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

Background

Slowly progressive distal weakness, muscle atrophy, and sensory loss due to an inherited peripheral neuropathy was described independently in 1886 by Charcot and Marie in France and by Tooth in England.^{[1, 2]} A few years later, Dejerine and Sottas recognized and described a more severe, infantile form of inherited neuropathy.^[3]

As more heterogeneity and overlap in clinical appearance, pathological features, and forms of inheritance were recognized in the following decades, an improved classification system was needed to avoid confusion. Starting in the 1950s, the clinical use of nerve conduction studies combined with pathological information allowed patients to be divided into 2 major groups.

• Group 1 was characterized by slow nerve conduction velocities and evidence of hypertrophic demyelinating neuropathy.
• Group 2 was characterized by relatively normal nerve conduction velocities and axonal degeneration.

Most of the families demonstrated autosomal dominant inheritance, and affected relatives in each family could all be categorized in the same group.^{[4, 5, 6]}

In 1975, Dyck expanded the classification system of what was now known as hereditary motor and sensory neuropathy (HMSN) to include forms with additional features.^[7]

• HMSN types 1A and 1B (dominantly inherited hypertrophic demyelinating neuropathies)
• HMSN type 2 (dominantly inherited neuronal neuropathies)
• 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 spastic paraplegia)
• HMSN type 6 (with optic atrophy)
• HMSN type 7 (with retinitis pigmentosa)

In the 1980s it became clear that this revised classification system, based on clinical and electrophysiologic characteristics, was inadequate to describe the genetic heterogeneity within each of these categories. Linkage studies revealed Charcot-Marie-Tooth type 1 loci on both chromosome 1^[8] and chromosome 17^[9] , and X-linked and recessively inherited forms were increasingly recognized.

In 1991, 2 groups showed that the most common form of CMT1, known as CMT1A, was associated with a duplication within chromosome 17p11.2.^{[10, 11]} This duplication is believed to be in the peripheral myelin protein 22kD (PMP22) gene, and overexpression of the gene product appears to be causative, since a gene dosage effect has been demonstrated.^[12] It is estimated that this duplication is responsible for about 70% of CMT1 cases^[13] and the vast majority of CMT1A cases, with rare exceptions such as partial 17p trisomy.^{[12, 14]}

Other Charcot-Marie-Tooth genes were discovered in the 1990s. The second most common form of CMT1 (CMT1B) and some cases of Déjerine-Sottas syndrome were found to be associated with mutations in the myelin protein zero (MPZ) gene on chromosome 1.^{[15, 16, 17]} The most common form of CMTX (CMTX1), was found to be due to mutations in the gap junction protein beta 1/connexin 32 (Cx32) on chromosome Xq13.1.^[18] Interestingly, hereditary neuropathy with liability to pressure palsies (HNPP) was found to be associated with a deletion in the PMP22 gene^[19] , but this syndrome will not be reviewed here.

The difficulty classifying Charcot-Marie-Tooth subtypes is made more evident by the fact that mutations of each of these genes have been associated with multiple, overlapping phenotypes. For instance, myelin protein zero mutations are associated CMT1B, Déjerine-Sottas syndrome, and the axonal CMT2 phenotype.^{[20, 21, 22]} Déjerine-Sottas syndrome has been associated with mutations or deletions in PMP22, myelin protein zero, and early growth response 2 (EGR2) genes.^{[15, 23, 24]}

In addition, the boundaries between even the major types of CMT are not always as clear as the original series suggested. In the mid 1970s, Bradley, Davis, and Madrid performed a similar study to those performed by Dyck and Lambert, Thomas and Calne, and Buchthal and Behse, and proposed a CMT classification that included an intermediate group characterized by median motor nerve conduction velocities of 25-45 m/sec and intermediate pathological changes.^{[25, 26, 27]} A study performed by Brust, Lovelace, and Devi suggested a bimodality in nerve conduction velocities among type 1 patients, again raising the possibility of an intermediate form^[28] , but these were considered exceptions and were never incorporated into the major classification systems. In 1985, a large kinship with an intermediate form was described.

In 1998, sequencing of the PMP22 and MPZ genes in this kinship did not reveal mutations, underscoring that it is a distinct entity.^{[29, 30]} Several associated mutations have been discovered since, and as with other forms of CMT, these studies have demonstrated genetic heterogeneity.

Given what is now known about clinical and genetic heterogeneity, a system that takes both clinical and genetic characteristics into account is not possible. This review will use the following system:

• CMT1 is a dominantly inherited, hypertrophic, predominantly demyelinating form.
• CMT2 is a dominantly inherited predominantly axonal form.
• Dejerine-Sottas is a severe form with onset in infancy.
• CMTX is inherited in an X-linked manner.
• CMT4 includes the various demyelinating autosomal recessive forms of Charcot-Marie-Tooth disease.

• References

Pathophysiology

CMT1A

The extra PMP22 gene copy within the 1.5 mB duplication on chromosome 17 is believed to cause most cases.^[12] PMP22 is a 160 amino acid integral membrane protein that is expressed at high levels in myelinating Schwann cells, localizing to compact myelin and making up 2–5% of total myelin protein.^{[31, 32]} PMP22 expression in CMT1A nerve biopsies is increased^[33] , but the process by which protein overexpression actually causes the Charcot-Marie-Tooth phenotype remains unclear.

Abnormal expression of PMP22 seems to alter Schwann cell growth and differentiation both in vivo and in vitro, and may impair the ability of the Schwann cell to maintain normal myelin stability and turnover. A putative interaction between PMP22 and MPZ could play a role in maintaining myelin compaction and stability, and an imbalance in one could explain why changes in expression in either gene can lead to the clinically and pathologically indistinguishable CMT1A and CMT1B phenotypes.^[34]

Despite the evidence of demyelination found on pathological and electrophysiological studies and the more recent implication of myelin proteins, the signs and symptoms of weakness and sensory loss are likely the result of axonal degeneration rather than demyelination. Anatomical evidence of progressive length-dependent axonal loss following demyelination in CMT1 exists.^[35] Children with CMT1A have slow nerve conduction velocities in the first years of life, generally preceding the development of signs and symptoms.^[36] Krajewski and colleagues demonstrated that compound motor action potential amplitudes correlate best with weakness in CMT1A rather than nerve conduction velocities.^[37]

In vivo studies of CMT1A patients have demonstrated altered axonal excitability, in the form of elevated stimulation thresholds and a markedly abnormal threshold electrotonus. These findings suggested that demyelination causes exposure of fast K+ channels, which are normally sequestered under the myelin.^[38]

CMT1B

Myelin protein zero is an integral type I membrane protein, and is the most abundant structural protein of compact peripheral nerve myelin.^{[39, 15]}

More than 80 mutations in myelin protein zero have been described. Most are associated with the typical CMT1B phenotype, but correlations have been found with other clinical phenotypes including CMT2, Dejerine Sottas syndrome, and congenital hypomyelination neuropathy.^{[40, 41]}

Predominantly axonal and predominantly demyelinating forms appear to be due to different mutations in the same gene. Mutations that introduce a charged amino acid, removed or added a cysteine residue, or altered an evolutionarily conserved amino acid alter the tertiary structure of the MPZ protein as a result and lead to the more severe early onset phenotype. As with diseases of PMP22 expression, the mechanism for either demyelinating or axonal forms remains unclear, but may be due to impaired myelin-axon interaction.^{[42, 43, 44]}

CMTX

CMTX is caused by mutations in connexin32/Gap Junction Beta 1 (Cx32 or GJB1), which maps to chromosome Xq13. Connexins assemble to form intercellular gap junctions, which allow the diffusion of ions and small molecules across apposed cell membranes. Connexin 32 is expressed in many tissues, but is localized in the myelin sheath of large diameter fibers near the nodes of Ranvier.^{[18, 45]}

Axonal and demyelinating changes are mixed in CMTX. Men are clinically and electrophysiologically more severely affected than affected women. Interestingly, nerve conduction velocities in affected women can vary markedly within the same limb, in contrast to men whose conduction velocities tend to resemble the diffusely slow velocities seen in CMT1. This may be partly explained by X-inactivation of Schwann cell precursors during development. The mechanisms by which different Cx32 mutations cause CMT1X are not fully understood. Phenotype-genotype correlations in CMT1X will be difficult to establish because of phenotypic variability both within and between kindreds.^{[46, 47, 48]}

CMT2

The most common mutation responsible for CMT2 has been found in the mitochondrial GTPase mitofusin 2 (MFN2) gene.^[49] This is referred to as CMT2A.

MFN2 is a dynamin family GTPase that spans the outer mitochondrial membrane and is believed to primarily be involved in mitochondrial docking, tethering, and fusion. Recent data were supportive of a mitochondrial trafficking insult as a possible mechanism of length-dependent axonal neuropathy.^{[50, 51]}

CMT4

The causes of CMT4 are diverse and very rare and will not be reviewed here.

• References

Epidemiology

Frequency

International

CMT is the most common inherited neuromuscular disorder. Estimates of the frequency of Charcot-Marie-Tooth disease vary widely. In 1974, Skre and colleagues reported a prevalence of 1 case per 2,500 individuals. A worldwide meta-analysis estimated a prevalence of 1 per 10,000 individuals, and a prevalence of 10.8 per 100,000 was found in western Japan.^{[52, 53]}

Charcot-Marie-Tooth disease type 1 accounts for about two thirds of CMT cases. Of these, 70% are due to duplications in PMP22. Duplications in PMP22 therefore account for roughly half of all combined CMT subtypes.^{[13, 54]} CMT1B makes up about 5% of CMT1 and about 1.6% of all CMT cases.^{[54, 55]}

Charcot-Marie-Tooth disease type 2 accounts for about 22% of CMT cases.^[54] CMT2A (MFN2 mutation) has been estimated to account for 11-23% of all CMT2 cases.^[56]

Charcot-Marie-Tooth disease type X accounts for about 16% of CMT cases.^[54] CMTX1 (Cx32 mutation) accounts for most CMTX cases and may be the second most common cause of CMT overall, at 7-20%.^{[42, 43]}

A 2016 systematic review of previously published epidemiologic Charcot-Marie-Tooth disease studies showed significant variation in the worldwide prevalence of CMT dependent on country, region, and/or ethnicity.^[57]

Mortality/Morbidity

Most people with CMT have a normal life expectancy, the exceptions being patients with respiratory involvement or severe disability. Disability varies greatly both between and within families, and can range from asymptomatic with minimal examination findings to severe. Marked differences in clinical severity have even been reported in monozygotic twins with CMT1A (despite similar nerve conduction velocities)^[58] and myelin protein zero mutations^[59] .

A 2001 study showed that 44% of CMT1A patients were significantly disabled, and 18% were depressed. It was estimated that CMT1 patients suffer emotional stress similar to patients with stroke and comparable disability.^[60]

CMT is nearly always slowly progressive. A longitudinal study showed steady progression in nerve conduction velocity and disability, and severity could be predicted based on nerve conduction velocity abnormalities in childhood.^[61] Killian and colleagues studied nerve conduction velocities and neurologic examinations in 8 members of a single family over 22 years and found minimal progression of disability.^[62] Another study of 43 patients with CMT2 over 5 years documented slow progression of weakness and disability, and most patients remained ambulatory.^[63]

As CMT is relatively common, it can occur with other inherited or acquired neuromuscular conditions. If progression accelerates, these possibilities should be pursued.^[64]

Race

No racial predilection is recognized in the common forms of CMT. Rare, recessively inherited forms (CMT4) cluster in particular ethnic groups.

Sex

As expected, CMTX affects males earlier, more frequently, and more severely than females. Other forms of CMT do not show predilection for either sex.

Age

Onset is usually in childhood. Thomas and colleagues found that 75% of patients with CMT1A developed clinical evidence of disease before age 10, and 85% before age 20.^[65] Some patients experience very slow progression of mild, lifelong symptoms, and may seek medical attention only late in life.

There are patients and families in which CMT has a late onset, as late as the fifth or sixth decade in some MPZ mutations, and even as late as the seventh decade in CMT2.^{[41, 66]}

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Prognosis

Life expectancy is not altered in all but the most severe cases. Disability is highly variable within and between kindreds and cannot be predicted with any certainty, even among siblings. More marked disability does seem to be linked to earlier onset.

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Patient Education

The CMT Association is a nonprofit organization concerned with patient support, public education, and promotion and support of research into the cause and treatment of CMT.

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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]

• References

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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Complications

Patients with CMT are more susceptible to compression neuropathies and radiculopathies. Sprains and fractures are disabling and avoidable.

Medication toxicity is important to recognize when it occurs so that the offending agent can be discontinued. Preventing exposure to neurotoxic medications when possible is preferable. Weimer and Podwall found 26 case reports of CMT and toxic medication effects; 22 of these reports pertained to vincristine, 2 implicated nucleoside analogs, 2 cisplatin, 1 carboplatin, and 1 taxoids. The 22 reports about vincristine included 30 patients, and 26 of these patients had undiagnosed CMT. Only 10 had overt clinical signs or a known close relative with CMT, and many of them developed symptoms after only 1 or 2 doses.^[102]

Vinca alkaloid (Vincristine) is considered a definite high-risk medication for the development of CMT (including asymptomatic CMT). Prior to use, all patients should be asked about a family history of neuropathy and joint deformity and examined for clinical signs of a chronic neuropathy.

Commonly used medications that pose moderate to significant risk include the following:

• Amiodarone (Cordarone)
• Bortezomib (Velcade)
• Cisplatin and Oxaliplatin
• Colchicine (extended use)
• Metronidazole (extended use)
• Nitrofurantoin
• Pyridoxine (mega dose of Vitamin B-6)
• Taxols (paclitaxel, docetaxel)

A complete list of potentially neurotoxic drugs can be found at the Charcot-Marie-Tooth Association.

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Laboratory Studies

The workup should be primarily geared toward the identification or exclusion of a treatable neuropathy, including tests that address the causes of neuropathy. If a clear family history is identified and CMT has not been confirmed genetically, genotyping is warranted. Ascertaining the presence of a demyelinating or axonal form with nerve conduction studies, and establishing inheritance pattern with a pedigree can narrow the differential diagnosis and reduce the number of needed tests. De novo mutations are not rare, and genetic counseling can be pursued even in the absence of a family history of neuropathy.

Despite the lack of available treatments, genotyping is useful in providing information for prognosis and genetic counseling.^[84]

A negative genetic test does not exclude the diagnosis, especially in axonal forms. Beinfait and colleagues found mutations in only 3 out of 18 families (61 patients) with CMT2, and Bennett and colleagues found no mutations in 6 families with late-onset (median age 57), predominantly axonal neuropathies.^{[71, 83]}

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Imaging Studies

Nerve root hypertrophy can be directly imaged with an MRI of the spine, which may help in distinguishing hereditary from acquired demyelinating neuropathy.^[85] Sonography of peripheral nerves can play a similar role.^[86]

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Other Tests

Examination of the CSF is usually normal except for an elevated CSF protein. More marked elevations of protein are routinely seen in Dejerine-Sottas syndrome and may be more common in forms of CMT with MPZ mutations.^{[4, 87, 43]}

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Procedures

Electrodiagnostic studies are critical to narrow the differential diagnosis.

Harding and Thomas found median nerve conduction velocities below 38 m/s in patients with CMT1 and above 38 m/s in patients with CMT2.^[66] Thomas and colleagues found median nerve conduction velocities averaged 19.9 m/s and ranged from 5-34 m/s in patients with CMT1. Values in the lower limb nerves were more difficult to obtain because of denervation of small foot muscles, but peroneal and tibial nerve conduction velocity averaged 17 m/sec and ranged between 10-22 m/sec. Sensory nerve action potentials were usually absent or severely reduced in amplitude, but when present, showed similar reductions in velocity (mean 22.9 m/sec).^[65] Dyck and Lambert had previously shown that ulnar nerve conduction velocities were even more severely affected in patients with Dejerine-Sottas syndrome, consistently measuring less than 10 m/s.^{[4, 87]}

Lewis and Sumner compared 18 patients with CMT1 to 40 patients with chronic acquired demyelinating neuropathies, and found that slowing was uniform both along individual nerves and between different nerves in an individual patient with CMT1. There was no evidence of dispersion or conduction block in any of these patients. They concluded that this pattern serves to distinguish patients with CMT1 from patients with CIDP or AIDP, who demonstrate more multifocality. These findings were confirmed in a larger study of 129 patients with CMT1.^{[88, 89]}

Female carriers with CMTX often demonstrate intermediate nerve conduction velocities, averaging 45 m/sec (ranging from 26-61 m/sec), which is significantly faster than CMT1A. Affected men, by comparison, have slower conduction velocities, averaging 31 m/sec, also significantly higher than those found in CMT1. The combination of intermediate conduction velocities and more rapid velocities in affected females suggests CMTX.^[78] Interestingly, Dubourg and colleagues found that the difference between the median and ulnar motor nerve conduction velocities in affected female patients differed significantly when compared to the uniform velocities found in CMT1 and healthy subjects. Men with CMTX also demonstrated uniform slowing.^[48]

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Histologic Findings

CMT1

Dyck and Lambert observed an abnormally large transverse fascicular area in biopsied nerves, but a reduction in the number of myelinated fibers both per unit of fascicular area and per nerve. Large onion bulbs were seen, and there was marked variation in length and diameter of myelinated fiber internodes on teased fiber preparations, indicating chronic demyelination and remyelination. There was additional evidence of Wallerian degeneration in some nerve fibers, indicating concurrent axonal injury.^[4]

CMT1A

Sural nerve biopsies in patients with confirmed PMP22 duplications show nerve thickening and a reduction in myelinated fiber density even in the first year of life. As the first few years pass, active demyelination is prominent and onion bulbs are infrequent. By late childhood, active demyelination subsides and well-formed onion bulbs appear. There is loss of large fibers and a relative increase in small fibers as a result of regeneration of damaged axons.^[90]

CMT2

Behse and Buchthal demonstrated endoneurial areas to be normal. Onion bulbs were absent, and segmental demyelination was absent or rare on teased fiber analysis. The main abnormality was a reduction in the number of large fibers.^[91]

CMTX

Pathology of CMTX is mixed, as would be expected from electrophysiologic data. Hahn and colleagues found mild to moderate degeneration and loss of myelinated nerve fibers. Remaining fibers were surrounded by the thin myelin sheaths that would be expected with either repaired demyelination or regenerated nerve fibers. There were clusters of small fibers, indicating attempts at sprouting as part of the regenerative process. Teased fibers showed evidence of myelin instability in paranodal regions.^[47]

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Medical Care

Management of orthopedic complications is paramount.

• The common foot deformities of CMT can lead to discomfort, impaired ambulation, and disability and should be managed with physical therapy, which can be both preventive and therapeutic. Stretching, exercises, and adaptive maneuvers can all be helpful.
• Ankle weakness and instability can be treated with boots or orthoses, and can ease ambulation, keep patients active, and prevent potentially disabling injuries such as sprains or ankle fractures.
• While dysesthetic pain is not typical, it can occur, and responds to medications commonly used for neuropathic pain such as tricyclic antidepressants or anticonvulsants.
• More commonly, patients experience local musculoskeletal pain resulting from abnormal posture or overuse of certain muscle groups brought on by weakness or joint deformity.^[92] Joint deformity itself may be painful. NSAIDs and acetaminophen are first-line therapies.

There are no definitive medical therapies for CMT. Steroid responsive forms of Charcot-Marie-Tooth disease were originally recognized by Dyck in 1982. This finding has also been reported several times in patients with MPZ mutations and atypical features such as elevated CSF protein.^{[93, 94]} These may be patients with superimposed CIDP.^[95] It is unlikely that immunomodulatory therapy will be effective in typical cases of CMT.

Ascorbic acid has been shown to repress PMP22 gene expression in a dose-dependent manner, and multicenter international trials of long-term ascorbic acid treatment for CMT1A are underway.^{[96, 97]} The CMT-TRIAAL and CMT-TRAUK trial was a multicenter, 2-year trial to test the efficacy and tolerability of ascorbic acid in patients with CMT1A.^[98] The results suggest that ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A.

Studies in animal models have shown reduction in PMP22 mRNA levels and clinical improvement after treatment with progesterone antagonists. These findings may lead to a clinical trial.^[99] Clinical tools have been developed to follow progression of the disease in preparation for therapeutic trials.^[100]

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Surgical Care

If foot deformities are disabling, patients may benefit from tendon transfers or lengthening (especially the Achilles tendon), hammer toe correction, and release of the plantar fascia. The ankle can be fused to provide stability. Ideally, conservative measures such as those mentioned above, if instituted early, can prevent surgery.^[101]

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Consultations

See the list below:

• Physiatrists
• Physical therapists
• Orthotics specialists
• Podiatrists
• Genetic counseling

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Diet

A balanced diet is important to prevent obesity and diabetes, both of which can compound disability and pain and contribute to the development of certain entrapment neuropathies.

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Activity

Activity as tolerated. Moderate activity is recommended. Overexertion should be avoided.

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Prevention

Even if patients and carriers were to abstain from having children, CMT mutations occur de novo with some regularity and the disease would remain prevalent. Boerkoel and colleagues found that one third (6 of 16) of the point mutations detected in their series of 159 patients represent de novo events.^[42]  As examined by Hoogendijk and colleagues, of 10 patients with CMT1 and no family history, 9 of them had PMP22 duplications.^[72]

Prevention should focus on avoiding conditions that can cause or worsen generalized or focal neuropathy, such as diabetes mellitus, vitamin deficiency, medication toxicity, and prolonged immobilization of limbs during surgery.

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Medication Summary

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

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Ibuprofen (Motrin, Ibuprin)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Naproxen (Aleve, Naprelan, Naprosyn, Anaprox)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Class Summary

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.

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Nortriptyline (Pamelor, Aventyl HCl)

• Dosing, Interactions, etc.

Clinical Context:  Has demonstrated effectiveness in treatment of pain.

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Amitriptyline (Elavil)

• Dosing, Interactions, etc.

Clinical Context:  Has demonstrated effectiveness in treatment of pain.

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Class Summary

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.

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Paroxetine (Paxil)

• Dosing, Interactions, etc.

Clinical Context:  Considered an alternative to TCAs, with fewer adverse anticholinergic and cardiovascular effects.

• References

Class Summary

Serotoninergic antidepressants have had mixed reviews in the literature. Some of them have been reported to relieve painful sensory symptoms.

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Carbamazepine (Tegretol)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Gabapentin (Neurontin)

• Dosing, Interactions, etc.

Clinical Context:  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.

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Class Summary

These medications reduce neuronal excitability and prevent neuronal discharges associated with pain sensation.

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