Hereditary motor sensory neuropathy (HMSN), also known as Charcot-Marie-Tooth Disease (CMT), is the most commonly inherited peripheral polyneuropathy. It constitutes a group of inherited, progressive, motor and sensory peripheral nerve disorders with properties of demyelination, axonal degeneration, or both. It is classified by clinical characteristics, modes of inheritance, electrophysiologic features, metabolic defects, and specific gene markers. It overlaps with distal hereditary [pure] motor neuropathies (dHMN) but is distinct from hereditary sensory and autonomic neuropathy (HSAN) and motor neuron disease (MND). CMT is an evolving field with considerable phenotypic and genetic heterogeneity.1, 2
Over 100 genes, which code for proteins involved in nerve structure (myelin, gap junctions, Schwann cells, axons) and function (axonal transport, energy production) have been identified as causal for CMT and related disorders.2,3 Modes of inheritance include autosomal dominant, autosomal recessive, X-linked recessive, and X-linked semi-dominant (milder disease in carrier females).
Epidemiology including risk factors and primary prevention
CMT affects an estimated 150,000 people in the United States. It occurs in populations worldwide with a prevalence of about 1 in 3,300 individuals. 4 Risk factors include family history for autosomal dominant and X-linked forms, and consanguinity for autosomal recessive forms. The subtype frequency can vary with ethnicity. Primary prevention is genetic counseling. The major categories of CMT are CMT types 1 through 7 as well as an X-linked category. Within each category, a specific disease associated with a particular gene is assigned a letter (eg, CMT1A, CMT1B, etc.). 5
Overexpression of peripheral mylon protein 22 (PMP22) causes a demyelinating neuropathy. CMT1A has overproduction of peripheral mylin protein; other demyelinating forms have myelin compaction or impaired maintenance or development with problems in Schwann cell differentiation, function, or survival. Histologically, onion bulbs, focal folds and/or swelling occur. Axonal forms may have abnormal mitochondrial fusion or fission, or other defects in axonal transport and intracellular membrane trafficking.
Different changes in the same gene may cause different phenotypes; the best-known example is PMP22, for which duplication causes CMT1A, deletion causes hereditary neuropathy with susceptibility to pressure palsy (HNPP), and point mutations cause CMT1E. HNPP comprises about 2% of CMT cases.
Additionally, genes known to cause complex inherited disorders may present with an isolated neuropathy. This is to account for considerable overlap between CMT and other neurodegenerative disorders such as hereditary spastic paraplegia (HSP), hereditary ataxias and mitochondrial disease.2
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
The classical presentation of CMT shows progressive loss of strength and sensation distally to proximally, “length-dependent” affecting lower extremities first.
Early onset: severe forms may have infant hypotonia with delayed motor milestones, toe walking and even arthrogryposis; most present before age 20, with clumsiness and abnormal gait. Later onset cases may mimic slowly progressive acquired neuropathies.
Later course: foot deformity, foot drop, and quadriceps weakness may further limit unaided mobility. Falls increase with fatigue and proprioceptive loss. Fine motor performance is more affected, with hand weakness, cramping pain, and visible atrophy.
Rare forms may have proximal or predominantly upper extremity involvement.
Specific secondary or associated conditions and complications
CMT subtypes have some variable clinical features.
CMT1 is an autosomal dominant demyelinating form that accounts for 50%-80% of all CMT cases (nerve conduction velocity 5-30 m/sec). 6 CMT1A is associated with duplication or a point mutation of PMP22 gene on chromosome 17p11.2-p1; duplication leads to overexpression of PMP22 .CMT1A accounts for 70-80% of cases within this group.6 CMT1B is due to myelin protein zero (MPZ) gene point mutation on chromosome 1q22, which cause overexpression of the major myelin structural protein. Musculoskeletal features commonly seen in CMTIA include pes cavus, and hammer or claw toes. Scoliosis and hip disorders are uncommon. “Roussy-Levy syndrome”, a severe variant of CMT 1, describes a clinical picture of early onset CMT with tremor and ataxia.
CMT2 is characterized by primarily axonal damage (nerve conduction velocity 35-48 m/sec), and autosomal dominant or recessive mode of inheritance, accounting for 12-36% of all CMT cases. 7 Laryngeal dysfunction is characteristic of CMT2C due to alterations in TRPV4 gene. Other features include optic atrophy in CMT 2A and skin ulcers seen in CMT2B, a predominantly sensory disorder.
CMT3 comprises two disorders: Dejerine-Sottas syndrome and congenital hypomyelinating neuropathy. These are severe, early-onset peripheral neuropathies caused by an inability of Schwann cells to produce normal myelin.6, 8 Dejerine-Sottas presents with infantile onset, palpable nerves, and marked onion-bulb formation.
CMT4 is a rare autosomal recessive form of CMT, typically more severe and early onset. It may be demyelinating, intermediate, or axonal. Sleep apnea, restrictive disease, vocal cord paralysis, glaucoma, cataracts and intellectual disability are associated with CMT4. Scoliosis and hip are notable.
CMTX is an X-linked form of CMT, with both demyelinating and axonal features. CMTX1 is due to GJB1 alterations and comprises 7-12% of all CMT cases. 5 Hearing impairment is described in CMTX1, audiologic screening should always be performed. Intellectual disability may be present in CMTX4 (Cowchock) and CMTX5 (Rosenberg-Chutorian/Arts). Learning difficulties and cerebral white matter changes may be seen in CMTX1 and others.
Essentials of Assessment
Family history: ask about any family members with incoordination, gait, or leg problems, as well as CMT diagnosis. Inquire sensitively about possible consanguinity.
Investigate delayed gross and fine motor milestones, awkward/slow running, frequent falls, recurrent ankle injuries, progressive fatigue/poor endurance, distal extremity pain/cramps and prior history of nerve entrapment ( such as wrist drop or foot droop). Sensory loss is typically not noticeable to the patient. Neuropathic pain (tingling, burning, and aching) is less common.
Other associated symptoms are: voice, respiratory, hearing or visual impairments, and need for educational modifications.
Classic pictures of CMT1A have “inverted champagne bottle” legs due to atrophy around the ankle and preserved proximal muscle. Pes cavovarus, hammer/claw toes are noted with foot intrinsic atrophy, with later loss of palmar arches. Planovalgus may occur with early hypotonia. Hand intrinsic atrophy may be present. Scoliosis and hip dysplasia are less common.
Foot drop (steppage) gait pattern may progress to waddling gait in more advanced disease.
Neurologic findings include: diminished or absent reflexes (particularly in lower extremity), mild proprioceptive deficit with preserved pinprick/light touch in most types, length dependent weakness pattern in lower extremities, milder hand weakness and eventually abnormal grip. Romberg may be positive, but pure cerebellar (nystagmus, dysmetria) or upper motor neuron signs should not be present. CNS stroke-like events or white matter changes have been associated with CMTX.
Findings with less common CMT types include proximal weakness, upper extremity predominance, scapular winging, voice changes, calcaneovalgus, early onset scoliosis, or evidence of decreased protective sensation.
ADLs and mobility: Specifically ask about the extent of any help provided with daily activities, and about any difficulties in school. Fasteners and shoe-tying may be difficult. Handwriting speed and legibility may be a barrier to academic achievement. Limited ability to participate in sports, recreation and other community activity due to pain and fatigue, and effects on mood and behavior should be addressed.
CMT is a genetic heterogenous disorder. Genetic testing is a key in confirming the disease, determining a mode of inheritance and identifying associated clinical issues related to the genotype. Other causes of neuropathy (nutritional, toxic, and autoimmune) need to be ruled out. PMP22 duplication (CMT1A) can be tested first if history and exam are typical. If negative, some sources recommend testing CMT1B, or testing CMTX1 if X-linked pedigree is possible. Panel testing is first line for atypical presentations and may be narrowed by electrodiagnostic findings.
Whole genome sequencing (WGS) is frequently employed in patients where targeted panels have not identified any pathogenic variants in known CMT genes. 2 Increasing evidence has emerged showing that genes known to cause some mitochondrially inherited or other multisystem disorders may present with an isolated neuropathy.1, 2
Brain MRI may show positive changes in some forms, with abnormal signal in parieto-occipital regions, internal capsule, cerebellum, deep white matter and corpus callosum as well as enlargement of cranial nerves.9,10 If there is clinical doubt that incoordination is purely proprioceptive and weakness-related, cerebellar abnormality may be an important clue to alternative diagnosis such Friedreich’s ataxia or spinocerebellar disorders.
Orthopedic imaging of hips or spine is performed when clinically indicated.
Muscle and nerve ultrasound or MRI may reveal enlarged peripheral nerves and pattern of distal atrophy but is not usually essential to diagnosis. Muscle imaging can reveal intramuscular fat accumulation which may be associated to functional outcomes. 11
Supplemental assessment tools
Electrodiagnosis is the mainstay of clinical classification into demyelinating (low or very low NCV), axonal (near-normal NCV early, more denervation) or intermediate forms. It can assist in determining the subsequent genetic testing needed. Note that Friedreich and other ataxias and hereditary spastic paraparesis may also show abnormal results so that finding a reduced NCV does not always confirm CMT as a primary diagnosis.
Sural nerve or neuromuscular biopsy is rarely indicated but may help to confirm effect of a genetic variation of uncertain pathogenicity. If done, electron microscopy (EM) studies can delineate details of anatomic findings in the nerve or structural defects of mitochondria.
Early predictions of outcomes
Most forms are slowly progressive and compatible with normal general health and lifespan, with needs for augmentative mobility later in adult life. In general, early onset and greater severity of onset correlate with faster progression.
Assessment should be done for home, school, work and barriers to participation, e.g., uneven terrain, stairs, long distances. Fall prevention includes removing loose rugs, adding handrails for stairs and bathroom. Voice dictation and typing facilitate lengthier written communications. Specialized OT evaluation is often warranted for proprioceptive loss that may impede driving without hand controls.
Social role and social support system
Patients and families need support and information. Encourage affected adults to seek care for themselves. Advocate for modified recreation, camp and sports participation, accommodations at school and work, consider referral for vocational rehabilitation, and joining registries, MDA affiliations, and/or disease-specific national associations.
Referral for genetic counseling should be made, with attention to relief of guilt about passing on the condition, and the effects of a diagnosis on employment, non-medical insurance, reproductive decisions, and family relationships. Truly asymptomatic children in an affected family are not typically tested.
Rehabilitation Management and Treatments
Available or current treatment guidelines
HMSN or CMT-specific comprehensive guidelines are not available. Reviews of effectiveness of orthotic management including custom (not off-the-shelf) inserts for relief of foot pain and flexible AFOs for foot drop are generally favorable. Some surgeries appear beneficial. Evidence to avoid vincristine in CMT1A is strong. Several disease-specific organizations post suggestions for management such as a “practice brief” focused on foot care published by the Centre of Research Excellence in Neuromuscular Disorders Murdoch Children’s Research Institute/University of Sydney, Australia at: https://www.mcri.edu.au/sites/default/files/media/charcot_marie_tooth_-_why_feet_matter_3.pdf
At different disease stages
- Review options for diagnosis with family. Genetic testing for CMT is important to assess the genotype to determine surveillance of vision, hearing or other symptoms.
- Curative treatments are not available; clinical trials of medications, specific to genetic type, are underway though some have been tested and failed to demonstrate benefit.
- Current treatment options focus on managing symptoms and deformities with pain control, physiotherapy, orthotics and surgery.
- Educate HNPP patients to avoid pressure at nerve entrapment area to prevent recurrent wrist or foot drop.
- Night splints are generally not helpful for foot deformity but stretching, serial casting, and therapy for functional improvement and mobility skills have shown benefit. Physical therapy is effective in CMT. It is associated with improvements of walking performance, balance and muscle strength in upper and lower extremities. 12,13
- Recommend alternatives to reduce volume of handwritten work, limiting overuse of distal leg muscle, and treating with NSAIDs and acetaminophen for pain.
- Formal 504 plans address physical accommodation needs including not grading on penmanship; elevator use, extra time or shorter distances due to falls, fatigue and endurance; lunch tray assistance, extra set of books at home. IEPs should usually be reserved for cases where multiple aspects of learning are problematic.
- Reassure that though progressive, most CMT is compatible with gainful employment and normal lifespan.
- Orthotics such as ankle foot orthoses (AFO) are key in the rehabilitative approach in CMT. The use of AFOs demonstrated improving in walking velocity, balance and ankle range of motion.12,14
- The use of hand orthoses may be beneficial. It has demonstrated improvement in manual dexterity, upper limb functioning and activities of daily living.13
- Screen regularly for scoliosis during growth.
- Introduce gait aids including cane, walker, and manual or powered wheelchair only as needed to promote safe and efficient mobility. In advanced stages, individuals may need powered mobility because of hand/upper limb weakness.
- Promote strengthening and use of proximal muscle in exercise and recreation.
- Orthopedic surgery can be considered for correction of foot deformities, tendon transfer and tendon lengthening.15
Coordination of care
An interdisciplinary approach is ideal; team includes patient and family, primary care physician, physiatrist, neurologist, geneticist and/or genetic counselor, physical therapist, occupational therapist, orthotist, and psychologist, social worker or educational specialist. Routine orthopedic evaluation is recommended. Neuropsychology, speech therapy, ENT, ophthalmology, audiology and pulmonology are needed for some forms as well.
Patient & family education
Explain that although CMT is an MDA-covered condition, it is not “muscular dystrophy” but rather peripheral neuropathy. Avoid pursuing occupations requiring above-average fine motor skills. Teach self-advocacy for avoiding overwork and obtaining modifications. Encourage using orthotics, adaptive equipment and techniques to avoid limiting participation. Educate about registries, support organizations, and possible clinical trial participation.
Measurement of treatment outcomes including those that are impairment-based, activity participation-based and environmentally based
Neuropathy Impairment Score (NIS) and CMT Neuropathy score (CMTNS, CMTNS2) have been validated for CMT1A to monitor progression for clinical and research purposes. The CMTNS may not be as sensitive to changes over time. In children, the CMT pediatric scale and CMT disease Infant Scale (CMTInfS) are valid and sensitive outcome measure of disability in children with CMT from the age of 3 years, 16 or younger than 3 years of age.17 Timed 6-10 meter comfortable walk and Maryland Foot Score have been used for orthopedic purposes.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
Abnormal electrodiagnostic study without either thorough neurologic examination or genetic confirmation can lead to misdiagnosis of CMT in cases of HSP, SCA, toxic, metabolic, and mitochondrial disorders.
Help patients avoid sedentary, inactive lifestyles.
Many patients and families are ashamed and fearful about diagnosis, and benefit from meeting others with CMT. MDA resources including MDA camps are available to young people and can greatly increase self-efficacy and self-confidence. Empower patients and families to raise funds and awareness of “the biggest disease no one has ever heard of”.
As a provider it is essential to be aware of clinical trials opportunities and new treatments available for the children with CMT.
Cutting Edge/ Emerging and Unique Concepts and Practice
A phase III clinical trial is investigating PXT3003 for the treatment of CMT1A.18 PXT3003 is a combination of three drugs: baclofen, naltrexone hydrochloride and D-sorbitol. In preclinical studies, this combination, demonstrated lowering of PMP22 mRNA expression and improvement in myelination. It was found to be safe and well tolerated in phase II trials. 6
An anti-progestin (ulipristal acetate) was studied for CMT1A however, the clinical trials was terminated due to its liver toxicity (NCT02600286). 6 Other drugs including ascorbic acid, creatine, curcumin, and ubiquinone were helpful in rodent models with no demonstrable clinical benefit.
Gene therapies are currently under investigation for CMT1A and CMT4C. Engenesis is a gene therapy focus on using DNA molecules plasmids for delivering hepatocyte growth factor for nerve regeneration and further muscle dystrophy prevention.19 Gene replacement therapy for CMT4C focus on intrathechal delivery of SH3TC2 gene into the nervous system, specifically to Schwan cells to improve myelination.20
Cost-effective routes to specific diagnosis and optimal exercise programs are still subjects of study and require individual clinical judgement.
Gaps in the Evidence- Based Knowledge
A cure for CMT is not available; however, for the most common forms of CMT, numerous promising compounds are under study, mainly targeting either the protein degradation pathway or protein overexpression. New genes and modifiers of known genes are being sought to explain some variation in severity and possibly open up other avenues for treatment.
Efforts are devoted to developing responsive outcome measures and biomarkers for this disorder, with quantitative muscle MRI resulting the most sensitive-to-change measure.
- Charcot–Marie–Tooth Diseases: An Update and Some New Proposals for the Classification, Stéphane Mathis et. al. J Med Genet. 2015;52(10):681-690.
- Laurá M, Pipis M, Rossor AM, Reilly MM. Charcot-Marie-Tooth disease and related disorders: an evolving landscape. Curr Opin Neurol. 2019 Oct;32(5):641-650.
- Murakami T, Sunada Y. Schwann Cell and the Pathogenesis of Charcot-Marie-Tooth Disease. Adv Exp Med Biol 2019; 1190:301.
- U.S. Department of Health and Human Services National Institutes of HealthSeptember 2020, Charcot-Marie-Tooth disease, https://medlineplus.gov/genetics/condition/charcot-marie-tooth-disease/#frequency
- Fridman V, Bundy B, Reilly MM, et al. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis. J Neurol Neurosurg Psychiatry 2015; 86:873.
- Boutary S, Echaniz-Laguna A, Adams D, et al. Treating PMP22 gene duplication-related Charcot-Marie-Tooth disease: the past, the present and the future. Transl Res. 2021 Jan;227:100-111.
- Barreto LC, Oliveira FS, Nunes PS, et al. Epidemiologic Study of Charcot-Marie-Tooth Disease: A Systematic Review. Neuroepidemiology 2016; 46:157.
- Phillips JP, Warner LE, Lupski JR, Garg BP. Congenital hypomyelinating neuropathy: two patients with long-term follow-up. Pediatr Neurol 1999; 20:226.
- Huynh, W., & Masters, L. (2020). Multiple cranial nerve enlargement IN Charcot-Marie-Tooth disease. Journal of Neurology, Neurosurgery & Psychiatry, 92(2), 216-217.
- Tian, D., Zhao, Y., Zhu, R., et al. (2020). Systematic review of cmtx1 patients with episodic neurological dysfunction. Annals of Clinical and Translational Neurology, 8(1), 213-223.
- Morrow, J. M., Sinclair, C. D., Fischmann, A., et al. (2016). MRI biomarker assessment of neuromuscular disease progression: A prospective observational cohort study. The Lancet Neurology, 15(1), 65-77.
- Kenis-Coskun, O., & Matthews, D. (2016). Rehabilitation issues in Charcot-Marie Tooth disease. Journal of Pediatric Rehabilitation Medicine, 9(1)31-34.
- Mori, L., Signori, A., Prada, V., et al. (2019). Treadmill training in patients affected by charcot–marie–tooth neuropathy: Results of A multicenter, prospective, randomized, single‐blind, controlled study. European Journal of Neurology, 27(2), 280-287.
- Õunpuu, S., Garibay, E., Acsadi, G., Brimacombe, M., & Pierz, K. (2021). The impact of orthoses on gait in children With Charcot-Marie-Tooth disease. Gait & Posture, 85, 198-204. doi:10.1016/j.gaitpost.2021.02.005
- Matilde, L. (2018). Prevalence and orthopedic management of foot and ankle deformities in Charcot–Marie–Tooth disease. Muscle and Nerve, 57(2), 255-259.
- Burns,J., Ouvrier, R., Estilow, T., Shy, R., Laurá, M., Pallant, J. F., . . . Finkel, R. S. (2012). Validation of the charcot-marie-tooth disease pediatric scale as an outcome measure of disability. Annals of Neurology, 71(5), 642-652.
- Manadrakas, M. et.al. (2018). Development and validation of the Charcot-Marie-Tooth Disease Infant Scale. Brain, 141(12), 3319-3330.
- Attarian S. Assessing long term safety and tolerability of Pxt3003 in patients With Charcot-marie-tooth disease type 1a – full text view. https://clinicaltrials.gov/ct2/show/NCT03023540. Published January 18, 2017. Accessed March 10, 2021.
- Ray, F.(2020, July 29). Phase 1/2A trial of gene THERAPY Engensis for CMT1A begins in Korea. Retrieved March 13, 2021, from https://charcot-marie-toothnews.com/2020/07/29/phase-1-2a-trial-of-gene-therapy-engensis-for-cmt1a-begins-in-korea
- Schiza, N. et.al. (2019). Gene replacement therapy in a model of Charcot-Marie-Tooth 4C neuropathyNatasa. Brain, 142(5), 1227-1241. doi:doi: 10.1093/brain/awz064.
Original Version of the Topic:
Joline Skinner, MD. Hereditary Motor Sensory Neuropathy (HMSN). 5/5/2011.
Previous Revision(s) of the Topic:
Vikki A. Stefans, MD. Hereditary Motor Sensory Neuropathy (HMSN). 11/16/2016.
Yuxi Chen, MD
Ipsen, Research Grant paid to institution, PI for Pediatric lower limb spasticity study and Adult lower limb spasticity study
MERZ, Payment, Advisory board
Andrew Bloomfield, MD
Nothing to Disclose
Coral Candelario-Velazquez, MD
Nothing to Disclose