Matilde Laurá
MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK

Gita Ramdharry
Faculty of Health, Social Care and Education, Kingston University and St George’s, University of London, UK

https://doi.org/10.36866/pn.98.30

CMT also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN), or peroneal muscular atrophy (PMA), is a condition characterised by nerve degeneration, which leads to failure in transmission of nerve action potentials. This could be secondary due to disruption of either the axon or the myelin sheath.

The health of the neuron from the proximal to the distal end is maintained by axonal transport. In fast conducting, myelinated neurons, propagation of the action potential rely on the interaction between the nerve axon and myelin. In motor neurons, a clustering of voltage gated sodium channels occurs at the axon hillock where the initial depolarisation occurs. In sensory neurons, depolarisation occurs through stimulation of the sensory end organ. Clusters of channels also exist at the nodes of Ranvier in myelinated fibres. This allows the conduction to jump between the node of Ranvier enabling fast conduction. This process is called saltatory conduction. Action potentials are generated at the nodes by opening of the voltage gated sodium channels leading to an influx of Na⁺ ions, which depolarises the membrane. Closure of the Na⁺ channels and opening of addition K⁺ channels restores the membrane potential.

A commonly used diagnostic tool for investigating polyneuropathy is measurement of the conduction velocity by transcutaneous electrical stimulation and recording. Slowing of conduction for example <38 m/s in the upper limbs is seen with primary demyelinating disorders. Electrical studies also allow the measurement of the amplitude of the motor response, the compound muscle action potential (CMAP), or the sensory nerve action potential (SNAP). A reduction in the amplitude of the CMAP or SNAP indicates a loss of axons. These studies help to distinguish between different types of neuropathy.

Charcot-Marie-Tooth Disease types

CMT affects about 1 in every 2,800 people. The first gene causing the CMT phenotype was identified in 1991 (1.4 Mb duplication of Chromosome 17p11.2 encoding Peripheral Myelin Protein 22 (PMP22)). To date, about 80 causative genes have been identified. The most common types of CMT show a slowly progressive distal muscle weakness and sensory loss in the upper and lower limbs in a length dependent manner. CMT can be inherited as an autosomal dominant or X-linked or autosomal recessive condition. In Northern Europe and US, the most common inheritance is autosomal dominant or X-linked. Autosomal recessive inheritance is rarer and it occurs more frequently in areas where consanguinity is prevalent. Family history is an important step in deciding if and how a neuropathy is inherited.

CMT can be classified in two main subtypes on the base of neurophysiology : CMT1, demyelinating, when nerve conduction velocities in the upper limbs are below 38m/s; and CMT2, axonal, when nerve conduction velocities in the upper limbs are above 38 m/s. More than 80% of patients with CMT1 usually receive a molecular diagnosis and PMP22 duplication accounts for 70% of all the cases. Type 1 CMT (CMT1) presents with demyelination of the more thickly myelinated, fast conducting axons, for example the alpha motor neurons and 1a afferent sensory neurons. Axonal loss occurs with prolonged demyelination and the degree of axonal loss relates to the degree of motor-sensory impairment. In conditions with chronic axonal loss there is collateral re-innervation of the muscles, therefore the reduction of CMAP amplitude is not seen early on in the disease.

Type 2 CMT (CMT2) presents with primary degeneration of the nerve axon. The axonal forms of CMT are less common than type 1 and a molecular diagnosis is reached in more the 25% of cases, the majority caused by either Gap Junction protein Beta 1 (GJB1) or Mitofusin 2 (MFN2) mutations. The next most common type is CMTX, where there is an X-linked pattern of inheritance in the family history with no occurrences of male to male transmission.

Presentation

Muscle wasting is one of the key signs described for people with CMT with the classic ‘inverted champagne bottle’ appearance of the distal lower limb and ‘claw hand’ of the upper limbs. Magnetic resonance imaging (MRI) reveals that atrophy of the distal lower limb muscles can occur even when an individual appears unaffected on clinical examination. The distal lower and upper limb muscles tend to weaken first – showing a slow decline in strength over decades. The degree and extent of weakness has been correlated with axonal loss rather than demyelination in studies of the hand. The proximal limb muscles are less affected but some studies have found they are still weak compared to normative data (Carter et al., 1995).

In addition to weakness and wasting, a length dependent gradual loss of sensation occurs. People with CMT show a principal impairment of the thickly myelinated large diameter sensory nerves that mediate the sensations of light touch and vibration. However, sensations conveyed by smaller diameter fibres, e.g. pain, temperature or pinprick, may also be reduced.

Exploration of upper limb function has revealed that people with CMT can have impaired manual dexterity and upper limb functional task that are related to muscle weakness. In the lower limb, distal weakness has been related to foot drop and failure of the plantarflexors, which influences the pattern of gait as people with CMT walk. Gait analysis has revealed primary distal gait impairments with problems with foot clearance during swing and reduced contribution of the plantarflexor muscles to progression of the trunk and swing leg (Newman et al., 2007). Further exploration revealed that people with CMT utilize additional movements of the proximal joints during walking to compensate for the
primary impairments of distal weakness and sensory loss.

People with CMT complain of more pain than the general population, though it is unclear whether the pain is directly due to the neuropathy or secondary musculoskeletal deformities. Some research has found increased reports of pain in people with CMT who had a pes cavus foot deformity suggesting that musculoskeletal alignment may be a cause of foot pain.

Problems with balance are reported in the clinic by people with CMT. Falls are more prevalent and investigation of balance impairments reveal a relationship between greater sensory dysfunction and increased falls plus poorer balance performance. Reduced balance scores have also been seen in children with CMT.

Investigations of quality of life for people with CMT have found lower scores than the general population and similar to those reported for people with stroke and other disabilities (Vinci et al., 2005). The reason for this is multi-factorial and measures of ambulation and axonal loss correlate with quality of life measure. An interesting link has also been observed between quality of life and occupation was found in a study of 121 people. Using the Short-form 36 measure, investigators found lower scores for physical functioning, physical role, emotional role and mental health for subjects who did not work (Vinci et al., 2005). It is unclear whether working improves these domains or whether the most physically, emotionally and
mentally well people are able to continue to work for longer.

References

Charcot JM, & Marie P (1886). Sur une forme particulière d’atrophie musculaire progressive: souvent familiale débutant par les pieds et les jambes et atteignant plus tard les mains. Revue médicale 6, 97–138.

Tooth H (1886). The peroneal type of progressive muscular atrophy. Dissertation, London.

Vinci P, Serrao M, Didda A, De Santis F, Capici S, Martini, D & Pierelli F (2005). Quality of life in patients with Charcot-Marie-Tooth disease. Neurology vol 65, 922–924..

Further reading

CMT United Kingdom – http://cmt.org. uk/

CMT on Wikipedia – http://en.wikipedia. org/wiki/Charcot%E2%80%93Marie%E2 %80%93Tooth_disease

Prof Mary Reilly’s page – https://iris.ucl. ac.uk/iris/browse/profile?upi=MREIL38