33]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]The most common clinical phenotype is the CMT syndrome with distal muscle wasting and weakness, tendon areflexia, usually mild sensory loss, and foot deformity.^[4]A subgroup of patients with CMT-1A can present with proximal muscle wasting and weakness.^[34]Cranial nerve deficits in a member of a CMT-1 family carrying an EGR2 mutation have been reported.^[35]

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.^{[13, 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.^{[36, 37, 38]}
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 pain may be present due to significant deformities. Neuropathic pain is also quite common and can cause significant disability.^{[32, 39, 40]}Muscle cramping is a common complaint.
Neuropathic pain may be present in a significant number of patients with CMT. A study by Bjelica et al found that almost one third of the report’s patients with CMT-1A suffered from neuropathic pain, with the pain being moderate on average. Neuropathic pain was linked to greater functional disability and depression.^[41]
Autonomic symptoms usually are absent, but a few men with CMT have reported impotence.

A study by Tozza et al indicated that in patients with CMT-1A, the greatest disturbance in daily life results from weakness in the lower limbs, while the lowest impact is produced by upper limb weakness. However, in older patients and those with greater disability, balance problems were the most disruptive deficits.^[42]

A prospective cohort study by Kennedy et al conservatively estimated that the incidence of falls in children and adolescents with CMT is 33 times greater than that of peers undergoing typical development. Moreover, falls in the study’s patients with CMT more commonly resulted in injury than did those in the control group (34.2% of falls vs 11.5%, respectively).^[43]

A large prospective study by Pipis et al indicated that in patients with autosomal dominant CMT-2A, greater disease severity is most significantly predicted by childhood onset, with this risk factor being independent of disease duration. The rate at which the study’s childhood-onset patients employed AFOs and engaged in full-time wheelchair use was significantly higher than for those with adult-onset disease. Childhood onset was also associated with worse dexterity problems, and patients in this group also tended to have “a significantly higher CMT Examination Score (CMTESv2) and CMT Neuropathy Score (CMTNSv2) at initial assessment.”^[44]

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 following images).^{[13, 3]}

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

Foot of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
View Media Gallery
Hand deformities can occur with wasting of intrinsic hand muscles and claw hand. See the following image.

Hands of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
View Media Gallery
Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT-1.

Other characteristics of CMT include the following:

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 ^{[45, 46]}
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 ^{[45, 46]}

A study by Reynaud et al indicated that in patients with CMT-1A, the isokinetic muscle strength (IMS) of the knee extensors correlates with walking speed, while for patients under age 50 years, IMS of the knee flexors also relates to speed.^[47]

A study by Cardoso et al indicated that children with CMT exhibit higher peak pressure (medial midfoot, medial forefoot) and a greater pressure-time integral (rearfoot, lateral midfoot, medial forefoot) than do young people without CMT. In adolescents with CMT, according to the report, the contact area (whole foot) is smaller and the contact time (medial midfoot) is greater than in controls.^[48]

Causes

Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM). More than 900 mutations in 60 genes are associated with the disease.^{[49, 50]}The list can be found at http://www.molgen.vib-ua.be/CMTMutations/Home/IPN.cfm.

Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison (Open Table in a new window)

CMT Type	Chromosome; Inheritance Pattern	Age of Onset	Clinical Features	Average NCVs^§
CMT-1A (PMP-22^¶ dupl.)	17p11.2; AD*	First decade	Distal weakness	15-20 m/s
CMT-1B (P₀ -MPZ)**	1q23.3; AD	First decade	Distal weakness	< 20 m/s
CMT-1C (non-A, non-B) (LITAF)	16p13.13;AD	Second decade	Distal weakness	26-42 m/s
CMT-1D (EGR-2)^#	10q21.3; AD	First decade	Distal weakness	15-20 m/s
CMT-1E (PMP22)	17p11.2; AD	First decade	Distal weakness, deafness	15-20 m/s
CMT-1F (NEFL)	8p21.2; AD	First decade	Distal weakness	15-20 m/s
CMT-X (connexin-32)^{[51, 52, 53, 54]}	Xq13; XD^‡	Second decade	Distal weakness	25-40 m/s
CMT-2A	1p36; AD	10 y	Distal weakness	>38 m/s
CMT-2B	3q21; AD	Second decade	Distal weakness, sensory loss, skin ulcers	Axon loss; Normal
CMT-2C	12q23-q24, AD	First decade	Vocal cord, diaphragm, and distal weakness	>50 m/s
CMT-2D	7p14; AD	16-30 y	Distal weakness, upper limb predominantly	Axon loss; N^††
CMT-2E	8p21; AD	10-30 y	Distal weakness, lower limb predominantly	Axon loss; N
CMT-2F	7q11-q21; AD	15-25 y	Distal weakness	Axon loss; N
CMT-2G	12q12-q13; AD	9-76 y	Distal weakness	Axon loss; N
CMT-2H	8q21; AD	15-25 y	Distal weakness, pyramidal features	Axon loss; N
CMT-2I	1q23; AD	47-60 y	Distal weakness	Axon loss; N
CMT-2J	1q23; AD	40-50 y	Distal weakness, hearing loss	Axon loss; N
CMT-2K	8q13-q21; AD	< 4 y	Distal weakness	Axon loss; N
CMT-2L	12q24; AD	15-25 y	Distal weakness	Axon loss; N
CMT–R-Ax (Ouvrier)	AR	First decade	Distal weakness	Axon loss; N
CMT–R-Ax (Moroccan)	1q21; AR	Second decade	Distal weakness	Axon loss; N
Cowchock syndrome	Xq24-q26	First decade	Distal weakness, deafness, mental retardation	Axon loss; N
HNPP^\|\| (PMP-22 deletion)^[55] or tomaculous neuropathy	17p11; AD	All ages	Episodic weakness and numbness	Conduction Blocks
Dejerine-Sottas-syndrome (DSS) or HMSN-3^[56]	P₀; AR PMP-22; AD 8q23; AD	2 y	Severe weakness	< 10 m/s
Congenital hypomyelination (CH)	P₀, EGR-2 or PMP-22 AR	Birth	Severe weakness	< 10 m/s
CMT-4A^[57]	8q13; AR	Childhood	Distal weakness	Slow
CMT-4B (myotubularin- related protein 2)^{[58, 59]}	11q23; AR	2-4 y	Distal and proximal weakness	Slow
CMT-4C	5q23; AR	5-15 y	Delayed walking	14-32 m/s
CMT-4D (Lom) (N-myc downstream- regulated gene 1)	8q24; AR	1-10 y	Distal muscle wasting, foot and hand deformities	10-20 m/s
CMT-4E (EGR-2)	10q21; AR	Birth	Infant hypotonia	9-20 m/s
CMT-4G	10q23.2; AR	8-16 years	Distal weakness	9-20 m/s
CMT-4H	12p11.21-q13.11; AR	0-2 years	Delayed walking	9-20 m/s
CMT-4F	19q13; AR	1-3 y	Motor delay	Absent
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).^{[60, 61]}Hereditary neuropathy with diffusely slow nerve conduction velocity (hypertrophic neuropathy) is HMSN-I.

HMSN-I (CMT-1) with different subclassifications.^[62]
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)^[63]:
- 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

A study by Rose et al of 30 pediatric patients with CMT indicated that a significant association exists between functional ankle instability in children with disease and cavus foot structure, female sex, and impaired balance.^[64]

Differential Diagnoses

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Media Gallery

Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).
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.
Foot of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
Hands of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
Right ulnar motor nerve conduction study in a 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
Left ulnar motor nerve conduction study in 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.

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Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

CMT Type	Chromosome; Inheritance Pattern	Age of Onset	Clinical Features	Average NCVs^§
CMT-1A (PMP-22^¶ dupl.)	17p11.2; AD*	First decade	Distal weakness	15-20 m/s
CMT-1B (P₀ -MPZ)**	1q23.3; AD	First decade	Distal weakness	< 20 m/s
CMT-1C (non-A, non-B) (LITAF)	16p13.13;AD	Second decade	Distal weakness	26-42 m/s
CMT-1D (EGR-2)^#	10q21.3; AD	First decade	Distal weakness	15-20 m/s
CMT-1E (PMP22)	17p11.2; AD	First decade	Distal weakness, deafness	15-20 m/s
CMT-1F (NEFL)	8p21.2; AD	First decade	Distal weakness	15-20 m/s
CMT-X (connexin-32)^{[51, 52, 53, 54]}	Xq13; XD^‡	Second decade	Distal weakness	25-40 m/s
CMT-2A	1p36; AD	10 y	Distal weakness	>38 m/s
CMT-2B	3q21; AD	Second decade	Distal weakness, sensory loss, skin ulcers	Axon loss; Normal
CMT-2C	12q23-q24, AD	First decade	Vocal cord, diaphragm, and distal weakness	>50 m/s
CMT-2D	7p14; AD	16-30 y	Distal weakness, upper limb predominantly	Axon loss; N^††
CMT-2E	8p21; AD	10-30 y	Distal weakness, lower limb predominantly	Axon loss; N
CMT-2F	7q11-q21; AD	15-25 y	Distal weakness	Axon loss; N
CMT-2G	12q12-q13; AD	9-76 y	Distal weakness	Axon loss; N
CMT-2H	8q21; AD	15-25 y	Distal weakness, pyramidal features	Axon loss; N
CMT-2I	1q23; AD	47-60 y	Distal weakness	Axon loss; N
CMT-2J	1q23; AD	40-50 y	Distal weakness, hearing loss	Axon loss; N
CMT-2K	8q13-q21; AD	< 4 y	Distal weakness	Axon loss; N
CMT-2L	12q24; AD	15-25 y	Distal weakness	Axon loss; N
CMT–R-Ax (Ouvrier)	AR	First decade	Distal weakness	Axon loss; N
CMT–R-Ax (Moroccan)	1q21; AR	Second decade	Distal weakness	Axon loss; N
Cowchock syndrome	Xq24-q26	First decade	Distal weakness, deafness, mental retardation	Axon loss; N
HNPP^\|\| (PMP-22 deletion)^[55] or tomaculous neuropathy	17p11; AD	All ages	Episodic weakness and numbness	Conduction Blocks
Dejerine-Sottas-syndrome (DSS) or HMSN-3^[56]	P₀; AR PMP-22; AD 8q23; AD	2 y	Severe weakness	< 10 m/s
Congenital hypomyelination (CH)	P₀, EGR-2 or PMP-22 AR	Birth	Severe weakness	< 10 m/s
CMT-4A^[57]	8q13; AR	Childhood	Distal weakness	Slow
CMT-4B (myotubularin- related protein 2)^{[58, 59]}	11q23; AR	2-4 y	Distal and proximal weakness	Slow
CMT-4C	5q23; AR	5-15 y	Delayed walking	14-32 m/s
CMT-4D (Lom) (N-myc downstream- regulated gene 1)	8q24; AR	1-10 y	Distal muscle wasting, foot and hand deformities	10-20 m/s
CMT-4E (EGR-2)	10q21; AR	Birth	Infant hypotonia	9-20 m/s
CMT-4G	10q23.2; AR	8-16 years	Distal weakness	9-20 m/s
CMT-4H	12p11.21-q13.11; AR	0-2 years	Delayed walking	9-20 m/s
CMT-4F	19q13; AR	1-3 y	Motor delay	Absent
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