Charcot-Marie-Tooth disease

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder¹ . The typical CMT phenotype involves distal limb muscle wasting and sensory loss, with proximal progression over time. However, disease course is varied, reflecting both genotypic and phenotypic heterogeneity² .

Epidemiology

• It is the most common inherited neuromuscular disorder affecting 1 in 2,500 people¹ .

• It has no predilection for a particular race or sex.

Pathogenesis

Autosomal dominant inheritance is the most common mode of inheritance but autosomal recessive, and CMT X-linked (CMTX) forms, have also been identified. Mutations may also arise de novo so that there may be no previous family history of the disease³ .

The majority of autosomal dominant forms are CMT type 1 (CMT1) subgroup. CMT1A is the most common type. CMTX1 (X-linked, dominant) is the second most common type⁴ .

Online Mendelian Inheritance in Man (OMIM) provides detailed gene locus and abnormality information⁵ :

• In most cases, CMT1 is characterised by a gene duplication leading to production of abnormal myelin, which 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 (CMT2 - also known as hereditary motor and sensory neuropathy type II (HMSN-II)) is primarily an axonal disorder, not a demyelinating disorder. CMT2 results in peripheral neuropathy through direct axonal death.

• CMT type 3 (CMT3 - also known as Dejerine-Sottas neuropathy) is characterised by marked segmental demyelination, with thinning of the myelin around the nerve.

• CMTX and CMT type 4 (CMT4 - also known as Refsum's disease) are also demyelinating neuropathies⁵ .

• There are other rarer variants such as CMT type 5 (CMT5) with pyramidal involvement and CMT type 6 (CMT6) with optic atrophy.

Presentation⁶

Onset is insidious and slowly progressive. The typical presenting symptom is weakness of the feet and ankles. The initial physical findings are depressed or absent tendon reflexes with a weakness of foot dorsiflexion at the ankle. An affected adult typically has a bilateral foot drop, symmetrical atrophy of muscles below the knee (stork leg appearance), pes cavus, atrophy of intrinsic hand muscles, especially the thenar muscles of the thumb, and absent tendon reflexes in both upper and lower extremities⁷ .

CMT1

This is the most common form. Onset is usually by the age of 10 years with:

• Muscle weakness and wasting starting from the intrinsic muscles of the feet, and gradually affecting the lower leg and lower thigh. The pattern of distal wasting in the legs is sometimes described as 'inverted champagne bottles'. Hands and forearms may also be involved. Wasting of the small muscles of the hands causes finger curling and difficulty in straightening or abducting them.

• Sensory loss follows the same pattern, beginning in the distal legs and arms with decreased sensation of vibration and touch. Proprioceptive sensory loss can cause sensory ataxia and a steppage gait. Tasks involving fine motor control of the hands may also become progressively more difficult.

• Pain is rarely an initial symptom but most patients experience pain during the course of their disease⁸ .

• Generalised tendon areflexia.

• There may be foot drop and foot deformity. Pes cavus (high arch) has a 25% occurrence rate in the first decade of life and a 67% occurrence rate in later decades. Hammer toes and pes planus (flat feet) are also seen. Patients may experience difficulty walking or running, often tripping. Pressure palsies are common.

• Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT1.

• Other common symptoms and signs include hand tremors, muscle cramps and acrocyanosis.

• It may be possible to palpate enlarged and excessively firm nerves.

CMT2

Primary peripheral axonal neuropathy (CMT2 or HMSN-II) with onset usually in the second decade, but may not appear until later. The pattern of peripheral weakness and wasting is similar to CMT1.

CMT3

This is characterised by infantile onset, usually by 2 years. Onset can occur by the time of birth, presenting with hypotonia or floppy baby syndrome. It results in severe demyelination with delayed motor skills and is much more severe than type 1.

CMTX

CMTX1 is usually mild in women but in men there is moderate-to-severe peripheral neuropathy. With other CMTX forms, only men are affected. For CMTX1 there is usually subclinical central nervous system involvement (eg, mild clinical signs, MRI cerebral white matter abnormalities, and EEG abnormalities).

Differential diagnosis

• Other genetic neuropathies.

• Friedreich's ataxia.

• Acquired neuropathies - eg, related to alcohol, vitamin B12 deficiency, thyroid disease, diabetes mellitus, and infection (HIV, leprosy, syphilis).

• Vasculitis.

• Amyloidosis.

• Occult malignancy.

• Heavy metal intoxication.

• Motor neuropathy with multiple conduction block.

• Motor neurone diseases.

Investigations⁶

• Exclude other causes of neuropathy with tests that may include:
  

  • Blood tests: FBC, TFTs, LFTs, VDRL, vitamin B12, folate, antinuclear antibodies, creatine kinase.

  • Serum and urine protein electrophoresis.

  • Muscle biopsy.

  • Cerebrospinal fluid (CSF) examination.

  • MRI of the brain and spinal cord.

• Genetic studies - family history may be falsely negative due to the variable expression of mutations. First-degree relatives may also undertake clinical and sometimes electrophysiological testing to ascertain the inheritance pattern.

• Electrophysiology: nerve conduction studies show:
  

  • Low conduction velocities (<38 m/s in upper limb motor nerves) in peripheral demyelinating neuropathy such as CMT1 and CMT4.

  • Normal or only mildly slowed conduction velocities (>38 m/s) and reduced action potential amplitudes in axonal degeneration with CMT2.

  • Intermediate nerve conduction velocities (25-45 m/s) should raise the possibility of CMTX1. Nerve conduction abnormalities in CMTX1 can be asymmetric and non-homogeneous along nerve trunks.

• Molecular testing - there are now so many genes associated with CMT disease that a rational approach needs to be applied to the use of such tests. For example, in autosomal dominant or sporadic CMT with electrophysiological evidence of demyelination (CMT1), the CMT1A duplication should be looked for initially. Where this is absent, CMTX1 should be considered and relevant mutations explored.

• Neuropathology - nerve biopsy is now unnecessary in most cases, although it may still be used in sporadic cases for differential diagnosis or where the main genetic investigations have been negative.

Management⁶

Currently there are no effective treatments to reverse or slow the underlying disease process. Supportive treatment is offered based on rehabilitation and surgical corrections of skeletal deformities. Patients should be managed by a multidisciplinary team which has experience of the disorder, including a neurologist, geneticist, orthopaedic surgeon, physiotherapist and occupational therapist.

Rehabilitation

• Mild-to-moderate exercise is effective and safe for patients with CMTdisease. It leads to significant improvements in walking and lower limb strength. High-intensity resistance training is controversial, as it is unclear whether this improves functional ability or exacerbates weakness.

• Obesity makes walking more difficult and should be avoided.

• Daily heel-stretching exercises prevent Achilles tendon shortening.

• Interventions designed to improve posture and balance may also be helpful.

• Orthotic devices are widely used - eg, plantars (correcting foot position), ankle-foot orthoses (to overcome foot drop and facilitate walking - custom fitting may be required), and bracing orthotics (where upper limb involvement is severe).

• Night splinting does not appear helpful to increase the range of ankle movements⁹ .

Pharmacological

• Pain is common and is related to skeletal deformities, postural abnormalities, muscle fatigue and nerve damage. Treatment should include physical therapy, corrective surgery and orthotics but analgesics for non-neuropathic and neuropathic pain may also be required.

• Avoid neurotoxic drugs (eg, vincristine), as these may exacerbate the condition and they have been responsible for precipitating an acute neuropathy in patients with unrecognised CMT¹⁰ .

• None of the drugs developed to date has been effective as specific therapy for CMT but, with the increased understanding of the molecular basis of CMT, work continues based on transgenic animal models.

Surgical

Foot and ankle problems are common, of which the cavovarus deformity is the most common¹¹ . This tends to develop as a flexible deformity during childhood and adolescence and becomeS fixed by adulthood. Treatments include:

• Soft-tissue surgeries - eg, plantar fasciotomy, tendon transfers and tendon releases.

• Osteotomies on the calcaneal, metatarsal, tarsometatarsal and tarsal bones.

• Triple arthrodesis (surgical fusion of the talocalcaneal, talonavicular and calcaneocuboid joints) - considered a salvage procedure only for the most severe cases for relief of pain, but this may result in a high occurence of osteoarthritis of other foot joints¹² .

Surgery may also be undertaken for scoliosis or to improve hand function (eg, tendon transfers to improve thumb opposition or wrist extension).

Genetic counselling

• Individuals and families affected by the disease need to understand the implications of CMT disease as a genetic disease and the relevant inheritance pattern to be able to make informed medical and reproductive choices.

• Prenatal and pre-implantation genetic diagnosis may be possible.

Complications

• As protective sensation is usually lost distally in all four limbs, patients with CMT disease are susceptible to skin breakdown or burns, non-healing foot ulcers and cellulitis of both feet. Good foot care is important.

• Ankle sprains and fractures are common secondary to muscular weakness.

• Laryngeal dysfunction with aspiration pneumonia.

• CMT in pregnancy increases the risk for complications during delivery and a higher risk of intervention¹³ .

Prognosis

This is dependent on subtype; clinical impairment and disability correlate with axonal loss:

• Most patients with CMT1A have normal life expectancy and remain ambulatory throughout their lives⁷ . Disease usually progresses slowly with little disability, although there is substantial disease variability even within the same family.

• CMTX1 usually manifests in the first or second decades in men, with an inevitably progressive course and substantial impairment in later life.

• The most severe forms (eg, Dejerine-Sottas syndrome) tend to have an early onset and reduced life expectancy.