# Charcot-Marie-Tooth Disease

Evaluate suspected Charcot-Marie-Tooth disease with phenotype, nerve conduction studies, and sequential genetic testing; distinguish uniform inherited demyelination from acquired neuropathy and pressure-palsy phenotypes, then initiate early rehabilitation, orthotic, orthopedic, genetic, and complication-directed care.

**Clinical question:** How should physicians confirm, genetically classify, and manage Charcot-Marie-Tooth disease while excluding acquired neuropathy?

Updated: 2026-08-24T17:51:34.962890+00:00

## What matters in practice
- After a compatible clinical examination, obtain nerve conduction studies to classify the neuropathy and direct genetic testing. [14][5]
- Order PMP22 deletion/duplication analysis first in a proband with CMT; the 17p11.2 PMP22 duplication may account for as much as 50% of CMT. [21]
- Uniform demyelinating sensorimotor neuropathy warrants initial PMP22 duplication testing even without a dominant family history, because de novo duplications occur. [19][18]
- Recurrent focal palsies after minor compression suggest HNPP and should prompt testing for PMP22 deletion; most HNPP is caused by a 1.5-Mb 17p11.2 deletion. [18][19]
- No pharmacologic disease-modifying therapy is established; begin individualized rehabilitation, orthotic assessment, and early orthopedic evaluation for functional deficits and deformity. [4][14]

## Identify the inherited neuropathy pattern and exclude acquired mimics

The diagnostic priority is separating a chronic inherited neuropathy from a potentially treatable acquired process.

Suspect CMT in a length-dependent motor and sensory neuropathy with distal weakness, distal sensory loss, absent deep-tendon reflexes, and foot or hand deformity, particularly when the course is slowly progressive or the pedigree suggests autosomal dominant, X-linked, or recessive inheritance. Document age at onset, walking milestones, progression, prior foot and tendon procedures, focal compression palsies, and a three-generation pedigree before ordering molecular testing. [4][14][23]

Do not use the absence of family history to exclude CMT. PMP22 duplications can arise de novo, and a patient with a sporadic, uniformly demyelinating sensorimotor polyneuropathy should still undergo CMT1A-directed testing. [18][19]

Escalate evaluation for an acquired neuropathy when the presentation is not a stable, length-dependent inherited pattern, particularly with prominent asymmetry, recurrent stepwise deterioration, or other features not explained by the family phenotype. Electrodiagnostic testing is the required next discriminator because it separates demyelinating from axonal patterns and helps distinguish generalized inherited neuropathy from focal pressure-related disease. [14][19]
- At baseline, document distal motor function, sensory deficits, deep-tendon reflexes, gait, foot architecture, toe deformity, and hand intrinsic function to guide rehabilitation and orthopedic planning. [4][17]
- Ask specifically about transient or recurrent mononeuropathies after minor trauma or compression; this history shifts testing toward PMP22 deletion analysis for HNPP. [18][19]
- Refer early to neuromuscular neurology or clinical genetics when phenotype, electrophysiology, inheritance, or variant interpretation is uncertain. Genetic testing requires phenotype definition, pedigree analysis, and pretest counseling. [23]

*Clinical patterns that change the first genetic test and next diagnostic action. [18][19][21]*

| Pattern | Key discriminator | First molecular action | Interpretation and next step |
| --- | --- | --- | --- |
| Typical chronic CMT phenotype | Distal motor-sensory neuropathy with deformity and reduced reflexes [4][14] | PMP22 deletion/duplication analysis [21] | A PMP22 duplication establishes CMT1A; if testing is negative, proceed according to electrophysiology and phenotype with a multigene panel. [19][21] |
| Uniform demyelinating sensorimotor neuropathy | Demyelinating pattern on nerve conduction studies, including patients without family history [19] | PMP22 duplication analysis [19][21] | Negative duplication testing should be followed by a CMT1 multigene panel when available. [19] |
| Recurrent focal compression palsies | Asymmetric dysfunction at compression sites after minor trauma; mild slowing and increased motor latencies may occur electrophysiologically [18] | PMP22 deletion analysis [18][21] | A pathogenic deletion supports HNPP; counsel regarding avoidance of nerve compression and recognize that repeated injuries can create CMT1-like chronic deficits. [18] |
| Known familial pathogenic variant | Affected relative with an established molecular diagnosis [23] | Targeted testing for the familial variant [23] | Use the result for diagnostic confirmation, counseling, reproductive planning, and possible trial eligibility. [23] |

## Use nerve conduction studies to classify the neuropathy before broad sequencing

Electrophysiology is the bridge between bedside phenotype and efficient molecular testing.

Obtain a formal neurophysiological study after clinical suspicion of CMT. The study should establish whether the neuropathy is predominantly demyelinating or axonal and should assess motor and sensory nerves rather than relying on clinical subtype labels alone. [14][5]

For a classical phenotype, upper-extremity motor nerve conduction velocity (MNCV) of greater than 15 to 35 m/s is categorized as slow; MNCV of 15 m/s or less identifies a severely slow subgroup associated with delayed walking in the cited testing algorithm. These categories can direct phenotype-specific testing but do not encompass every genetic cause of CMT. [20]

In suspected HNPP, electrophysiology supports the clinical diagnosis by showing mild conduction slowing and increased motor latencies; findings must be interpreted with the compression-palsy history because chronic repeated focal injury can overlap clinically with CMT1. [18]
- Classify demyelinating disease before applying a CMT1-oriented panel; PMP22 duplication remains the initial molecular test in this branch. [19]
- Use an axonal electrodiagnostic pattern with the clinical phenotype and inheritance pattern to select a broader CMT panel rather than sequentially testing genes without phenotypic direction. [5][23]
- If electrodiagnostic findings or clinical tempo are discordant with inherited CMT, reconsider acquired neuropathies before assigning a genetic diagnosis. [14][19]

*Electrodiagnostic categories used in published CMT testing strategies. [20]*

| Upper-extremity MNCV category | Clinical context in the testing algorithm | Testing implication |
| --- | --- | --- |
| 15 to 35 m/s | Classical phenotype with slow MNCV [20] | Use phenotype-guided inherited neuropathy testing; in a demyelinating pattern, begin with PMP22 duplication analysis. [19][20] |
| 15 m/s or less | Delayed walking with severely slow MNCV [20] | Use the severe demyelinating phenotype to guide targeted or panel-based genetic evaluation after appropriate PMP22 copy-number testing. [20][21] |
| Mild slowing with increased motor latencies | Possible HNPP, especially with focal compression palsies [18] | Order PMP22 deletion analysis and interpret in the context of recurrent pressure-related neuropathies. [18][21] |

## Apply sequential genetic testing rather than indiscriminate gene-by-gene testing

Copy-number analysis and phenotype-directed panels provide the practical diagnostic sequence.

Order separate PMP22 deletion/duplication analysis as the first test for a proband with CMT unless the chosen laboratory explicitly includes validated PMP22 copy-number analysis in its panel. The assay differs from methods used in many multigene panels, and the PMP22 duplication at 17p11.2 accounts for as much as 50% of CMT. [21]

For autosomal dominant or sporadic demyelinating hereditary neuropathy, screen first for chromosome 17p duplication encompassing PMP22. If negative, obtain a disease-specific next-generation sequencing panel that includes known CMT genes rather than serial single-gene testing when available. [5][19]

If a multigene panel is nondiagnostic in a familial case, consider whole-exome sequencing; published algorithms reserve this escalation for familial cases after negative PMP22 testing and panel-level evaluation. [19] Whole-genome sequencing has also identified pathogenic variation in CMT, but its role should be individualized to unresolved cases and the laboratory's ability to detect relevant variant classes. [1][5]

Interpret the molecular result alongside phenotype and electrophysiology. A genetic finding can establish diagnosis, support counseling and reproductive planning, and identify patients for research or therapeutic trials; pretest counseling should address these implications before testing. [23]
- If a relative has a known pathogenic variant, order targeted familial-variant testing rather than repeating a broad diagnostic sequence. [23]
- If PMP22 copy-number analysis is normal, request that a subsequent multigene panel not duplicate PMP22 deletion/duplication testing unless clinically indicated. [21]
- For a demyelinating phenotype with negative PMP22 duplication testing, include genes associated with CMT1 in the subsequent panel. [19]

### PMP22-related branch

PMP22 dosage produces two clinically useful syndromic branches. Duplication of the 1.5-Mb 17p11.2 interval including PMP22 causes CMT1A, whereas deletion of the corresponding interval causes most HNPP. The latter presents with recurrent dysfunction at nerve-compression sites and may progressively resemble CMT1 when repeated injuries do not fully reverse. [18][19]
- A PMP22 duplication result supports CMT1A and should redirect care toward chronic functional, orthopedic, and rehabilitation surveillance. [18][14]
- A PMP22 deletion result supports HNPP and should prompt counseling to reduce mechanical compression and trauma to vulnerable peripheral nerves. [18][19]

*Sequential molecular testing pathway for suspected CMT. [5][19][21][23]*

| Step | Who should receive it | Test | Action after result |
| --- | --- | --- | --- |
| 1 | All probands with clinically suspected CMT [21] | PMP22 deletion/duplication analysis [21] | Duplication supports CMT1A; deletion supports HNPP; if normal, proceed using electrophysiology and phenotype. [18][21] |
| 2 | Demyelinating phenotype with negative PMP22 duplication [19] | CMT1 multigene next-generation sequencing panel [19] | Use the identified variant with phenotype and segregation information for diagnostic classification and counseling. [19][23] |
| 2 | Other unresolved CMT phenotypes after phenotype characterization [5][23] | Phenotype-specific broad CMT panel [5] | Avoid gene-by-gene testing when parallel panel testing is available. [5][19] |
| 3 | Familial disease remaining unresolved after prior testing [19] | Whole-exome sequencing [19] | Reassess phenotype, segregation, and variant interpretation with neuromuscular genetics support. [19][23] |

## Treat disability and deformity early with multidisciplinary rehabilitation and orthopedic care

Management is functional and complication-directed because established pharmacologic disease modification is unavailable.

There is no established pharmacologic disease-modifying treatment for any CMT subtype. Do not defer symptomatic and functional care while genetic testing is pending: initiate multidisciplinary management focused on individualized exercise, muscle-strength training, orthotic devices, symptom relief, and surveillance for associated complications. [4][14]

Refer for rehabilitation assessment early, with individualized exercise guidance and orthotic adaptation targeted to the observed functional deficit. Strength training and orthoses are core rehabilitative approaches, and early intervention is intended to identify and improve functional limitations before fixed disability or deformity becomes more difficult to address. [4][14]

Obtain orthopedic assessment when foot deformity, gait limitation, progressive imbalance, or fixed musculoskeletal abnormality compromises function. Conservative surgical options, including tendon procedures, are part of orthopedic management and should be considered in the context of deformity and functional goals rather than delayed until advanced disability. [14][17]

At longitudinal visits, reassess gait, distal strength, hand function, sensory loss, reflexes, foot structure, orthotic fit, falls or mobility limitations, and need for surgical reassessment. Standardized outcome measures include the CMT Neuropathy Score in adults and the Charcot-Marie-Tooth Pediatric Scale in children and adolescents. [17]
- Use orthotic evaluation for gait or distal weakness affecting mobility; revise the device when function, alignment, or deformity changes. [4][14]
- Use physical and occupational rehabilitation to address lower-extremity weakness, hand intrinsic weakness, gait impairment, and activity-specific limitations. [4][17]
- Coordinate genetic counseling after molecular confirmation to address inheritance, relatives at risk, and reproductive planning. [23]
- Consider therapeutic-trial or research referral after molecular diagnosis when relevant, because genetic confirmation can support trial selection. [23]

*Functional management actions linked to common CMT deficits. [4][14][17]*

| Clinical problem | Assessment action | Intervention | Follow-up focus |
| --- | --- | --- | --- |
| Distal weakness or gait impairment | Document gait and distal motor function [4][17] | Individualized exercise guidance, muscle-strength training, and orthotic assessment [4][14] | Reassess mobility and orthotic fit as function changes. [14] |
| Foot deformity or toe clawing | Assess foot architecture, deformity progression, and functional limitation [17] | Early orthopedic evaluation; consider conservative tendon surgery when indicated by deformity and function. [14][17] | Monitor alignment, gait, footwear and orthotic needs. [14] |
| Hand intrinsic weakness | Document hand function and activity limitations [17] | Occupational and rehabilitative interventions directed to functional deficits. [4][17] | Reassess task-specific function and adaptive needs. [17] |
| Pediatric CMT | Use a pediatric functional scale where available [17] | Multidisciplinary rehabilitation, orthotics, and early orthopedic management. [4][14] | Track disability longitudinally with CMTPedS. [17] |

## Recognize subtype-associated disease beyond the peripheral nerves

A molecular diagnosis may alter surveillance when a CMT subtype has extra-neurologic associations.

CMT associated with INF2 mutations has been reported with renal disease, particularly focal segmental glomerulosclerosis. In a patient with INF2-associated CMT or an unresolved CMT phenotype accompanied by proteinuric kidney disease, coordinate nephrology evaluation rather than attributing renal findings to nonspecific comorbidity. [2]

Use syndrome-specific features to refine broad-panel results. The CMT genetic spectrum includes phenotypes with deafness, cataracts, retinitis pigmentosa, intellectual disability, and other non-neurologic manifestations; these findings should prompt focused review of genes and referral to the relevant specialty. [21]

For HNPP, management must include prevention of recurrent mechanical nerve injury because focal dysfunction can follow minor compression or trauma. Repeated injuries may leave persistent deficits and produce clinical overlap with CMT1 over time. [18]
- For INF2-associated CMT with renal manifestations, evaluate for FSGS through nephrology rather than treating the neuropathy as an isolated disorder. [2]
- For suspected HNPP, document compression triggers and counsel patients to reduce focal nerve compression and trauma. [18][19]
- When extra-neurologic findings accompany neuropathy, ensure the selected genetic panel and variant interpretation address syndromic inherited neuropathies. [21][23]

*Genotype-phenotype associations that warrant an additional clinical action. [2][18][21]*

| Association | Clinical clue | Action |
| --- | --- | --- |
| INF2-associated CMT | Neuropathy with renal disease or proteinuria [2] | Assess for FSGS and involve nephrology. [2] |
| PMP22 deletion / HNPP | Recurrent focal palsies after minor compression or trauma [18] | Confirm with PMP22 deletion testing and implement compression-injury prevention. [18][21] |
| Syndromic inherited neuropathy | Neuropathy with deafness, cataract, retinitis pigmentosa, or intellectual disability [21] | Use phenotype-directed genetic interpretation and specialty referral for the associated manifestation. [21][23] |

## References
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## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.