The Charcot-Marie-Tooth syndrome is a clinically and genetically heterogeneous group of inherited neuropathies. In 1886, Charcot and Marie in France and Tooth in England were the first to describe the clinical features of a group of inherited motor and sensory neuropathies that now bears their names, Charcot-Marie-Tooth (CMT) syndrome, also named Hereditary Motor and Sensory Neuropathy (HMSN). The classification of CMT has been evolving over the past decades, due to the rapid advances in the description of causative genes of which the disrupted proteins may affect the myelin or the axon primarily. Mutations in the same genes may even lead to either a predominantly demyelinating or axonal neuropathy, making the classification rather complicated. Currently, for the clinician it is recommended to first distinguish between a demyelinating (CMT type 1), axonal (CMT type 2), and intermediate neuropathy based on nerve conduction velocities. Further subclassification takes into account the inheritance pattern, the severity of symptoms and signs, and the causative gene, and is indicated alphabetically or numerically (see genetics).
Authors
M. de Visser, M.D., Ph.D., Professor of Neuromuscular Diseases
C. Verhamme, M.D.
Clinical features
The CMT or HMSN syndrome is characterised clinically by distal muscle weakness and wasting, legs more than arms, impaired distal sensation, and reduced or absent reflexes. Moreover, foot and hand deformities (pes cavus and claw hands, respectively) are often encountered. Besides the general CMT phenotype that accounts for all types, in CMT1 palpably enlarged (hypertrophic) peripheral nerves may be present (the greater auricular nerve, difficult to assess objectively). Depending on the causative gene, other additional symptoms and signs may be present, giving direction to the diagnosis.
The family history may point to a hereditary neuropathy. The severity and onset of the disease can vary considerably between patients, also in the same family. However, one should bear in mind that affected family members may consider themselves asymptomatic. Therefore patients may erroneously as ‘sporadic’ cases, especially in small families. Moreover, patients may have de novo gene mutations. It is not feasible to make a distinction between the different forms of CMT on the basis of history and physical examination, in a new patient without known genetic classification in the family.
As said before, the first step to distinguish between the different forms of CMT is to perform nerve conduction studies. CMT1 (dys/demyelinating) is diagnosed when the median motor nerve conduction velocity is less than 38 m/s.
Nerve biopsies of CMT1 patients, which are no longer used for diagnostic purposes nowadays, show segmental demyelination and remyelination, as well as union bulbs (concentric arrangement of supernumerary Schwann cells around an incompletely remyelinated axon) and axonal loss.
Natural course and prognosis
In general CMT1 is a slowly progressive disease without shortened lifespan, but proper longitudinal studies are scarce. Some forms of the Dejerine-Sottas syndrome have a more progressive course and the forms with amyelination may be lethal in days to months. Most investigations have been done in either mixed populations of patients with CMT1 or patients with CMT1A.
In childhood, disease progression has been shown in CMT1A.Still, there is controversy about the natural course of CMTIA in adults. Clinical deterioration was noted by some, whereas this was refuted by others.All studies agree that disease severity is variable: a group of CMT1A patients is asymptomatic (5-10%), whereas other patients are wheelchair dependent (5-10%), but most have a classical CMT phenotype. Lifespan is not shortened.Epidemiology
The estimated prevalence of hereditary demyelinating neuropathies is 1 in 2500. The prevalence of CMT1 is 15 per 100,000. CMT1A is the most prevalent form (10 per 100 000).
Differential diagnosis
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Ancillary investigations
Nerve conduction studies
Nerve conduction studies are used to classify the CMT as demyelinating (<38 m/s), intermediate and axonal. Still, there are some overlap syndromes between axonal and demyelinating, like CMTX1. Moreover, HNPP is included in the classification, although it has higher nerve conduction velocities with signs of a multifocal polyneuropathy.
Molecular diagnosis
In the Netherlands, a patient with a CMT phenotype and with nerve conduction velocities in the demyelinating range (< 38 m/s) first will be screened for a duplication of the 1.5Mb fragment of chromosome 17 containing the PMP22 gene, as this is the most prevalent form of CMT (CMT1A). If this screening is negative and if there is a positive family history, cases without male to male transmission will be screened for mutations of the Cx32/GJB1 gene (CMT1X). In all other cases screening for MPZ, PMP22 and LITAF mutations (CMT1A, CMT1B, CMT1C respectively) is performed. If clinical and electrophysiological examinations are compatible with HNPP, there will be screened for a deletion of the 1.5Mb fragment of chromosome 17 containing the PMP22 gene, and if this is negative for a point mutation in this gene. Other genetic tests are as yet only performed for research purposes.
Nerve biopsy
As said before, these are no longer used for diagnostic puposes. Still, they may be useful in autosomal recessive and sporadic cases. We advise to leave indications for nerve biopsies to specialised neuromuscular centres.
Genetics
| Table 2: classification of de/dysmyelinating Charcot-Marie-Tooth disease, type 1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Therapy
Rehabilitation physician
It is recommended to refer all patients, children and adults with clear symptoms. Stance, balance, walking abilities and moreover hand function should be evaluated.
Medication
The benefits of prescribing medication which could cause or worsen a peripheral neuropathy should be carefully weighted against possible deterioration of CMT.
Genetic counseling
If a patient decides to have offspring this individual and his or her partner should be referred to a clinical geneticist.
Pregnancy
Prenatal testing is possible when a disease-causing mutation has been identified in an affected family member. Due to the often relatively benign character of the disease it is rarely performed. The consequences of prenatal testing should be thoroughly discussed with a clinical geneticist before pregnancy.
Therapy
Therapy is symptomatic and aims at maintaining functional possibilities and learning compensation mechanisms. A rehabilitation physician co-ordinates this process.
Exercise and sport activities
Muscle strength increasing exercises are found to give some increase in strength and facilitate daily life activities. Studies about effects of controlled exercise training in patients with neuropathy are scarce, but are currently performed and seem beneficial. Even more importantly, sport activities are not harmful, but special care should be taken to avoid overuse (pain, extreme fatigue after exercise).
Aids
Non-structural changes: to prevent worsening: redressing shoe inlays, (night) orthoses (ankle/foot or hand), orthopaedic shoes.
Rigid deformities: to improve stance and balance: shoe inlays, orthoses, orthopaedic shoes.
Walking canes, wheelchair.
Surgery
In general, operative interventions should be carefully weighted and discussed when conservative management is no longer beneficial. The rehabilitation physician and a specialised orthopaedic or hand surgeon should be involved in the decision process (addresses: see VSN). Usually, in children management is conservative. The aim is to improve stance and balance walking abilities, or hand function. Surgical interventions include transposition of muscle tendons, tenotomies, arthrodesis, hammertoe surgery, lengthening of the Achilles tendon and scoliosis correction. There are some observational studies evaluating triple arthrodesis which are not conclusive: the technique is favoured by some or it is emphasized that the procedure should be limited to patients with severe, rigid deformity due to the large number of unsatisfactory long-term results. Results about tendon transfers in upper limb involvement are scarce and observational,and hand surgery should be reserved for severely affected patients after evaluation in a multidisciplinary hand team. There are very few reports on the use of anaesthetics. In a retrospective series of 161 surgical procedures on 86 Charcot-Marie-Tooth patients, it was found that patients had no difficulties tolerating anesthetics.
Respiratory dysfunction
In cases with respiratory dysfunction due to phrenic nerve involvement and diaphragmatic weakness or severe kyphoscoliosis, respiratory function may be monitored and if needed artificially supported.
