Charcot-Marie-Tooth disease: Management and prognosis

INTRODUCTION — 

Charcot-Marie-Tooth disease (CMT) is a group of hereditary neuropathies characterized by progressive motor and sensory nerve dysfunction, including a characteristic atrophy of calf muscles in several subtypes. CMT is the most common hereditary peripheral neuropathy. It is caused by one of several pathogenic variants in genes whose protein products are expressed in myelin, gap junctions, and/or axonal structures within peripheral nerves.

This topic will review the management and prognosis of CMT. The genetics, clinical features, and diagnosis of CMT are discussed separately. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis".)

MANAGEMENT — 

Management of CMT is currently supportive; however, such supportive therapy can dramatically improve a patient's quality of life. Specific disease-modifying therapies are not available. Several agents are under active investigation in clinical trials. Optimal management is multidisciplinary, with care provided by neurologists, genetic counselors, nurses, physical and occupational therapists, physiatrists, and orthopedic surgeons [1].

Rehabilitation — A comprehensive rehabilitation program plays a crucial role in the management of individuals affected by CMT [1]. All patients should be evaluated for weakness (both distal and proximal), joint contractures, physical conditioning, ambulation, balance, coordination, and manual dexterity. A major goal is the prevention of complications such as joint deformity and falls. Daily stretching exercises early in the course of the disease may help delay ankle contractures [2]. Moderate quality evidence suggests progressive resistance exercise programs may improve functional outcomes [2-4]. Occupational therapy can help to improve function with activities of daily living. An intensive rehabilitation regimen demonstrated benefit in one study, but the therapeutic effects attenuated after cessation of the program [5].

Orthotics, including ankle-foot orthoses, are often used to help stabilize the ankles and enhance gait function [6]. Tolerability and response to orthotics should be monitored to optimize compliance [7]. Orthopedic foot surgery may be beneficial for severe manifestations of contractures, pes cavus deformity, and hammer toes, typically during adolescence or early adulthood.

However, there are only limited data from high-quality studies to support the utility of rehabilitation interventions for patients with CMT [8-10]. A systematic review published in 2016 identified only seven small randomized controlled trials and four small cohort studies examining physiotherapy or orthotics for patients with CMT [9]. There was evidence that mild to moderate endurance, stretching, and strength training exercises are safe for patients with CMT, can increase arm, pelvic girdle, and knee strength, and can improve performance with activities of daily living. Outcomes for orthotic interventions were mixed, but the one small trial that measured walking ability found that wearing plastic ankle-foot orthoses improved walking control compared with wearing ordinary shoes [11].

The role of vitamin supplementation — CMT is not directly associated with vitamin deficiencies, and supplementation has not been proven to be beneficial in traditional forms of CMT. However, patients with CMT who also have vitamin deficiencies that may cause neuropathy should receive appropriate replacement therapy to prevent worsening symptoms. (See 'Concomitant neuropathic conditions' below.)

Some patients with uncommon inherited neuropathies that may mimic CMT can respond to certain types of vitamin supplementation. As examples, Brown-Vialetto-van Laere disease (BVVL) is an autosomal recessive disease that may respond to riboflavin therapy [12]; a distinct syndrome associated with biallelic pathogenic variants in SLC5A6 may respond to a combination of biotin, pantothenic acid, and lipoic acid [13]. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Differential diagnosis'.)

Avoid exacerbating factors

Concomitant neuropathic conditions — Patients with CMT may experience further impairments with disorders that cause or exacerbate neuropathy, a list that includes diabetes mellitus, vitamin deficiencies, and immune-mediated neuropathies [1]. Therefore, patients should be screened periodically for these conditions and treated promptly if any are detected. In particular, patients with CMT who experience unusually rapid progression of symptoms should be evaluated for a superimposed immune-mediated or inflammatory neuropathy.

Medications — Because patients with CMT have an existing peripheral neuropathy, they are considered to be more susceptible to injury when treated with standard "nontoxic" dosages of neurotoxic agents [14]. A systematic review published in 2006 identified 26 publications, mainly case reports or small case series, describing CMT exacerbation associated with toxic medications, of which 22 involved vincristine [15]. Acute worsening or onset of weakness in patients with CMT was observed after vincristine administration of 2 to 4 mg for adults or 1.5 mg/m² per dose in children. Most of the patients had undiagnosed demyelinating forms of CMT (eg, CMT1A).

Thus, vincristine is considered to be a definite high-risk medication for patients with CMT, including those who are asymptomatic and/or undiagnosed. Vincristine has long been labeled as contraindicated for patients with demyelinating forms of CMT.

Data for other drugs are quite limited, but a list of medications considered to have moderate to significant risk for patients with CMT is as follows [15]:

●Amiodarone

●Bortezomib

●Cisplatin, carboplatin, oxaliplatin

●Colchicine (extended use)

●Dapsone

●Dichloroacetate

●Disulfiram

●Gold salts

●Leflunomide

●Metronidazole/misonidazole (extended use)

●Nitrofurantoin

●Nitrous oxide (inhalation abuse or vitamin B12 deficiency)

●Perhexiline (not used in the United States)

●Pyridoxine (high dose)

●Stavudine (largely discontinued worldwide)

●Suramin

●Tacrolimus

●Taxol (paclitaxel, docetaxel)

●Thalidomide

●Zalcitabine

A longer list of drugs of concern for patients with CMT, including drugs of uncertain or minor risk and negligible or doubtful risk, can be found online at the Charcot-Marie-Tooth Association website.

Special scenarios

Uncertain risks with anesthesia — Local anesthesia has been controversial due to theoretical concerns that patients with CMT may have an increased susceptibility to further nerve damage with the use of local anesthetic agents [16]. However, the available limited clinical data suggest otherwise.

Regional and general anesthesia have been controversial due to the concern for neuromuscular weakness. A number of small case series and case reports have described uneventful outcomes with regional anesthesia, including both peripheral nerve and neuraxial blocks [17-19]. In individual reports, general anesthesia with propofol and midazolam have been used successfully, but prolonged respiratory neuromuscular weakness with rocuronium has been reported [20,21].

Pregnant patients — The management of pregnant patients with CMT is similar to that of pregnant patients without CMT. CMT by itself is not an indication for cesarean delivery, which should be reserved for the usual obstetric indications only. However, pregnant patients with CMT should be monitored for complications during labor and delivery.

An observational study of 193 pregnancies in 86 patients with CMT showed increased rates of placenta previa, abnormal presentations, and preterm deliveries, but not postpartum bleeding [22]. It is not clear whether the increased frequency of malpresentation was related to early symptoms in affected fetuses because the disorder typically does not present until later in childhood. CMT status worsened in nearly 10 percent of the pregnancies during gestation, with no recovery in most of those patients in this study. Other studies have similarly found elevated rates of abnormal fetal presentations in patients with CMT but also reported higher rates of postpartum bleeding than the general obstetric population [23]. One possible explanation for this finding is atony related to the effect of the disease on uterine adrenergic nerves. Birth weights were comparable with those in unaffected pregnancies.

Investigational therapies — Experimental therapies are being tested in both animal models and human participants. This includes neurotropic and symptomatic medications as well as viral vectors to deliver both primary genes and gene-silencing agents. Some such experimental agents include:

●Small molecule agents

•Progesterone antagonists may reduce overexpression of PMP22 and slow disease progression [24,25]. Progesterone can increase PMP22 expression, and studies in humans have suggested disease exacerbation in pregnancy, a setting in which plasma progesterone increases up to 10-fold [26]. Observations in an animal model were consistent with these findings as the administration of progesterone resulted in a more progressive neuropathy [24,25].

•Ascorbic acid (vitamin C), which is known to promote myelination, appeared promising in an animal model of CMT1A [27]. Ascorbic acid therapy reduced the expression of PMP22 to a level below that required to induce the disease. This change was associated with remyelination, amelioration of the CMT1A phenotype, and prolonged lifespan. However, there was no clear benefit of ascorbic acid in a 12-month randomized controlled trial of 81 children with CMT1A [28], in a similar trial of 179 adults with CMT1A [29], or in a smaller trial of 11 patients younger than age 25 years [30]. Since disease progression in CMT1A is typically slow, trials with longer treatment periods may be necessary to detect any benefit [31,32]. However, it is discouraging that any potential benefit would be that modest.

•Curcumin has been studied in a mouse model of CMT1A and led to rejuvenation of myelinated axons in this model [33].

•A compound oral agent consisting of baclofen, naltrexone, and D-sorbitol (PXT3003) in individuals with CMT1A showed benefit in the Overall Neuropathy Limitations Scale in a small clinical trial [34].

•Small molecule MFN2 agonists have been found to improve mitochondrial defects in a mouse model of CMT2A [35].

●Protein growth factor

•Neurotrophin-3 (NT3) is a protein growth factor improved axonal regeneration and associated myelination in both a xenograft model of Schwann cells with a PMP22 duplication and in a mouse model with a pathogenic PMP22 single-nucleotide variant (SNV) [36]. In the same report, a single-blinded pilot clinical trial involving eight patients with CMT1A found that NT3 treatment for six months was associated with improved sural nerve myelinated fiber regeneration compared with placebo treatment.

●Molecular therapy

•Antisense oligonucleotide suppression of PMP22 mRNA levels in a model of CMT1A [37] – A molecular approach for CMT1A is to silence the excess expression of PMP22. A study in a rat model of CMT1A showed improvement on functional and myelination measures after intraneural delivery of AAV2/9 carrying shRNAs targeting PMP22 mRNA [38]. In transgenic mouse models of CMT1A, administration of siRNA targeting PMP22 resulted in functional and histopathologic improvement [39].

•Antisense oligonucleotide suppression of mutant forms of NEFL have shown therapeutic effects in motor neurons derived from induced pluripotent stem cells of patients with CMT2E [40].

•GARS has been the target of several preclinical studies. A study testing intramuscular AAV-mediated gene transfer of NT-3 into mice with pathogenic variants in GARS (modeling CMT2D) showed functional and electrophysiologic improvements [41]. AAV-mediated delivery of RNAi sequences targeting variant GARS mRNA into mouse models of CMT2D showed therapeutic effects, especially when treatment was administered at birth [42].

•Direct gene replacement is a promising strategy for multiple forms of CMT [37]. A mouse model of CMT4J was dosed with AAV9 containing FIG4, showing good motor function, neurophysiologic outcomes, and histopathologic findings [43]. Intrathecal injection of AAV9 carrying GJB1/Cx32 into Gjb1-null mice led to improved motor function and electrophysiologic parameters [44].

•Intrathecal gene therapy was studied in mouse models of CMTX1 replicating several different variants of GJB1, and the response varied significantly based on the specific variants represented [45].

•Axonal neuregulin 1 type III (Nrg1TIII) promotes myelination via specific pathways including PI3K/Akt and MAPK/Erk. Genetic overexpression of Nrg1TIII was shown to improve neurophysiologic and morphologic parameters in a mouse model of CMT1B [46].

•AAV-mediated delivery of full-length Morc2a and a key functional domain of Morc2a improved key features of a mouse model of CMT2Z, which is associated with pathogenic variants in MORC2 [47].

•One study using a CRISPR/Cas9 approach in a mouse model of CMT1A showed that TATA-box targeting of PMP22 led to downregulation of PMP22 expression and preservation of myelin and axons [48].

Monitoring disease progression — Periodic evaluations should be performed to monitor symptoms and assess neurologic function. Evaluations should include a comprehensive neurologic examination and may also include specialized clinical tools that have been used as outcome measures in clinical trials.

For adults, a multi-item CMT Functional Outcome Measure (CMT-FOM) has been validated [49,50], and other single-item and multi-item outcome measures have been studied [51]. Outcome measures have been proposed specifically for infants with CMT [52], including an alternate multi-item scale that was validated for this age group [53]. Electrophysiologic outcome measures could also potentially track progression and monitor for treatment effects. In addition to standard electrophysiologic measures, more advanced techniques such as motor unit number index (see "Overview of nerve conduction studies", section on 'Motor unit number estimates (MUNE)') may be considered for such purposes [54]. Imaging modalities such as magnetic resonance imaging (MRI) are being adopted for use as outcome measures and for monitoring of clinical progression in CMT [55-57]. It is expected that these outcome measures will become increasingly used in clinical trials, and some of the individual measures may be useful for tracking disease progression during routine clinical care.

PROGNOSIS — 

CMT in most cases is characterized by onset in the first or second decade of life with very slow progression [58]. Disability generally increases with age, but there is considerable variability in age of onset, rate of progression, and clinical severity both between and within different CMT subtypes. Functional outcomes vary from minor impairments to severe lower limb atrophy and wheelchair dependence. Nevertheless, many patients retain at least partial ambulatory abilities for all or most of their lives, and it is rare for CMT to shorten life expectancy.

With CMT1A, the most common subtype, progression often results in gait difficulty, but complete loss of ambulation is uncommon, and life expectancy is generally normal. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'CMT1'.)

With CMTX1, the second most common CMT subtype, disease progression to severe disability occurs on average by the fifth decade in males [59], but lifespan is not shortened [60]. Females with CMTX1 tend to have milder clinical courses. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'CMT1'.)

Respiratory failure due to neuromuscular weakness of the diaphragm or vocal cords is a rare complication of CMT but has been reported in some CMT subtypes, including CMT1A [58,61].

CMT has a major impact on the quality of life of affected individuals. A 2019 study from Germany of 397 patients with genetically confirmed diagnoses of CMT estimated that the total annual cost of illness per patient was USD $22,362 [62].

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Charcot-Marie-Tooth disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Management – Specific disease-modifying therapy for Charcot-Marie-Tooth disease (CMT) is not yet available. Optimal management is multidisciplinary. (See 'Management' above.)

•A comprehensive rehabilitation program plays a crucial role in the management of individuals affected by CMT. Stretching, endurance, and strengthening exercises and orthotics may help to improve function. (See 'Rehabilitation' above.)

•Patients with CMT should be screened periodically for conditions that cause or exacerbate neuropathy, such as diabetes mellitus, vitamin deficiencies, and superimposed immune-mediated neuropathies. (See 'Concomitant neuropathic conditions' above.)

•Patients with CMT should avoid drugs that can exacerbate neuropathy, particularly vincristine. (See 'Medications' above.)

●Prognosis – CMT in most cases is characterized by onset in the first or second decade of life with very slow progression. Disability generally increases with age. However, there is considerable variability in age of onset, rate of progression, and clinical severity, both between and within different CMT subtypes. (See 'Prognosis' above.)