Charcot-Marie-Tooth Disease

                                    Dr. KS Dhillon

Introduction

Charcot-Marie-Tooth Disease (CMT), also known as peroneal muscular atrophy, is a common autosomal dominant hereditary motor sensory neuropathy. It is characterized by inherited neuropathies that have no known metabolic derangements [1,2].  These disorders are distinct from hereditary sensory neuropathies and hereditary motor neuropathies. 

In 1886, Professor Jean-Martin Charcot of France and his student Pierre Marie published the first description of distal muscle weakness and wasting beginning in the legs. They called it peroneal muscular atrophy.

Howard Henry Tooth described the same disease. He called the condition peroneal progressive muscular atrophy. Tooth was the first to attribute symptoms correctly to neuropathy rather than to myelopathy.

Hoffman in 1912, identified a case of peroneal muscular atrophy with thickened nerves. This disease was referred to as Hoffman disease. Later it was known as Charcot-Marie-Tooth-Hoffman disease.

In 1968, CMT disease was subdivided into two types, CMT 1 and CMT 2, based on pathologic and physiologic criteria. It has been subdivided further based on the genetic cause of the disease. With the advent of genetic testing, all of the diseases currently falling under the heading of CMT syndrome will eventually become distinguishable [3].

All routine laboratory tests are normal in individuals with CMT disease.  Special genetic tests are available for some types.

Electromyography (EMG) and nerve conduction studies are done if CMT disease is suspected. Magnetic resonance imaging (MRI) of lower-limb muscles may be done to follow disease progression. Nerve biopsy is rarely indicated. It is sometimes done in cases where there is diagnostic dilemma.

Currently, there is no proven medical treatment to reverse or slow the natural disease process. Orthopedic surgery may be required for severe pes cavus deformities, scoliosis, and other joint deformities. Treatment depends on the age of the patient and the cause and severity of the deformity. Surgical procedures include soft-tissue procedures, osteotomy, and joint-stabilizing procedures. 

Pathophysiology

CMT disease is a heterogeneous group of genetically distinct disorders that have similar clinical presentations [1].  Their genetic spectrum spans more than 80 genes [4]. The gene discovery has been revolutionized by new high-throughput molecular technologies [5].  CMT disease is divided into several types:

CMT 1

CMT type 1 is a disorder of peripheral myelination. It results from a mutation in the peripheral myelin protein-22 gene [6,7,8]. Mutations in the gene encoding the major PNS myelin protein, myelin protein zero (MPZ), account for 5% of the patients with CMT disease. The mutation results in abnormal myelin that is unstable and breaks down spontaneously. This process results in demyelination, which leads to uniform slowing of conduction velocity. Slowing of conduction in motor and sensory nerves can cause weakness and numbness. However, Krajewski et al suggested that neurologic dysfunction and clinical disability in CMT 1A are caused by loss of or damage to the large-diameter motor and sensory axons [9,10,11].

Pain and temperature sensations are usually not affected because they are carried by the unmyelinated type C nerve fibers. In response to demyelination, the Schwann cells proliferate and they form concentric arrays of remyelination [12]. Repeated cycles of demyelination and remyelination form a thick layer of abnormal myelin around the peripheral axons. These changes cause an onion bulb appearance.

CMT 2

CMT type 2 primarily is a disorder of the axon. It is not a demyelinating disorder [7,13,14,15]. There is peripheral neuropathy through direct axonal death and wallerian degeneration. It is associated with mutations in the ATP1A1 gene [16].

CMT 3

CMT type 3 is also known as Dejerine-Sottas disease. It is characterized by infantile onset. There is severe demyelination with delayed motor skills. It is much more severe than CMT type 1. Marked segmental demyelination with thinning of the myelin around the nerve occurs.

CMT X and CMT 4

CMT 4 and CMT X (X-linked CMT) are also demyelinating neuropathies [17,18].  CMT X is associated with mutations in the PRPS1 gene [19].

Etiology

Hereditary motor and sensory neuropathies (HMSNs) are classified by Online Mendelian Inheritance in Man (OMIM). A broad division can be made between HMSNs with diffusely slow nerve conduction velocity and those with normal or borderline abnormal nerve conduction velocity [20].

HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy)

HMSN I (i.e. CMT 1) includes the following subtypes [6,7] :

• CMT 1A - Autosomal dominant band 17p11.2-12 is most common. It is milder than CMT 1B.

• CMT 1B - Autosomal dominant band 1q21-25.

• CMT 1C - Unknown autosome.

• CMT X1 - X-linked dominant band Xq13-21.

• CMT X2 and CMT X3 - X-linked recessive

• Autosomal recessive CMT 1 - Arm 8q.

HMSN III, also known as Dejerine-Sottas disease, hypertrophic neuropathy of infancy, and congenital hypomyelinated neuropathy, is inherited in an autosomal recessive manner.

HMSN IV also known as Refsum syndrome, and phytanic acid excess, has an autosomal recessive inheritance and is characterized by a tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebrospinal fluid protein.

HMSN with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)

HMSN II (i.e., CMT 2) includes the following subtypes [7,13,15] :

• CMT 2A - Band 1p35-36; typical type; no enlarged nerves; later onset of symptoms; feet are more severely affected than the hands.

• CMT 2B [14, 24] - Band 3q13-22; typical type with axonal spheroids.

• CMT 2C - Not linked to any known loci; there is diaphragm and vocal cord weakness.

• CMT 2D - Band 7p14; muscle weakness and atrophy are more severe in the hands than in the feet.

• Autosomal recessive CMT 2

In patients with HMSN V (i.e., spastic paraplegia) the upper limbs are normal and there are no sensory symptoms. The Roussy-Levy syndrome has an autosomal dominant inheritance and it is characterized by essential tremor. HMSN VI is characterized by optic nerve atrophy. HMSN VII is characterized by retinitis pigmentosa. Prednisone responsive hereditary neuropathy is the final HMSN of this type.

Epidemiology

United States statistics

In the United States, the prevalence of CMT disease is 1 person per 2500 population or about 125,000 people in the United States. The incidence of CMT 1 is about 15 persons per 100,000 population. The incidence of CMT 1A is 10.5 persons per 100,000 population or 70% of CMT 1. The incidence of CMT 2 is about 7 persons per 100,000 population. Individuals with CMT X represent at least 10-20% of people with CMT syndrome.

International statistics

In Japan, the prevalence is 10.8 cases per 100,000 population. In Italy it is 17.5 cases per 100,000 population; and in Spain, it is 28.2 cases per 100,000 population [21,22].

According to a Norwegian genetic epidemiologic study, CMT disease is the most common inherited disorder of the peripheral nervous system. Its estimated prevalence is 1 in 1214. CMT 1 and CMT 2 are equally frequent in their general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ, and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of de-novo mutations in CMT families was estimated to be 22.7%. Genotype-phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3), and MPZ (2) have been described [23].

Prognosis

Prognoses for the different types of CMT disease varies and it depends on clinical severity. CMT disease is a slowly progressive neuropathy that causes eventual disability secondary to distal muscle weakness and deformities. The motor performance deterioration in CMT 1A appears to accelerate after the age of 50 years [24]. In rare cases, phrenic nerve involvement of the diaphragm can cause breathing difficulties. CMT disease does not usually shorten the life expectancy.

Shy et al  [25] have developed a CMT neuropathy score, which is a modification of the total neuropathy score. It has been shown to be a validated measure of length-dependent axonal and demyelinating CMT disability.

History

Charcot-Marie-Tooth (CMT) disease patients have a significant family history. This history varies depending on the inheritance and penetrance pattern of the particular disease. Spontaneous mutations can also occur.

The age of presentation depends on the type of CMT disease. The onset usually occurs in the first two decades of life.

There is slowly progressing weakness in the distal limb muscles. It typically occurs in the lower extremities. The upper limbs are involved later. A subgroup of patients with CMT 1A can present with proximal muscle wasting and weakness.

The patients initially complain of difficulty in walking and frequent tripping due to foot and distal leg weakness. Frequent ankle sprains and falls are common. Parents often report that a child is clumsy or not very athletic. As the weakness becomes more severe, foot drop occurs. Gait in which the individual must lift the leg in an exaggerated fashion to clear the foot off the ground is also common.

Weakness of the intrinsic foot muscle often results in the foot deformity known as pes cavus [26]. Symptoms due to structural foot abnormalities include calluses, cellulitis, ulcers, and lymphangitis.

Weakness of the hand results in complaints of poor finger control, poor handwriting, difficulty using buttons and zippers, and clumsiness in handling small objects. A multidisciplinary assessment is needed to evaluate the impairment of manual function [27]. The hand can be affected at all ages in children with CMT 1A. Hand problems in these patients may be underrecognized in the early stages of the disease, causing potential delays in therapy [28].

Usually, patients do not complain of numbness. This may be because patients with CMT disease never had normal sensations. Therefore they simply do not perceive their lack of sensation.

Musculoskeletal and neuropathic types of pain may be present. Muscle cramping is also common [29]. Autonomic symptoms are usually absent. However, a few men with CMT disease have reported impotence.

Physical Examination

Physical examination may show distal muscle wasting in the legs. In long standing CMT disease bony abnormality such as pes cavus can be seen. The occurrence rate of pes cavus is about 25% in the first decade of life and 67% in later decades. Selective denervation of intrinsic foot musculature, rather than an imbalance of lower leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity [30]. Other foot deformities such as Charcot joints can also develop [31].

Spinal deformities such as thoracic scoliosis occur in 37-50% of patients with CMT 1. Deep tendon reflexes are markedly reduced or are absent. Vibration sensation and proprioception are also significantly decreased, but the patients usually have no sensory symptoms.

Patients can have sensory gait ataxia. A Romberg test is usually positive. The Romberg test is performed by asking the patient to stand upright with the feet together and the eyes closed. Pronounced swaying, or occasionally even toppling over, constitutes a positive test. The patient's unsteadiness increases when the eyes are closed.

There is an impairment of vestibular function. This can be measured by the video head impulse test. It may be reflected in worse postural balance, as measured by postural tests such as the modified clinical test of sensory integration in balance [32].

The sensation of pain and temperature is usually intact. Tremors are present in 30-50% of patients with CMT disease. There is sensory neuronal hearing loss in 5% of patients. Palpable and enlarged peripheral nerves are common. Phrenic nerve involvement with diaphragmatic weakness is rare but has been reported. Vocal cord involvement and hearing loss can also occur in rare forms of CMT disease.

Complications

Patients with CMT disease are susceptible to skin breakdown or burns, nonhealing foot ulcers, and, in severe cases, bony deformities of both feet because of the loss of protective sensation distally in all four limbs. Orthoses are required for the treatment of foot drop or to accommodate bony foot deformities. The orthoses themselves can become a source of skin breakdown secondary to associated distal sensory impairment if the orthoses are not fitted properly.

There can be an increased risk of complications during delivery in the

presence of maternal CMT disease. This increased risk is related to a higher frequency of emergency interventions during birth [33].

Diagnostic Considerations

Besides the conditions listed in the differential diagnosis there are diagnostic considerations and these include:

• Thyroid disease

• Diabetes mellitus

• Vasculitis

• Amyloid associated with chronic inflammation

• Occult malignancy

• Heavy-metal intoxication

• Acquired nongenetic causes of peripheral neuropathies

• Vitamin B12 deficiency

• Chronic inflammatory demyelinating polyneuropathy

• Motor neuropathy with multiple conduction block

• Other genetic neuropathies

• Familial brachial plexus neuropathy (i.e., hereditary neuralgic amyotrophy)

• Autosomal recessive genetic disorders, such as Refsum disease or metachromatic leukodystrophy

• X-linked recessive genetic disorders, such as adrenomyeloneuropathy or Pelizaeus-Merzbacher disease

• Amyloid neuropathies

• Hereditary ataxias with neuropathy (e.g., Friedreich ataxia)

• Blindness, seizures, dementia, and mental retardation are not part of Charcot-Marie-Tooth syndrome.

Differential Diagnoses

The differential diagnosis includes:

• Leprosy

• Neurosyphilis

• Alcoholism

• Pediatric HIV Infection

Laboratory Studies

Routine laboratory tests are usually normal in patients with CMT disease. Special genetic tests, however, are available for some types of CMT disease.

About 70 to 80% of CMT 1 cases are designated as CMT 1A. CMT 1A is caused by the alteration of the PMP22 gene (chromosome band 17p11). Pulsed-field gel electrophoresis and a specialized fluorescent in-situ hybridization assay are the most reliable genetic tests [34]. DNA-based testing for the PMP22 duplication (CMT 1A) is widely available. It detects more than 98% of patients with CMT 1A [35]. Point mutations in the PMP22 gene, which causes fewer than 2% of cases of CMT 1A, can be identified by this technique.

Genetic testing for CMT 1B is usually done for research purposes, but it is available in a few commercial laboratories. About 5-10% of CMT 1 cases are designated CMT 1B. They are caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosome band 1q22).

Mutations can occur, very rarely, in the EGR2 gene or the LITAF gene, causing CMT 1D and CMT 1C, respectively. 

The four major subtypes of CMT 2 are indistinguishable clinically. They are differentiated solely on the basis of genetic linkage findings. The chromosomal loci for CMT 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2L have been mapped. The genes have yet to be identified. Molecular genetic testing is available clinically only for CMT 2A, 2B1, 2E, and 2F.

Approximately 90% of cases of CMT X can be detected by means of molecular genetic testing of the GJB1 (Cx32) gene. Genetic testing is not available for other types of CMT disease.

A study by Millere et al [36] found that plasma neurofilament light chain concentrations were higher in patients with CMT than in healthy control subjects. They suggested that NfL might prove useful as a biomarker in the setting of suspected CMT disease.

Imaging Studies

In patients with CMT 1A, high-resolution ultrasonography of the median nerve and other peripheral nerves can serve as an adjunct to electrodiagnosis. Cartwright et al [37] characterized the ultrasound findings in peripheral nerves of patients with CMT 1B. They found that persons with CMT 1B had larger median and vagus nerves than healthy individuals.  There was, however, no difference in cranial nerve size between CMT 1B patients who had cranial neuropathies and those who did not [37].

Magnetic resonance imaging of lower-limb muscles can be used to follow the progression of the disease in patients with CMT neuropathies [38].

Electrodiagnostic Studies

Nerve conduction studies (NCV) and electromyography (EMG) are done if CMT disease is suspected [39]. Findings will vary, depending on the type of CMT disease. In demyelinating types such as CMT 1, diffuse and uniform slowing of nerve conduction velocities is seen. 

The Harding and Thomas criteria for diagnosing CMT 1 include a median motor NCV of less than 38 m/s, with a compound motor action potential (CMAP) and amplitude of at least 0.5 mV. There should be no focal conduction block or slowing present unless it is associated with other focal demyelinating processes. Sensory and motor nerve testing will show the same degree of marked slowing.

Absolute values for NCV will vary. They are approximately 20-25 m/s in CMT 1 and less than 10 m/s in Dejerine-Sottas disease and congenital hypomyelination. Nerve conduction slowing can also be found in asymptomatic individuals.

In neuronal/ axonal types, the NCV is usually normal, but markedly low amplitudes are noted in sensory and motor nerve studies. Increased insertional activity is seen as fibrillation potentials and positive sharp waves are observed. Motor unit potentials show decreased recruitment patterns and neuropathic changes.

Kitaoji et al [40] carried out a study (N = 58) aimed at evaluating the utility of the proximal-to-distal CMAP duration ratio for distinguishing between demyelinating CMT disease (n = 39) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP; n = 19). They found that this ratio could effectively make the distinction between these two conditions. 

Biopsy

Nerve biopsy is rarely indicated for the diagnosis of CMT disease when genetic testing is available. When there are diagnostic dilemmas biopsies sometimes are performed. Findings will vary in different types of CMT disease.

In patients with CMT 1 the peripheral nerves contain few myelinated fibers, and the intramuscular nerves are surrounded by rich connective tissue and hyperplastic neurilemma. Lengths of myelin along the fibers are atrophic. Concentric hypertrophy of the lamellar sheaths is also seen. Onion bulb formation is often seen and is made of circumferentially directed Schwann cells and their processes.

In patients with CMT 2, axon loss with wallerian degeneration is usually seen. In patients with CMT 3, or Dejerine-Sottas disease, demyelination with thinning of the myelin sheath is seen. Inflammatory infiltrate, indicating an autoimmune demyelinating process, is not present.

Histologic Findings

The histologic findings vary according to the type of CMT disease as follows:

• CMT 1 - The peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by a rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. There is concentric hypertrophy of the lamellar sheaths. Formation of the typical onion bulb is noted and is made of circumferentially directed Schwann cells and their processes.

• CMT 2 - Axonal degeneration is seen.

• CMT 3 - Demyelination with thinning of the myelin sheath is present. 

There should be no inflammatory infiltrate indicating an autoimmune demyelinating process.

Treatment

Nonoperative Therapy

There is no medical treatment that reverses or slows the natural disease process. There is nothing that can correct the abnormal myelin, prevent its degeneration, or prevent axonal degeneration [41]. There is an improved understanding of the genetics and biochemistry of the disorder and that offers hope for an eventual treatment. Studies in animals suggest that targeting myelin lipid metabolism with lipid supplementation may be a possible therapeutic approach in CMT 1A [42].

If the cavovarus deformity of the foot is flexible and correctible as tested with the Coleman block test an insert with lateral posting and recession under the first ray can provide mechanical stability. The shoes can also have a lateral flare along the outer border of the outsole, which can help to prevent the ankles from rolling over. High-top lace-up shoes can also provide additional stability. 

A study by Knak et al [43] suggested that aerobic antigravity exercises may be useful in patients with CMT 1A or CMT X. 

Surgical Therapy

If there is severe pes cavus deformity, scoliosis, and other joint deformities surgery would be required. Treatment will depend on the age of the patient and the cause and severity of the deformity.

Three types of surgical procedures can be performed, namely: 

• Soft-tissue procedures (plantar fascia release, tendon release, or transfer)

• Osteotomy (metatarsal, midfoot, calcaneal)

• Joint-stabilizing procedures (triple arthrodesis)

Procedures are usually staged. The initial procedure is a radical plantar or plantar-medial release-plantar fasciotomy, with a dorsal closing-wedge osteotomy of the first metatarsal base if necessary. Tendo calcaneus lengthening should not be performed as part of the initial procedure, because the force used to dorsiflex the forefoot causes the calcaneus to dorsiflex into an unacceptable position.

Posterior tibial tendon transfer can be done as part of the initial procedure for severe anterior tibial weakness if the hindfoot is flexible and a posterior release is not necessary [44].  Dreher et al [45] in a prospective study of 14 patients with CMT disease who had cavovarus foot deformity found that tibialis posterior tendon transfer was effective at correcting the foot-drop component of cavovarus foot deformity. The transfer apparently worked as an active substitution. 

Early aggressive treatment with soft-tissue releases can delay the need for more extensive reconstructive procedures when the hindfoot is flexible. The Jones procedure includes the transfer of the extensor hallucis longus tendon to the first metatarsal head and the arthrodesis of the interphalangeal (IP) joint of the big toe.

A review paper by Faldini et al [46] concluded that in the absences of fixed hindfoot deformity, plantar fasciotomy, midtarsal osteotomy, the Jones procedure, and dorsiflexion osteotomy of the first metatarsal yielded adequate correction of flexible pes cavus in patients with CMT disease.  The Coleman block test can help to decide what type of surgery is best. In patients with cavovarus deformity, the test evaluates hindfoot flexibility [36]. The test is performed by placing the patient's foot on a wood block that is 2.5-4 cm thick. The heel and lateral border of the foot is placed on the block while bearing full weight. The first, second, and third metatarsals are allowed to hang freely into plantarflexion and pronation. If the heel varus corrects when the patient is standing on the block, the hindfoot is considered flexible. If the subtalar joint is supple and corrects with the block test, then surgical procedures can be directed at correcting forefoot pronation. The forefoot pronation is usually due to plantarflexion of the first metatarsal. If the hindfoot is rigid, then surgical correction of the forefoot as well as the hindfoot is required.

Triple arthrodesis serves as a salvage procedure for patients with untreated fixed deformities and for patients in whom other procedures have been unsuccessful.

Children less than 8 years of age with supple hindfeet usually respond to plantar releases and appropriate tendon transfers. In some cases, a first metatarsal osteotomy is needed. 

Children less than 12 years of age with rigid hindfoot deformities may need radical plantar medial release, first metatarsal osteotomy, and Dwyer lateral closing-wedge osteotomy of the calcaneus to correct the deformities.

The Akron dome osteotomy was developed, in the early 1970s, as a salvage surgical option to manage rigid cavus deformity of the foot. Weiner et al [48] in a retrospective study showed that this operation is a valuable salvage procedure in the management of the rigid cavus deformity in children with CMT disease. 

Wukich and Bowen [49] reported that only 14% of patients with CMT disease required a triple arthrodesis. They also reported hindfoot stability with triple arthrodesis, and when the tibialis posterior tendon was transferred anteriorly, there was no need for a postoperative drop-foot brace. They reported good or excellent results in 88% of patients who had triple arthrodesis. 

Ward et al [50] studied the long-term results of surgical reconstruction procedures for flexible cavovarus foot deformity in 25 patients with CMT disease. They had undergone the procedure between 1970 and 1994 and were evaluated at a mean follow-up of 26.1 years. They found that the use of soft-tissue procedures and first metatarsal osteotomy resulted in lower rates of degenerative changes and reoperations as compared to those with triple arthrodesis.

The spinal deformities in children with CMT disease can be treated with the same techniques as those used for idiopathic scoliosis.

Prevention

Joint contractures and deformities can be prevented by regular follow-up and proper therapeutic interventions. 

Proper genetic counseling helps parents understand the risk of having children with this disorder. It gives them a chance to make informed decisions regarding pregnancy [33,51].

A study by Pitceathly et al [52] of mitochondrial data from 442 patients suggested that MT-ATP6 mutations are an important cause of CMT disease and it can be evaluated with a simple blood test.

Long-Term Monitoring

In the long term, patients should have regular follow-up visits to check for deterioration in function and the development of contractures. These follow-up visits allow early detection of complications. Proper early intervention helps to avoid significant and permanent functional limitations [53].

Medication 

Drugs such as vincristine [54], isoniazid, and nitrofurantoin which are known to cause nerve damage should be avoided. The cause of any pain must be identified as accurately as possible. Musculoskeletal pain can be treated with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). Neuropathic pain can respond to tricyclic antidepressants or antiepileptic drugs, such as carbamazepine or gabapentin.

Dyck et al [55], as well as Ginsberg et al [56], have described several individuals with Charcot-Marie-Tooth (CMT) disease type 1 with sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin produced variable levels of improvement. Sahenk et al [57] studied the effects of neurotrophin-3 on individuals with CMT 1A. 

Passage et al [58] reported benefits from ascorbic acid in a mouse model of CMT 1.  In adult patients with symptomatic CMT 1A, Pareyson et al [41], however, found that ascorbic acid supplements (1.5 g/day) had no significant effect on neuropathy compared with placebo after 2 years. There is hence no evidence to support treatment with ascorbic acid in adults with CMT 1A.  A Cochrane review in 2015 did not find evidence of benefit of ascorbic acid in adults or children [59].

A randomized double-blind placebo-controlled phase 2 study of a combination of baclofen, naltrexone, and sorbitol (PXT3003) in patients with CMT 1A confirmed that PXT3003 was a safe and well-tolerated treatment for adults [60]. The trial enrolled 80 CMT 1A patients in France. They were randomly assigned to a low, medium, or high dose of PXT3003 or a placebo for 12 months. Based on the results of the study the PLEO-CMT phase 3 trial (NCT02579759) was conducted.

PLEO-CMT was a 15-month double-blind study. It assessed the efficacy and safety of two doses of PXT3003 as compared with placebo in 323 patients with mild-to-moderate CMT 1A. PXT3003 was given twice daily with food as a liquid formulation. The higher dose contained naltrexone 1.4 mg, baclofen 12 mg, and sorbitol 420 mg, and the lower dose contained baclofen 6 mg, naltrexone 0.7 mg, and sorbitol 210 mg. Official study results have not been published as of early spring 2019. The study sponsor, Pharnext, however, states that PXT3003 consistently eased disability in these patients.

A study published in 2019 found that early short-term PXT3003 combinational therapy delayed disease onset in a transgenic rat model of CMT 1A [61]. These results suggest that PXT3003 therapy can be a bona fide option for children and young adolescent patients suffering from CMT 1A.

Nonsteroidal anti-inflammatory drugs

NSAIDs have analgesic, anti-inflammatory, and antipyretic effects. Their mechanism of action is not known. They may inhibit cyclooxygenase (COX) activity and prostaglandin synthesis. Other mechanisms may exist as well. These include lysosomal enzyme release, inhibition of leukotriene synthesis, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Some of the NSAIDs include:

1. Ibuprofen (Motrin, Ibuprin)

It is used for patients with mild to moderate pain. It Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

2.Naproxen (Naprelan, Naprosyn, Anaprox)

It is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

3. Cyclooxygenase-2 inhibitors

Although increased cost can be a negative factor, the incidence of costly and potentially fatal GI bleeds is clearly less with COX-2 inhibitors as compared with traditional NSAIDs. The cost of GI bleed is avoided with COX-2 inhibitors. One of the COX-2 inhibitors is Celecoxib (Celebrex)

Celebrex inhibits COX-2. COX-2 is considered an inducible isoenzyme. It is induced during pain and inflammatory stimuli. Inhibition of COX-1 can contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited. Hence GI toxicity can be decreased. The lowest therapeutic dose of celecoxib should be used by patients.

Tricyclic antidepressants

Tricyclic antidepressants are a complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. They have central effects on pain transmission. They block the active reuptake of norepinephrine and serotonin. Some of the tricyclic antidepressants include:

1. Amitriptyline (Elavil)

Amitriptyline is used as an analgesic for certain chronic and neuropathic pain. It inhibits the membrane pump responsible for the uptake of norepinephrine and serotonin in the adrenergic and serotonergic neurons.

2. Nortriptyline (Pamelor)

Nortriptyline has demonstrated effectiveness in the treatment of chronic pain. This drug increases the synaptic concentration of neurotransmitters in the central nervous system by inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane.

Pharmacodynamic effects, such as the desensitization of adenyl cyclase and the down-regulation of beta-adrenergic receptors and serotonin receptors, also play a role in its mechanisms of action.

3. Doxepin (Sinequan)

Doxepin inhibits histamine and acetylcholine activity and has proven useful in the treatment of various forms of depression associated with chronic and neuropathic pain.

4. Desipramine (Norpramin)

Desipramine increases the synaptic concentration of norepinephrine in CNS by inhibiting reuptake by presynaptic neuronal membrane. It also has effects in the desensitization of adenyl cyclase, down-regulation of beta-adrenergic receptors, and down-regulation of serotonin receptors.

Anticonvulsants

Anticonvulsants are used to manage pain and provide sedation in patients with neuropathic pain. The commonly used anticonvulsant is gabapentin (neurontin). It is a membrane stabilizer, a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Gabapentin paradoxically is thought not to exert an effect on GABA receptors. It appears to exert action via the alpha(2)delta1 and alpha(2)delta2 subunit of the calcium channel.

Analgesics

Pain control is essential for quality patient care. Analgesics ensure patient comfort. Analgesics have sedating properties, which are beneficial to patients who experience pain. The commonly used analgesic is acetaminophen (Tylenol).

It is used for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.

References

1. Saporta MA. Charcot-Marie-Tooth disease and other inherited neuropathies. Continuum (Minneap Minn). 2014 Oct. 20 (5 Peripheral Nervous System Disorders):1208-25.

2. Pareyson D, Saveri P, Pisciotta C. New developments in Charcot-Marie-Tooth neuropathy and related diseases. Curr Opin Neurol. 2017 Oct. 30 (5):471-480.

3. Kazamel M, Boes CJ. Charcot Marie Tooth disease (CMT): historical perspectives and evolution. J Neurol. 2015. 262 (4):801-5.

4. Jani-Acsadi A, Ounpuu S, Pierz K, Acsadi G. Pediatric Charcot-Marie-Tooth disease. Pediatr Clin North Am. 2015 Jun. 62 (3):767-86.

5. Baets J, De Jonghe P, Timmerman V. Recent advances in Charcot-Marie-Tooth disease. Curr Opin Neurol. 2014 Oct. 27 (5):532-40.

6. Bird TD, Ott J, Giblett ER, Chance PF, Sumi SM, Kraft GH. Genetic linkage evidence for heterogeneity in Charcot-Marie-Tooth neuropathy (HMSN type I). Ann Neurol. 1983 Dec. 14 (6):679-84. 

7. Carter GT, Abresch RT, Fowler WM Jr, Johnson ER, Kilmer DD, McDonald CM. Profiles of neuromuscular diseases. Hereditary motor and sensory neuropathy, types I and II. Am J Phys Med Rehabil. 1995 Sep-Oct. 74 (5 Suppl): S140-9. 

8. Ruskamo S, Nieminen T, Kristiansen CK, Vatne GH, Baumann A, Hallin EI, et al. Molecular mechanisms of Charcot-Marie-Tooth neuropathy linked to mutations in human myelin protein P2. Sci Rep. 2017 Jul 26. 7 (1):6510.

9. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000 Jul. 123 ( Pt 7):1516-27. 

10. Suter U, Nave KA. Transgenic mouse models of CMT1A and HNPP. Ann N Y Acad Sci. 1999 Sep 14. 883:247-53. 

11. Thomas PK. Overview of Charcot-Marie-Tooth disease type 1A. Ann N Y Acad Sci. 1999 Sep 14. 883:1-5.

12. Saporta MA, de Moraes Maciel R. Analysis of Myelinating Schwann Cells in Human Skin Biopsies. Methods Mol Biol. 2018. 1739:359-369. 

13. Berciano J, Combarros O, Figols J, Calleja J, Cabello A, Silos I, et al. Hereditary motor and sensory neuropathy type II. Clinicopathological study of a family. Brain. 1986 Oct. 109 ( Pt 5):897-914. 

14. Elliott JL, Kwon JM, Goodfellow PJ, Yee WC. Hereditary motor and sensory neuropathy IIB: clinical and electrodiagnostic characteristics. Neurology. 1997 Jan. 48 (1):23-8. 

15. Vance JM. Charcot-Marie-Tooth disease type 2. Ann N Y Acad Sci. 1999 Sep 14. 883:42-6. 

16. Lassuthova P, Rebelo AP, Ravenscroft G, Lamont PJ, Davis MR, Manganelli F, et al. Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2. Am J Hum Genet. 2018 Mar 1. 102 (3):505-514.

17. Ben Othmane K, Hentati F, Lennon F, Ben Hamida C, Blel S, Roses AD, et al. Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet. 1993 Oct. 2 (10):1625-8. 

18. Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. 2000 May. 25 (1):17-9. 

19. Agrahari AK, Sneha P, George Priya Doss C, Siva R, Zayed H. A profound computational study to prioritize the disease-causing mutations in PRPS1 gene. Metab Brain Dis. 2018 Apr. 33 (2):589-600.

20. Shy ME, Lupski JR, Chance PF, Klein CJ, Dyck PJ. Hereditary motor and sensory neuropathies: an overview of clinical, genetic, electrophysiologic, and pathologic features. Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Philadelphia: Saunders; 2005. Vol 2: 1623-58.

21. Kurihara S, Adachi Y, Wada K, Awaki E, Harada H, Nakashima K. An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan. Neuroepidemiology. 2002 Sep-Oct. 21 (5):246-50. 

22. Morocutti C, Colazza GB, Soldati G, D'Alessio C, Damiano M, Casali C, et al. Charcot-Marie-Tooth disease in Molise, a central-southern region of Italy: an epidemiological study. Neuroepidemiology. 2002 Sep-Oct. 21 (5):241-5.

23. Braathen GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol Scand Suppl. 2012. Iv-22.

24. Tozza S, Bruzzese D, Pisciotta C, Iodice R, Esposito M, Dubbioso R, et al. Motor performance deterioration accelerates after 50 years of age in Charcot-Marie-Tooth type 1A patients. Eur J Neurol. 2018 Feb. 25 (2):301-306.

25. Shy ME, Blake J, Krajewski K, Fuerst DR, Laura M, Hahn AF, et al. Reliability and validity of the CMT neuropathy score as a measure of disability. Neurology. 2005 Apr 12. 64 (7):1209-14.

26. Bernasconi A, Cooper L, Lyle S, Patel S, Cullen N, Singh D, et al. Pes cavovarus in Charcot-Marie-Tooth compared to the idiopathic cavovarus foot: A preliminary weightbearing CT analysis. Foot Ankle Surg. 2021 Feb. 27 (2):186-195.

27. Reynaud V, Conforto I, Givron P, Clavelou P, Cornut-Chauvinc C, Taithe F, et al. Multidimensional evaluation is necessary to assess hand function in patients with Charcot-Marie-Tooth disease type 1A. Ann Phys Rehabil Med. 2021 Mar. 64 (2):101362.

28. Burns J, Bray P, Cross LA, North KN, Ryan MM, Ouvrier RA. Hand involvement in children with Charcot-Marie-Tooth disease type 1A. Neuromuscul Disord. 2008 Dec. 18 (12):970-3.

29. Carter GT, Jensen MP, Galer BS, Kraft GH, Crabtree LD, Beardsley RM, et al. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. 1998 Dec. 79 (12):1560-4.

30. Berciano J, Gallardo E, García A, Pelayo-Negro AL, Infante J, Combarros O. New insights into the pathophysiology of pes cavus in Charcot-Marie-Tooth disease type 1A duplication. J Neurol. 2011 Sep. 258 (9):1594-602. 

31. Singh D, Gray J, Laura M, Reilly MM. Charcot neuroarthropathy in patients with Charcot Marie Tooth Disease. Foot Ankle Surg. 2021 Dec. 27 (8):865-868.

32. Akdal G, Koçoğlu K, Tanrıverdizade T, Bora E, Bademkıran F, Yüceyar AN, et al. Vestibular impairment in Charcot-Marie-Tooth disease. J Neurol. 2021 Feb. 268 (2):526-531.

33. Hoff JM, Gilhus NE, Daltveit AK. Pregnancies and deliveries in patients with Charcot-Marie-Tooth disease. Neurology. 2005 Feb 8. 64 (3):459-62.

34. Shaffer LG, Kennedy GM, Spikes AS. Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet. 1997 Mar 31. 69(3): 325-31.

35. Anderson TJ, Klugmann M, Thomson CE, Schneider A, Readhead C, Nave KA, et al. Distinct phenotypes associated with increasing dosage of the PLP gene: implications for CMT1A due to PMP22 gene duplication. Ann N Y Acad Sci. 1999 Sep 14. 883:234-46.

36. Millere E, Rots D, Simrén J, Ashton NJ, Kupats E, Micule I, et al. Plasma neurofilament light chain as a potential biomarker in Charcot-Marie-Tooth disease. Eur J Neurol. 2021 Mar. 28 (3): 974-981.

37. Cartwright MS, Brown ME, Eulitt P, Walker FO, Lawson VH, Caress JB. Diagnostic nerve ultrasound in Charcot-Marie-Tooth disease type 1B. Muscle Nerve. 2009 Jul. 40 (1):98-102.

38. Gaeta M, Mileto A, Mazzeo A, Minutoli F, Di Leo R, Settineri N, et al. MRI findings, patterns of disease distribution, and muscle fat fraction calculation in five patients with Charcot-Marie-Tooth type 2 F disease. Skeletal Radiol. 2012 May. 41 (5):515-24.

39. Dyck PJ, Karnes JL, Lambert EH. Longitudinal study of neuropathic deficits and nerve conduction abnormalities in hereditary motor and sensory neuropathy type 1. Neurology. 1989 Oct. 39 (10): 1302-8.

40. Kitaoji T, Noto YI, Kojima Y, Tsuji Y, Kitani-Morii F, Mizuno T, et al. Compound muscle action potential duration ratio for differentiation between Charcot-Marie-Tooth disease and CIDP. Clin Neurophysiol. 2023 Feb. 146:124-130.

41. Pareyson D, Reilly MM, Schenone A, Fabrizi GM, Cavallaro T, Santoro L, et al. Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Lancet Neurol. 2011 Apr. 10 (4):320-8.

42. Fledrich R, Abdelaal T, Rasch L, Bansal V, Schütza V, Brügger B, et al. Targeting myelin lipid metabolism as a potential therapeutic strategy in a model of CMT1A neuropathy. Nat Commun. 2018 Aug 2. 9 (1):3025.

43. Knak KL, Andersen LK, Vissing J. Aerobic anti-gravity exercise in patients with Charcot-Marie-Tooth disease types 1A and X: A pilot study. Brain Behav. 2017 Dec. 7 (12): e00794.

44. Coleman SS, Chesnut WJ. A simple test for hindfoot flexibility in the cavovarus foot. Clin Orthop Relat Res. 1977 Mar-Apr. (123):60-2. 

45. Dreher T, Wolf SI, Heitzmann D, Fremd C, Klotz MC, Wenz W. Tibialis posterior tendon transfer corrects the foot drop component of cavovarus foot deformity in Charcot-Marie-Tooth disease. J Bone Joint Surg Am. 2014 Mar 19. 96 (6):456-62.

46. Faldini C, Traina F, Nanni M, Mazzotti A, Calamelli C, Fabbri D, et al. Surgical treatment of cavus foot in Charcot-Marie-tooth disease: a review of twenty-four cases: AAOS exhibit selection. J Bone Joint Surg Am. 2015 Mar 18. 97 (6):e30. 

47. Paulos L, Coleman SS, Samuelson KM. Pes cavovarus. Review of a surgical approach using selective soft-tissue procedures. J Bone Joint Surg Am. 1980 Sep. 62 (6):942-53.

48. Weiner DS, Morscher M, Junko JT, Jacoby J, Weiner B. The Akron dome midfoot osteotomy as a salvage procedure for the treatment of rigid pes cavus: a retrospective review. J Pediatr Orthop. 2008 Jan-Feb. 28 (1):68-80.

49. Wukich DK, Bowen JR. A long-term study of triple arthrodesis for correction of pes cavovarus in Charcot-Marie-Tooth disease. J Pediatr Orthop. 1989 Jul-Aug. 9 (4):433-7.

50. Ward CM, Dolan LA, Bennett DL, Morcuende JA, Cooper RR. Long-term results of reconstruction for treatment of a flexible cavovarus foot in Charcot-Marie-Tooth disease. J Bone Joint Surg Am. 2008 Dec. 90 (12):2631-42.

51. Steiner I, Gotkine M, Steiner-Birmanns B, Biran I, Silverstein S, Abeliovich D, et al. Increased severity over generations of Charcot-Marie-Tooth disease type 1A. J Neurol. 2008 Jun. 255 (6):813-9.

52. Pitceathly RD, Murphy SM, Cottenie E, Chalasani A, Sweeney MG, Woodward C, et al. Genetic dysfunction of MT-ATP6 causes axonal Charcot-Marie-Tooth disease. Neurology. 2012 Sep 11. 79 (11):1145-54.

53. Padua L, Shy ME, Aprile I, Cavallaro T, Pareyson D, Quattrone A, et al. Correlation between clinical/neurophysiological findings and quality of life in Charcot-Marie-Tooth type 1A. J Peripher Nerv Syst. 2008 Mar. 13 (1):64-70.

54. Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD. Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A. Cancer. 1996 Apr 1. 77 (7):1356-62.

55. Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH. Prednisone-responsive hereditary motor and sensory neuropathy. Mayo Clin Proc. 1982 Apr. 57 (4):239-46.

56. Ginsberg L, Malik O, Kenton AR, Sharp D, Muddle JR, Davis MB, et al. Coexistent hereditary and inflammatory neuropathy. Brain. 2004 Jan. 127 (Pt 1):193-202.

57. Sahenk Z, Nagaraja HN, McCracken BS, King WM, Freimer ML, Cedarbaum JM, et al. NT-3 promotes nerve regeneration and sensory improvement in CMT1A mouse models and in patients. Neurology. 2005 Sep 13. 65 (5):681-9.

58. Passage E, Norreel JC, Noack-Fraissignes P, Sanguedolce V, Pizant J, Thirion X, et al. Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease. Nat Med. 2004 Apr. 10 (4):396-401. 

59. Gess B, Baets J, De Jonghe P, Reilly MM, Pareyson D, Young P. Ascorbic acid for the treatment of Charcot-Marie-Tooth disease. Cochrane Database Syst Rev. 2015 Dec 11. CD011952.

60. Attarian S, Vallat JM, Magy L, Funalot B, Gonnaud PM, Lacour A, et al. An exploratory randomised double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with Charcot-Marie-Tooth disease type 1A. Orphanet J Rare Dis. 2014 Dec 18. 9:199.

61. Prukop T, Stenzel J, Wernick S, Kungl T, Mroczek M, Adam J, et al. Early short-term PXT3003 combinational therapy delays disease onset in a transgenic rat model of Charcot-Marie-Tooth disease 1A (CMT1A). PLoS One. 2019. 14 (1):e0209752.