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Hereditary Motor and Sensory Neuropathy/Charcot-Marie-Tooth disease type 1
25 March 2004

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. Read more

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. Read more

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

Table 1:
  Comment
Other genetic neuropathies
Other type of Charcot-Marie-Tooth
  • For differentiation electrophysiological and genetic testing
Hereditary sensory (and autonomic) neuropathies (HS(A)N)
  • Rare
  • In HSAN sensation disturbances are generally more severe
  • In  HSAN motor nerve conduction velocities are normal
  • Genetic testing may differentiate, currently 3 genes are known for HSAN
Distal hereditary motor neuropathy (HMN)
  • Clinical differentiation may be difficult, as also some CMT patients do not have sensory symptoms or signs
  • Electrophysiologically patients with CMT will always have sensory nerve involvement in contrast to patients with distal HMN
Autosomal recessive: Metachromatic leukodystrophy, Refsum disease, Krabbe disease
  • Also other signs and symptoms
  • Genetic testing
X-linked: adrenomyeloneuropathy, Pelizaeus-Merzbacher, Lowe syndrome 
  • Also other signs and symptoms
  • Genetic testing
Acquired demyelinating neuropathies
Chronic inflammatory demyelinating polyneuropathy (CIDP)
  • In CMT often long history extending back to childhood, foot deformities
  • In CIDP electrophysiology: no uniform demyelination, conduction blocks 
  • Especially CMT1X may cause difficulties with the differential diagnosis
Superimposed inflammatory neuropathy
  • Acute or subacute deterioration in clinical condition in a previously stable hereditary neuropathy 41
Multiple sclerosis
  • MS: symptoms and signs of central nervous system involvement
  • In CMT often long history extending back to childhood, foot deformities

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. Read more

Genetics

Table 2: classification of de/dysmyelinating Charcot-Marie-Tooth disease, type 1

Clinical type Location Gene
Autosomal dominant
CMT1A 17p11.2-p12 PMP22 including 1.5 Mb duplication/point mutation
CMT1B 1q22-q23 MPZ
CMT1C 16p13.1-p12.3 LITAF (SIMPLE)
CMT1D 10q21-q22 EGR2
X linked
CMT1X Xq13.1 Cx32 (GJB1)
Autosomal recessive
AR-CMT1A (CMT4A) 8q13 - q21.1 GDAP1
AR-CMT1B1 (CMT4B1) 11q22 MTMR2
AR-CMT1B2  (CMT4B2) 11p15 MTMR13
AR-CMT1C (CMT4C) 5q23-q33 KIAA1985
AR-CMT1D (CMT4D/HMSNL) 8q24 NDRG1
AR-CMT1E (CM4E) 10q21-q22 EGR2
AR-CMT1F (CMT4F) 19q13.1-13.3 PRX
HMSNR 10q23.2 ?
CCFDN 18q23-qter CTDP1
Dejerine-Sottas syndrome (DSS, HMSN III) / Congenital hypomyelinating neuropathy (CHN)
DSS/CHN A AD/AR 17p11.2-12 PMP22
DSS/CHN B AD/AR 1q22-q23 MPZ
DSS/CHN C AD/AR 10q21-q22 EGR2
Hereditary neuropathy with liability to pressure palsies (HNPP)
HNPP  AD 17p11.2 1.5 Mb deletion / point mutation PMP-22
  		 

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. Read more
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