Charcot-Marie-Tooth Syndrome

This is an inherited sensorineural peripheral polyneuropathy first described independently by Charcot and Marie in France and Tooth in England in 1886.

Prevalence

• It is the most common inherited disorder of the peripheral nervous system affecting 10-36 /100,000 individuals.¹
• It has no predilection for a particular race or sex.

• Autosomal dominant, autosomal recessive, and X-linked forms (CMTX) have been identified.
• The majority of autosomal dominant forms are Charcot-Marie-Tooth (CMT)1 subgroup.
• CMT1A is associated with a DNA duplication in chromosome 17p11.2-p12 in over 70% of patients with CMT1A.² There is a high new mutation rate in type CMT1A, so there may not be any family history.
• X-linked forms account for 16%.

There are many other forms, which are rarer. OMIM provides detailed gene locus and abnormality information:³

• CMT type 1 is characterised by a gene duplication leading to production of abnormal myelin, that is unstable and spontaneously breaks down. This process results in demyelination, leading to uniform slowing of conduction velocity. In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in an 'onion bulb' appearance.
• CMT type 2 is primarily a neuronal i.e. axonal disorder, not a demyelinating disorder. CMT type 2 results in peripheral neuropathy through direct axonal death.
• CMT type 3 is characterised by marked segmental demyelination, with thinning of the myelin around the nerve.
• CMT X (X-linked CMT) and CMT 4 (Refsum's disease) are also demyelinating neuropathies.³

Onset is insidious and slowly progressive.

Type 1

Primary peripheral demyelinating neuropathy (CMT1 or hereditary motor and sensory neuropathy type 1, HMSNI).³This is the most common form. Onset usually by age 10 with:

• Weakness
• Muscle wasting
• Sensory loss predominantly in the distal legs, or distal arms
• Generalised tendon areflexia
• There may be foot drop and foot deformity - pes cavus has a 25% occurrence rate in the first decade of life and a 67% occurrence rate in later decades¹
• Spinal deformities e.g. thoracic scoliosis occur in 37-50% of patients with CMT type 1
• Hammer toes, high arches and flat feet are also seen
• Pressure palsies are common
• It may be possible to palpate enlarged and excessively firm nerves
• Ankle sprains and fractures are common secondary to muscular weakness
• Pain and temperature sensations are usually not affected because they are carried by unmyelinated (type C) nerve fibres

Type 2

Primary peripheral axonal neuropathy (CMT2 or HMSNII) with onset usually in second decade, but may not appear until later. Pattern of peripheral weakness and wasting is similar. In subtype CMT2D there is:

• Severe weakness
• Atrophy of hands
• Only moderate lower limb weakness

Patients with either form may have other symptoms such as hyperhidrosis, nausea, vomiting, diarrhoea and heart block.

Type 3

This is also known as Dejerine-Sottas disease. It is characterised by:

• Infantile onset, usually by 2 years.
• Results in severe demyelination with delayed motor skills and is much more severe than type 1.

CMT X (X-linked CMT) and CMT 4

Usually see:

• Peripheral neuropathy, retinitis pigmentosa, cerebellar signs and increased cerebral spinal fluid (CSF) protein.

• Other genetic neuropathies e.g. Friedreich ataxia
• Alcoholism
• Vitamin B12 deficiency
• Thyroid disease or diabetes mellitus
• HIV infection, leprosy and neurosyphilis
• Vasculitis, amyloid associated with chronic inflammation
• Occult malignancy
• Heavy-metal intoxication
• Motor neuropathy with multiple conduction block

Exclude other causes of neuropathy:

• Thyroid function tests
• VDRL
• Vitamin B12
• Folate
• Antinuclear antibodies
• Serum and urine protein electrophoresis
• Special genetic tests are available for some types of CMT e.g. CMT 1A - pulsed field gel electrophoresis and a specialised fluorescent in situ hybridization (FISH) assay (the most reliable genetic tests, but are not widely available)
• Nerve conduction studies show low conduction velocities in peripheral demyelinating neuropathy (less than 38 m/s), and low amplitude in axonal degeneration
• Sural nerve biopsy may be necessary to show axonal loss, and MRI can demonstrate enlarged nerves

Currently there are no treatments to reverse or slow the natural disease process for the underlying disorder. Nothing can correct the abnormal myelin, prevent its degeneration, or prevent axonal degeneration.

General

Patients often are evaluated and treated symptomatically by a team that includes a neurologist, orthopaedic surgeon, physiotherapist and occupational therapist.

• Orthotic appliances
• Genetic counselling
• Routine exercise
• Obesity makes walking more difficult - it should be avoided
• Daily heel-stretching exercises prevent Achilles tendon shortening

Pharmacological

• Anti-inflammatories
• Drugs e.g. vincristine,⁴ isoniazid, paclitaxel, cisplatin, and nitrofurantoin are known to cause nerve damage and should be avoided

Surgical

Surgical correction of foot deformity or tendon transfer:

• Over 50% of the patients with Charcot-Marie-Tooth disease develop foot and ankle problems, of which the cavovarus deformity is by far the commonest.⁵
• Surgery using a variety of soft tissue procedures and osteotomies seems to be the treatment of choice for the progressive cavovarus deformity in younger patients.
• The Coleman Block Test is used to decide what type of surgery is best.⁶:
  • It evaluates hindfoot flexibility and is performed by placing the patient's foot on a 2.5-4 cm thick wooden block with the heel and lateral border of foot on the block and bearing full weight, while the first, second, and third metatarsals are allowed to hang freely into plantar flexion and pronation.
  • If heel varus corrects, while the patient is standing on the block, the hindfoot is considered flexible.
  • If the subtalar joint is supple and corrects with the block test, then surgical procedures may be directed to correcting forefoot pronation, which is usually due to plantar flexion of the first metatarsal.
  • If the hindfoot is rigid, then surgical correction of both the forefoot and hindfoot are required.
• For a patient who has severely rigid deformities a triple arthrodesis may be the only option, but is considered to be a salvage procedure. Only 14% of patients with CMT disease require this procedure.⁷

• As protective sensation is usually lost distally in all 4 limbs, patients with CMT are susceptible to skin breakdown or burns, non-healing foot ulcers and bony deformities of both feet.
• Laryngeal dysfunction with aspiration pneumonia.
• CMT in pregnancy increases the risk for complications during delivery and a higher risk of intervention.⁸

• Depends on subtype - but most patients with CMT have normal life expectancy. Disease usually progresses slowly with little disability.
• The most severe forms e.g. Dejerine-Sottas syndrome, generally die young.