Charcot-Marie-Tooth disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Charcot-Marie-Tooth disease affects peripheral axons, myelin or both. Distal motor units with the longest axons are lost first, producing intrinsic-foot imbalance, high arches, clawing and weakness of ankle dorsiflexion and eversion. Calf wasting creates the traditional inverted-champagne-bottle appearance. As disease progresses, hand intrinsic wasting impairs buttons, handwriting and grip. Sensory loss may be subtle on history but is demonstrable distally and contributes to poor balance when vision is removed.

The label does not define one gene or prognosis. CMT1A is common and often mild to moderate, while recessive or early-onset forms may produce severe deformity, scoliosis or respiratory involvement. X-linked CMT from GJB1 can affect men more severely and may occasionally produce transient central symptoms. A family history can look negative because of de novo variants, variable expression, adoption or small families. Genetic counselling should precede predictive and reproductive testing.

Management is anticipatory and function based. Physiotherapy maintains flexibility, strength and aerobic fitness without expecting exercise to restore lost motor units. Orthotists match ankle-foot devices to foot drop and instability. Surgeons correct a flexible or fixed cavovarus deformity only after neuromuscular and gait assessment, because isolated procedures can worsen imbalance. Neuropathic pain, cramps and musculoskeletal overuse need different strategies. All medicines should be necessary and monitored: vincristine is contraindicated in demyelinating Charcot-Marie-Tooth disease and any proposed neurotoxic chemotherapy warrants joint oncology and neuromuscular review.

Key points

Charcot-Marie-Tooth disease is a group of inherited motor and sensory neuropathies, typically causing slowly progressive length-dependent distal weakness, wasting, sensory loss and depressed reflexes.
Foot drop, frequent ankle sprains, tripping, difficulty heel walking, pes cavus, hammer toes and thin lower legs are common early clues; hand weakness often emerges later.
CMT1 is predominantly demyelinating with uniformly slow nerve conduction, CMT2 is predominantly axonal with relatively preserved velocities and reduced amplitudes, and intermediate forms overlap.
PMP22 duplication causes the common autosomal-dominant CMT1A, while PMP22 deletion causes hereditary neuropathy with liability to pressure palsies, a related but distinct phenotype.
Inheritance may be autosomal dominant, recessive, X linked or mitochondrial, so male-to-male transmission, skipped generations and maternal patterns can direct genomic testing.
Sensory symptoms are often milder than motor disability but loss of pain and proprioception increases ulcer, burn, imbalance and injury risk.
Tremor, scoliosis, hearing impairment, hip dysplasia, sleep-disordered breathing or diaphragmatic weakness occur in selected genotypes rather than every patient.
Nerve-conduction studies establish a hereditary demyelinating, axonal or intermediate pattern and help distinguish uniform inherited slowing from patchy acquired demyelination.
Genetic testing should follow phenotype, pedigree and neurophysiology through the NHS Genomic Test Directory, beginning with high-yield copy-number testing when appropriate.
There is no universal disease-modifying medicine; ankle-foot orthoses, targeted exercise, foot care, occupational adaptation, pain treatment and selected orthopaedic surgery preserve function.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

PMP22 copy-number disease

PMP22 duplication causes common demyelinating CMT, while deletion produces hereditary liability to pressure palsies, a related but clinically distinct inherited neuropathy.

Axonal and other inherited variants

Pathogenic variants affecting axonal transport, mitochondrial function, myelin and Schwann-cell biology produce autosomal-dominant, recessive, X-linked or mitochondrial CMT subtypes.

De novo or obscured inheritance

A small family, reduced penetrance, adoption or a new pathogenic variant can conceal the hereditary pattern, so absence of reported relatives does not exclude CMT.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Myelin or axonal dysfunction
The causal variant impairs Schwann-cell myelin maintenance or intrinsic axonal function, reducing efficient impulse transmission along peripheral nerves.
2
Length-dependent fibre loss
The longest motor and sensory axons fail first, producing distal leg weakness, sensory loss and depressed reflexes before later hand involvement.
3
Chronic denervation and imbalance
Repeated denervation and partial reinnervation cause distal wasting, while unequal muscle pull contributes to cavus feet, hammer toes and ankle instability.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Distal leg phenotype

Bilateral foot drop, weak eversion, frequent ankle inversion and distal calf wasting progress slowly over years while proximal hip power is relatively preserved.

Cavovarus foot

High medial arches, plantar-flexed first ray, claw or hammer toes and callus reflect chronic intrinsic-muscle imbalance and may become painful or rigid.

Length-dependent sensation

Vibration, joint position, pinprick and temperature reduce distally, contributing to positive Romberg testing and unnoticed foot injury.

Upper-limb evolution

Thenar, hypothenar and interosseous weakness later causes poor pinch, buttoning difficulty and visible hand wasting without an isolated nerve distribution.

Atypical rapid declineRed flag

Weakness progressing over days or weeks, marked asymmetry, proximal predominance or new sphincter and bulbar features requires urgent search for a superimposed disorder.

Pressure-palsy phenotype

Recurrent focal palsies after leaning, crossing legs or carrying straps suggests hereditary neuropathy with liability to pressure palsies rather than typical CMT1A.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Nerve-conduction studiesFirst step
Why
Classify demyelinating, axonal or intermediate inherited neuropathy and assess uniformity.
Interpretation and limitations
Uniform diffuse slowing supports hereditary myelin disease, whereas conduction block and temporal dispersion out of proportion may indicate acquired inflammatory neuropathy.
02
Electromyography
Why
Map chronic denervation, severity and competing root or motor-neurone disease.
Interpretation and limitations
Long-duration motor units and distal loss support chronic neuropathy; acute active denervation or focal asymmetry needs clinical explanation.
03
PMP22 copy-number analysis
Why
Detect the common CMT1A duplication or HNPP deletion when neurophysiology fits.
Interpretation and limitations
Use as a high-yield first genomic step in an appropriate demyelinating or pressure-palsy phenotype before broad sequencing.
04
Inherited neuropathy gene panel
Why
Identify a causal variant after pedigree and electrophysiological stratification.
Interpretation and limitations
Interpret pathogenicity and segregation through clinical genetics; a variant of uncertain significance does not confirm diagnosis or justify predictive family testing.
05
Targeted acquired-neuropathy screen
Why
Find treatable comorbidity when onset, pain or progression is atypical.
Interpretation and limitations
Glucose, B12, thyroid, paraprotein, renal, liver or autoimmune tests are selected from phenotype because inherited and acquired neuropathies can coexist.
06
Foot, gait and orthotic assessment
Why
Quantify deformity, pressure points, balance and equipment requirements.
Interpretation and limitations
Determine flexibility, hindfoot alignment, callus, skin integrity and footwear before orthosis or surgery; radiographs help operative planning rather than genetic diagnosis.
07
Respiratory or sleep testing
Why
Investigate morning headache, orthopnoea, weak cough or a genotype carrying diaphragmatic risk.
Interpretation and limitations
Measure sitting and supine vital capacity and overnight carbon dioxide through respiratory specialists; this is not routine for every mild subtype.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Acquired demyelinating neuropathy

Rapid or relapsing progression, non-uniform conduction block and proximal weakness favour CIDP, whereas uniform slowing, longstanding deformity and a pedigree support CMT.

Diabetic or toxic polyneuropathy

An exposure or metabolic timeline with predominantly axonal length-dependent loss may mimic CMT; childhood clumsiness, cavus feet and affected relatives support inheritance.

Distal myopathy

Distal muscle weakness with preserved sensation and relatively preserved sensory nerve responses favours a primary muscle disorder rather than motor-sensory neuropathy.

Hereditary pressure-palsy syndrome

Recurrent focal palsies after minor compression and PMP22 deletion suggest HNPP rather than the steadily length-dependent weakness typical of CMT.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected inherited neuropathyEstablish phenotype and pedigreeFirst stepSlow distal weakness, cavus feet or a family history suggests Charcot-Marie-Tooth disease.

1Map motor, reflex and sensory findings in all limbs, inspect feet and spine, and ask about childhood milestones, falls, hearing, breathing and relatives.
2Build a three-generation pedigree including ages and severity, while explaining that absence of known affected relatives cannot exclude inherited disease.
3Refer for neuromuscular assessment and nerve conduction before broad genomic testing, screening acquired contributors only where presentation supports them.

02Genomic confirmationChoose the molecular test from neurophysiologyClinical and electrophysiological evidence supports an inherited motor-sensory neuropathy.

1Use uniform demyelination, axonal loss, sex pattern and pressure-palsy history to select PMP22 copy number, targeted gene or NHS panel testing.
2Provide pre-test counselling about uncertain results, incidental findings, insurance questions and implications for parents, siblings and children.
3Confirm segregation and arrange genetic counselling before predictive testing or reproductive decisions, avoiding interpretation of an uncertain variant as causal.

03Function planPrevent falls and deformityFoot drop, instability, contracture or hand weakness limits daily life.

1Prescribe a personalised stretching, balance, moderate-strength and aerobic programme, then select footwear, insoles or ankle-foot orthoses from gait assessment.
2Use occupational therapy for hand tools, writing, work and fatigue conservation, and assess driving controls when ankle or hand weakness affects safety.
3Refer progressive painful or rigid cavovarus deformity to an orthopaedic foot service working with neuromuscular clinicians, discussing staged goals and recurrence.

04Unexpected changeFind disease on top of CMTPain, weakness or disability accelerates beyond the established trajectory.

1Re-examine localisation and tempo, checking diabetes, B12, thyroid, paraprotein, compression, inflammatory neuropathy, medicine toxicity and spinal disease.
2Repeat neurophysiology or image a focal root, nerve or cord when asymmetry, conduction block, sphincter symptoms or proximal weakness is new.
3Treat the superimposed diagnosis on its merits rather than accepting inherited neuropathy as a sufficient explanation for every neurological symptom.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

May reduce burning or shooting neuropathic pain but does not change hereditary nerve degeneration.

Amitriptyline

For neuropathic pain, start at a low nightly oral dose such as 10 mg and titrate cautiously using the current BNF and local pathway.

Anticholinergic effects, sedation, falls, postural hypotension, conduction disease and overdose toxicity require review, particularly where balance is already impaired.

An alternative for distressing neuropathic pain when non-drug measures and foot mechanics have been addressed.

Gabapentin

Use gradual oral titration under the current BNF with kidney-dose adjustment and a planned trial endpoint based on function and pain relief.

Dizziness, oedema, somnolence, misuse and respiratory depression with opioids can worsen gait safety; taper after sustained use rather than stopping abruptly.

This is a high-risk medicine warning because vincristine can produce profound, sometimes irreversible neuropathy in an already vulnerable peripheral nerve.

Vincristine avoidance

Do not administer vincristine to a person with the demyelinating form of Charcot-Marie-Tooth disease; this is a product contraindication rather than a dose-adjustment problem.

For an axonal or incompletely characterised inherited neuropathy, do not extrapolate a universal absolute ban: involve oncology, pharmacy and neuromuscular specialists, examine alternatives and document the tumour-specific risk-benefit decision.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Falls and progressive mobility loss

Foot drop, proprioceptive loss and ankle instability cause tripping, sprains and increasing reliance on orthoses or mobility aids.

Deformity and pressure injury

Cavus feet, hammer toes and reduced protective sensation create callus, ulcer, burn and footwear problems requiring regular foot care.

Pain and upper-limb disability

Neuropathic or mechanical pain and later hand weakness can impair writing, buttons, tools and employment despite relatively slow disease progression.

Genotype-specific systemic effects

Selected subtypes cause hearing, respiratory or spinal complications, so molecular diagnosis can direct surveillance without assuming these problems in every patient.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Review falls, walking distance, foot drop, hand function, pain, fatigue and participation rather than relying on strength grading alone.
Inspect feet for callus, ulcer, footwear pressure and burns, increasing podiatry input when sensation, diabetes or deformity raises skin risk.
Reassess orthosis fit as weakness and deformity evolve, because an old device can create pressure injury or fail to control the knee.
Monitor contractures, scoliosis and hip or knee pain, referring early when a flexible deformity begins to become fixed.
Ask about hearing, swallowing, breathing and sleep only with continued awareness of genotype-specific risks and new symptoms.
Update the medicine list for neurotoxicity before chemotherapy or major treatment and provide an accessible diagnosis alert for oncology teams.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Feet may predate weakness

Childhood high arches or recurrent ankle sprains can reveal inherited neuropathy years before the patient notices distal power loss.

Uniform slowing suggests genes

Inherited demyelination tends to affect nerves evenly, while patchy block and dispersion raises an acquired inflammatory process that may be treatable.

Copy number comes first

In a typical demyelinating phenotype, PMP22 duplication testing can be more efficient than immediately ordering a very broad sequence panel.

Pain has multiple sources

Neuropathic burning, joint overload, tendon strain and callus pressure need different treatment despite occurring in the same inherited condition.

An inherited diagnosis is not closure

Diabetes, compression and inflammatory neuropathy can coexist, so abrupt progression deserves a fresh diagnostic approach.

11Common pitfallsFrequent interpretation and management errors.

01
Assuming pes cavus alone proves Charcot-Marie-Tooth disease.
02
Ordering broad genetics before phenotype and nerve conduction are established.
03
Treating a variant of uncertain significance as a confirmed cause.
04
Missing ulcers because the patient reports little foot pain.
05
Discouraging all exercise rather than avoiding damaging overwork.
06
Giving vincristine without identifying demyelinating Charcot-Marie-Tooth disease or obtaining specialist review of another inherited neuropathy.
07
Attributing rapidly new proximal weakness to natural progression.