Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease Clinical Presentation
- Author: Divakara Kedlaya, MBBS; Chief Editor: Robert H Meier III, MD more...
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 following image).[2, 3]
Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A. - 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]
Causes
Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM).
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; AD* | First decade | Distal weakness | 15-20 m/s |
| CMT-1B (P0 -MPZ)** | 1q22; AD | First decade | Distal weakness | < 20 m/s |
| CMT-1C (non-A, non-B) | 16p13;AD | Second decade | Distal weakness | 26-42 m/s |
| CMT-1D (EGR-2)# | 10q21; AD | First decade | Distal weakness | 15-20 m/s |
| CMT-1E | 17p11; AD | First decade | Distal weakness, deafness | 15-20 m/s |
| CMT-1F | 8p21; AD | First decade | Distal weakness | 15-20 m/s |
| CMT-X (connexin-32) | Xq13; XD‡ | Second decade | Distal weakness | 25-40 m/s |
| CMT-2A | 1p36; AD | 10 y | Distal weakness | >38 m/s |
| CMT-2B | 3q; 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 | ?; AR† | 15-25 y | Distal weakness, pyramidal features | Axon loss; N |
| CMT-2I | 1q22; AD | 47-60 y | Distal weakness | Axon loss; N |
| CMT-2J | 1q22; AD | 40-50 y | Distal weakness, hearing loss | Axon loss; N |
| CMT-2K | 8q13-q21; AR | < 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) or tomaculous neuropathy | 17p11; AD | All ages | Episodic weakness and numbness | Conduction Blocks |
| Dejerine-Sottas-syndrome (DSS) or HMSN-3 | 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 | 8q13; AR | Childhood | Distal weakness | Slow |
| CMT-4B (myotubularin- related protein 2) | 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). 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
- HMSN-II (CMT-2)
- Roussy-Levy syndrome - Autosomal dominant with essential tremor
- HMSN-VI - With optic atrophy
- HMSN-VII - With retinitis pigmentosa
- Prednisone-responsive hereditary neuropathy
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| CMT Type | Chromosome; Inheritance Pattern | Age of Onset | Clinical Features | Average NCVs§ |
| CMT-1A (PMP-22¶ dupl.) | 17p11; AD* | First decade | Distal weakness | 15-20 m/s |
| CMT-1B (P0 -MPZ)** | 1q22; AD | First decade | Distal weakness | < 20 m/s |
| CMT-1C (non-A, non-B) | 16p13;AD | Second decade | Distal weakness | 26-42 m/s |
| CMT-1D (EGR-2)# | 10q21; AD | First decade | Distal weakness | 15-20 m/s |
| CMT-1E | 17p11; AD | First decade | Distal weakness, deafness | 15-20 m/s |
| CMT-1F | 8p21; AD | First decade | Distal weakness | 15-20 m/s |
| CMT-X (connexin-32) | Xq13; XD‡ | Second decade | Distal weakness | 25-40 m/s |
| CMT-2A | 1p36; AD | 10 y | Distal weakness | >38 m/s |
| CMT-2B | 3q; 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 | ?; AR† | 15-25 y | Distal weakness, pyramidal features | Axon loss; N |
| CMT-2I | 1q22; AD | 47-60 y | Distal weakness | Axon loss; N |
| CMT-2J | 1q22; AD | 40-50 y | Distal weakness, hearing loss | Axon loss; N |
| CMT-2K | 8q13-q21; AR | < 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) or tomaculous neuropathy | 17p11; AD | All ages | Episodic weakness and numbness | Conduction Blocks |
| Dejerine-Sottas-syndrome (DSS) or HMSN-3 | 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 | 8q13; AR | Childhood | Distal weakness | Slow |
| CMT-4B (myotubularin- related protein 2) | 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 | ||||
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