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

Updated: May 22, 2018
  • Author: Timothy C Parsons, MD; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Presentation

History

Despite wide genetic heterogeneity, the phenotypes of the different CMT subtypes are relatively similar. [67] Dysfunction of all mutated proteins, even those involved in myelin formation, leads to the common end point of length-dependent axonal degeneration. Most patients present in the first 2 decades of life with some combination of distal muscle wasting and weakness (especially in the peroneal-innervated muscles) and distal sensory loss in the legs. History and examination alone are not sufficient to distinguish between predominantly demyelinating and predominantly axonal forms. [68, 66] Inheritance is usually dominant, but may also be X-linked or sporadic.

Patients with CMT can present with many symptoms and signs, although motor symptoms predominate over sensory symptoms in all age groups. Onset may occur in infancy, with a delay in motor milestones, a gait or running impairment with otherwise normal rate of development, or with toe walking. [69] Adolescents may present with steppage gait, ankle injuries, or deformities like pes cavus or thin lower legs. Family members familiar with other affected relatives may bring children to medical attention based on other nonspecific motor problems. [65] Some patients with lifelong mild symptoms may not seek medical care until they experience frequent tripping or imbalance in late life, and only close questioning will reveal any evidence of prior impairment. [66] Asymptomatic patients can be detected during screening after a relative has been diagnosed.

  • Sensation is often experienced as normal, and positive sensory symptoms such as dysesthetic pain are not as common as with acquired peripheral neuropathies. Pain of musculoskeletal origin or from entrapped nerves or compressed nerve roots is more common. [70, 65]

  • Gait is impaired by distal weakness but usually remains independent; proximal weakness only affects a minority of patients. [71, 66]

  • As mentioned earlier, clinical progression is slow and any acceleration should lead to a workup for superimposed conditions. [64]

  • Family history is usually suggestive of autosomal dominant inheritance, but the complete lack of a family history does not rule out any of the CMT subtypes. Recessively inherited mutations may have little to no family history, and sporadic patients due to de novo mutations are common. [72, 42]

Some features of different subtypes that deviate from the standard history given above are listed below.

CMT1B

Rather than presenting with a classical Charcot-Marie-Tooth phenotype, patients seem to manifest signs and symptoms according to 1 of 2 phenotypes: either prior to walking or around age 40. [41]

CMT2

As with other forms of CMT, clinical variation is common between and within CMT2 families, but in general, weakness is often less marked and onset is later. [66] CMT2 with later onset can be difficult to distinguish from acquired axonal neuropathies, especially when the family history is unclear, because of the lack of distinctive physical examination and electrophysiologic findings.

Dejerine-Sottas

Onset of upper and lower extremity weakness and sensory loss occurs in infancy and tends to be not only earlier than other forms of CMT, but more severe. Dominantly inherited, recessively inherited, and sporadic cases exist.

CMTX

Symptoms due to distal weakness typically begin in childhood, as in CMT1. Weakness and atrophy of hand muscles and positive sensory phenomena are more prominent in CMTX. Female carriers may be asymptomatic. Those affected have a later onset and are less severely affected than males. [47] There is enough clinical overlap with CMT1 that the diagnosis should be considered in all patients who have a typical CMT story, especially if the family history lacks clear male-to-male transmission.

CMT4

Autosomal recessive forms are rare, often confined to small ethnic groups, and are clinically heterogeneous. Not only are other organ systems frequently involved, but as with many recessive conditions, clinical manifestations are often severe by comparison to the dominantly inherited forms.

Atypical

In a series of 61 patients with CMT1A, 34 patients presented with the classic Charcot-Marie-Tooth phenotype, and 27 patients had additional features such as CNS signs, prominent muscle cramps, tremor, or focal peripheral neuropathies. [65] CNS features should not be assumed to be due to CMT and always warrant further investigation.

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Physical

Nerves

Enlarged and excessively firm nerves were found in 17 of 67 patients in Dyck and Lambert’s original series [4] and are often visible in the superficial cervical nerves and palpable in the arms in patients with hypertrophic, demyelinating forms of CMT.

Motor

Motor signs tend to develop before sensory signs. Due to length dependent axonal degeneration, weakness and atrophy is first seen in intrinsic foot muscles, followed by ankle and toe dorsiflexors. This mismatch between strength in the affected peroneal-innervated muscles and the less affected tibial-innervated muscles leads to the typical high arched feet, hammer toes, and difficulty with heel walking seen early on physical examination. [4, 73]

Muscle atrophy and weakness progress proximally over time, and as distal leg muscle bulk is lost, the legs assume a characteristic “inverted champagne bottle” appearance. The distal thighs and hands can become involved, and weakness of intrinsic hand muscles gives rise to the typical “claw hand” deformity seen in CMT. Areflexia is frequent, especially distally. Proximal weakness only affects a small minority of patients. [71, 66] Gait is impaired by muscle weakness, foot deformities that result from weakness, and proprioceptive loss. Despite these obstacles, most patients remain ambulatory. [63]

Bienfait and colleagues found that CMT2 had later disease onset and had a lower incidence of areflexia, foot deformities, and weakness of foot dorsiflexors, but concluded that there were no robust clinical signs to differentiate CMT1 from CMT2. [74] Men affected by CMTX are more likely to show hand weakness with early thenar atrophy and relative preservation of tendon reflexes. [47]

Sensory

Sensory impairment tends to follow motor impairment, and remains less severe. Patients may remain asymptomatic despite substantial sensory loss on examination. Dyck and Lambert found large-fiber modalities like proprioception and vibratory sense to be affected out of proportion to other modalities, but Harding and Thomas found pansensory loss. [4, 66]

Orthopedic

Foot deformities are common in CMT but vary even among relatives in the same family, and are not specific. High arches, flat feet, hammer toes, and tight Achilles tendons can be seen. These deformities become more prevalent with age. [4]

Other

Some of the CMT2 subtypes have unusual associated clinical features that are of interest and may help with diagnosis.

  • CMT2B - Poorly healing foot ulcers [75]

  • CMT2C - Diaphragm weakness and vocal cord paralysis [76]

  • CMT2D - Weakness and atrophy that is more severe in the hands than in the feet [54]

  • CMT2 associated with MPZ mutation - Late-onset axonal polyneuropathy with prominent sensory involvement, pupillary abnormalities, and hearing loss [77]

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Causes

Please see the Pathophysiology section for a more thorough overview.

  • CMT1A -PMP22 duplication on chromosome 17

  • CMT1B -MPZ mutation on chromosome 1

  • CMT2A - MFN2 mutation on chromosome 1 (most common cause)

  • CMTX1 -Cx32 on the X chromosome

  • Dejerine-Sottas - Linked to mutations in MPZ, PMP22, Cx32, or EGR2 on chromosome 10

  • Dominantly inherited intermediate CMT - Genetically heterogeneous (Specific Cx32, MPZ, GDAP1, tyrosyl-tRNA synthetase (YARS), and neurofilament light chain (NF-L) mutations can cause velocities and morphologic changes that fall between CMT1 and CMT2. [78, 79, 80, 81, 82] )

Many mutations are not found with current genetic testing. Out of 153 patients with inherited neuropathies, a mutation was not found in 50 (32.7%). [42] A more recent study of 6 families with late-onset axonal neuropathies showed no mutations in an extensive screen of 9 genes known to cause CMT. [83]

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