What are the clinical manifestations, diagnostic evaluation, and treatment options for Charcot-Marie Tooth (CMT) disease in children?

Charcot-Marie-Tooth Disease in Children

Overview

Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy in children, characterized by progressive distal muscle weakness creating a "stork leg" appearance, sensory loss in a glove-and-stocking distribution, and bilateral pes cavovarus foot deformities, with diagnosis requiring electrodiagnostic studies followed by targeted genetic testing. 1

Clinical Manifestations

Motor Symptoms

• Distal muscle weakness and atrophy beginning in the lower limbs, particularly affecting peroneal muscles, creating the characteristic "stork leg" appearance 1, 2
• Progressive foot drop with steppage gait abnormalities 1
• Weakness typically starts distally and progresses proximally over time 3
• Symptoms usually begin in childhood or adolescence, though onset can occur at any age 1

Sensory Deficits

• Sensory loss in "glove and stocking" distribution reflecting length-dependent axonal involvement 1, 2, 4
• Decreased or absent deep tendon reflexes 1

Skeletal Deformities

• Bilateral pes cavovarus (high arch with inverted heel) is the most common foot deformity 1
• Foot deformities arise from chronic imbalance between intrinsic and extrinsic foot muscles 2
• Clumsiness of gait and foot drop are early manifestations 5

Preserved Function

• Cognitive function and development remain relatively normal, distinguishing CMT from other neurodevelopmental disorders 1

Diagnostic Evaluation

Step 1: Electrodiagnostic Studies (Essential First Step)

Electrodiagnostic studies are mandatory for proper classification and must be performed before genetic testing. 1, 4

• Demyelinating forms (CMT1): Slowed nerve conduction velocities 1
• Axonal forms (CMT2): Normal or slightly reduced conduction velocities with reduced amplitude 1
• CMTX (X-linked): Asymmetric and nonhomogeneous conduction slowing that can mimic acquired inflammatory neuropathies 1

Step 2: Targeted Genetic Testing

Follow a stepwise approach based on electrophysiological findings rather than broad panel testing initially. 1, 4

First-Tier Testing Based on Electrophysiology:

For Demyelinating Forms:

• Test for PMP22 gene duplication (CMT1A) first, as it accounts for approximately 70% of CMT1 cases 1, 2
• Point mutations in PMP22 can also cause CMT1A with similar phenotypes 2

For Axonal Forms:

• Test for MFN2 mutations first, accounting for approximately 33% of CMT2 cases 1, 2
• MFN2 mutations disrupt mitochondrial fusion and axonal transport mechanisms 2

For Possible X-Linked Inheritance:

• Test for Cx32(GJB1) mutations, accounting for approximately 12% of all CMT cases 1, 2

Genetic testing provides 100% specificity for established pathogenic mutations. 1, 4

Differential Diagnosis Considerations

CMT must be differentiated from acquired neuropathies including diabetic, toxic, or inflammatory neuropathies 1, 4

Common Diagnostic Pitfalls to Avoid

• Failure to perform electrodiagnostic studies before genetic testing - this is the most critical error as it prevents proper classification 1
• Overlooking hereditary causes in sporadic cases - 30% of mutations are de novo, so absence of family history does not exclude CMT 1
• Incomplete genetic testing by not following the tiered approach based on electrophysiology 1
• Misdiagnosing CMTX as acquired inflammatory neuropathy due to its asymmetric conduction slowing pattern 1
• Assuming all cases have family history when many represent new mutations 1

Treatment Approach

Rehabilitation (Mainstay of Treatment)

Since no curative medical treatments exist and surgical outcomes are problematic, rehabilitation is the primary treatment modality. 3

Exercise Programs:

• Aerobic exercise is effective in improving strength and general fitness 3
• Strengthening exercises improve muscle function 3, 6
• Stretching exercises are somewhat effective in maintaining range of motion 3, 6

Orthotic Management:

Orthotic devices are the mainstay of maintaining mobility, ambulation, and upper extremity function. 3

• Ankle-foot orthoses (AFOs) for foot drop and gait stabilization 3
• Upper extremity orthotics for hand function preservation 3

Multidisciplinary Care Components

Access to multidisciplinary care should be advocated for all children with CMT. 6

The following areas require management according to consensus-based recommendations:

• Balance and mobility impairment 6
• Sensory symptoms 6
• Muscle cramps 6
• Upper limb function impairment 6
• Respiratory impairment monitoring 6
• Joint range of motion maintenance 6
• Non-surgical management of joint deformity 6

Emerging Therapies (Not Yet Standard of Care)

Currently, no effective drug treatment is available for CMT, though multiple approaches are under investigation. 7

Investigational approaches include:

• PXT3003 is in the most advanced phase for CMT1A with an ongoing phase-III trial 7
• Gene silencing approaches (ASO, siRNA, CRISPR-Cas9) targeting PMP22 overexpression in CMT1A 7
• Gene therapy for recessive forms with loss-of-function mutations 7
• HDAC6 inhibitors showing promise in improving axonal transport 7

Surgical Intervention

Surgery for skeletal deformities has problematic outcomes and should be reserved for severe cases. 3, 7

Key Clinical Pearls

• CMT prevalence is approximately 1:2,500 people, making it the most common inherited neuromuscular disorder 1, 8
• Inheritance patterns include autosomal dominant (most common), X-linked, and autosomal recessive 1
• Over 40 genes are implicated in CMT, with constant revision as new genes are discovered 2, 8
• Nerve biopsy is not routinely performed but may show characteristic ultrastructural features that can guide genetic testing 8
• Clinical trials are ongoing for disease-modifying therapies, but none are currently approved 7, 8