Hereditary Motor Sensory Neuropathies

Definition: Hereditary Motor Sensory Neuropathies (HMSN), also known as Charcot-Marie-Tooth (CMT) disease, are a group of inherited peripheral neuropathies characterized by progressive distal muscle weakness and sensory loss.

Epidemiology:

• Incidence: 1 in 2500 (Most common inherited neuropathy).
• CMT1A: 50% of all CMT cases.
• Inheritance: Mostly Autosomal Dominant.

Historical Note: Named after Jean-Martin Charcot, Pierre Marie (France), and Howard Henry Tooth (UK) who independently described the condition in 1886.

Genetic Basis of HMSN/CMT:

Key Genetic Points:

• CMT1A (50%): PMP22 gene duplication (Chromosome 17). Most common cause.
• CMT1B: MPZ (Myelin Protein Zero) mutation. Demyelinating.
• CMT2A: MFN2 (Mitofusin 2) mutation. Axonal transport defect.
• CMTX: Connexin 32 mutation. X-linked inheritance.

Genetic Testing:

• First-line: PMP22 duplication/deletion analysis (detects 70% of CMT1).
• Second-line: Targeted gene panels or whole exome sequencing.
• Prenatal testing available for known familial mutations.

Cellular and Molecular Mechanisms:

CMT pathophysiology depends on the specific genetic defect:

CMT1 (Demyelinating - 60% of cases):

• Schwann Cell Dysfunction: PMP22 or MPZ mutations disrupt myelin formation.
• Demyelination/Remyelination Cycles: Repeated attempts at remyelination create characteristic 'onion bulb' formation on nerve biopsy.
• Result: Slowed nerve conduction velocities (less than 38 m/s).
• Clinical Effect: Progressive distal weakness and sensory loss.

CMT2 (Axonal - 20% of cases):

• Axonal Degeneration: MFN2 mutations affect mitochondrial function and axonal transport.
• Wallerian Degeneration: Distal axon breakdown without primary demyelination.
• Result: Normal conduction velocities but reduced amplitude.
• Clinical Effect: Similar weakness pattern, often later onset.

Mechanism of Cavovarus Foot Deformity:

The characteristic foot deformity results from selective muscle weakness:

1. Peroneus Brevis: Weakens first (primary evertor of hindfoot).
2. Tibialis Posterior: Relatively preserved. Unopposed inversion pulls hindfoot into varus.
3. Peroneus Longus: Relatively preserved. Plantarflexes 1st metatarsal creating forefoot equinus.
4. Intrinsic Muscles: Early weakness. Long flexors/extensors become dominant causing claw toes.
5. Plantar Fascia: Secondary contracture contributes to arch elevation.

Net Result: Cavovarus foot (High arch + Hindfoot Varus + Claw toes + Forefoot adduction).

Progression Pattern:

• Distal-to-proximal weakness ('dying back' neuropathy).
• Lower limbs affected before upper limbs.
• Sensory loss follows similar pattern.
• Deformity progresses throughout growth and into adulthood.

The "Tripod" Concept of the Cavovarus Foot: The forefoot is described as a tripod resting on the 1st metatarsal head, the 5th metatarsal head, and the heel. In CMT the strong peroneus longus plantarflexes the 1st metatarsal (1st ray), driving the medial leg of the tripod down. To keep all three points on the ground, the hindfoot compensates by rolling into varus. This is the mechanical basis of the "forefoot-driven" hindfoot varus that the Coleman block test unmasks.

Sequence of Muscle Imbalance (drives the deformity):

Net biomechanical cascade:

1. Plantarflexed 1st ray to forefoot pronation and cavus.
2. Forefoot-driven hindfoot varus (tripod compensation).
3. Over time the hindfoot varus becomes fixed (subtalar contracture, calcaneal varus tilt).
4. Varus heel laterally overloads the foot to recurrent ankle sprains, peroneal tendinopathy, 5th metatarsal stress fractures, and a varus ankle that can progress to medial ankle arthritis.

Why this matters surgically: Correction must be staged from distal deforming force outward — release tight static structures (plantar fascia), neutralise the deforming dynamic force (peroneus longus to brevis transfer), correct the bony apex (1st metatarsal dorsiflexion osteotomy), and only then add a calcaneal osteotomy if the hindfoot remains varus once the forefoot is balanced.

The cavovarus foot is the orthopaedic presentation, but a cavus foot is a red flag for an underlying neurological diagnosis until proven otherwise. Bilateral, symmetric, slowly progressive cavovarus with a positive family history points strongly to CMT, but the following must be considered and excluded.

History:

• Family History: Autosomal dominant (often affected parent).
• Onset: Usually childhood/adolescence.
• Symptoms: Difficulty walking, frequent ankle sprains, foot drop, clumsiness.

Physical Examination:

• Inspection:
  • 'Stork legs' (Distal wasting, Normal proximal).
  • Cavovarus foot (High arch, Hindfoot varus).
  • Claw toes.
  • Calluses (Metatarsal heads, Lateral foot).
• Motor:
  • Weak ankle dorsiflexion (Foot drop).
  • Weak eversion (Peroneus Brevis).
  • Weak toe extension/flexion (Intrinsics).
• Sensory: Glove-stocking sensory loss.
• Reflexes: Reduced/absent ankle jerks.
• Gait: Steppage gait (High stepping to clear foot).

Coleman Block Test:

1. Patient stands on a 2-3cm block.
2. Lateral foot on block. 1st ray (1st MT head) hangs off medially.
3. Observe Hindfoot: Does varus correct?
4. If Corrects: Varus is FOREFOOT-DRIVEN (1st ray plantarflexion). Surgery addresses 1st ray.
5. If Does Not Correct: Varus is FIXED/HINDFOOT. Surgery needs calcaneal osteotomy.

Diagnosis:

1. Clinical Examination: Often sufficient.
2. NCS/EMG:
   • CMT1: Slow conduction velocities (less than 38 m/s).
   • CMT2: Normal velocity, Reduced amplitude.
3. Genetic Testing: Confirms specific mutation (CMT1A = PMP22 duplication).
4. Nerve Biopsy: Rarely needed. 'Onion bulbs' in CMT1.

Orthopaedic Assessment:

1. Weight-Bearing X-rays: AP, Lateral foot. Assess arch height, Meary's angle.
2. Coleman Block Test: As above.
3. Spine X-ray: Screen for scoliosis.

After Osteotomies:

• NWB Cast 6-8 weeks.
• Transition to AFO or supportive footwear.
• Physiotherapy for ROM and strengthening.

After Tendon Transfers:

• Splint in corrected position 4-6 weeks.
• Gradual retraining of transferred muscles.

• Short-term: Reliable deformity correction is achievable with the combined soft-tissue + osteotomy ("joint-sparing") approach.
• Long-term: In the longest published series (mean 26-year follow-up of joint-sparing reconstruction), the cavus correction was well maintained but most feet showed some radiographic recurrence of hindfoot varus, reflecting the progressive nature of CMT. Despite this, no patient required salvage triple arthrodesis and rates of degenerative change and reoperation were lower than historically reported after triple arthrodesis.
• Function: Surgery improves plantigrade stance, reduces lateral-border overload and recurrent sprains, and improves gait efficiency. Patient-reported physical function (SF-36) remains below age-matched norms because of the underlying neuropathy.
• Smoking: An independent predictor of worse pain and disability scores after CMT cavovarus reconstruction — counsel cessation.
• Counselling: Patients (and parents) must understand that surgery corrects the deformity but does not cure the neuropathy; progression and possible revision should be anticipated.

Global epidemiology:

• CMT/HMSN is the most common inherited neuropathy, with a widely cited population prevalence of approximately 1 in 2,500 (around 1 in 1,200 to 1 in 3,300 across studies).
• CMT1A (PMP22 duplication) is the single most common subtype; in population-based genetic series the PMP22 duplication accounts for roughly 10 to 60% of genetically defined cases.
• Cavovarus foot deformity is the dominant orthopaedic manifestation; scoliosis is more frequent in early-onset and autosomal-recessive forms (e.g. CMT4C).

Side-by-side practice guidance (no single national framework governs CMT foot surgery):

Registries & data:

• No dedicated arthroplasty-style registry exists for CMT foot surgery; evidence is from specialist case series (e.g. the 26-year joint-sparing cohort).
• International CMT patient registries and natural-history consortia (e.g. the Inherited Neuropathies Consortium) underpin genotype-phenotype data and trial recruitment.

High- vs limited-resource practice variation:

• High-resource settings: broad NGS gene panels, gait analysis, custom orthotics/AFOs, staged joint-sparing reconstruction, MDT neuromuscular clinics.
• Limited-resource settings: diagnosis often clinical plus basic nerve conduction studies; management weighted toward bracing and a single definitive corrective procedure; emerging genetic and disease-modifying therapies are largely inaccessible.