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Charcot-Marie-Tooth disease type 4

ORPHA64749
Synonym(s) AR-CMT1
Autosomal recessive demyelinating Charcot-Marie-Tooth
CMT4
Prevalence 1-5 / 10 000
Inheritance Autosomal recessive
Age of onset Childhood
ICD-10
  • G60.0
OMIM -
UMLS -
MeSH -
MedDRA -

Summary

Charcot-Marie-Tooth disease type 4 (CMT4) belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases.

The prevalence of all forms of CMT is around 1 in 3,330; however, CMT4 is less common and often limited to certain ethnic groups.

The term CMT4 is classically applied to autosomal recessive demyelinating forms of CMT, although current trends point towards a reclassification of CMT4 forms to include autosomal recessive axonal types. CMT4 patients present with the typical CMT phenotype characterized by progressive, distally accentuated weakness and atrophy of muscles innervated by the peroneal nerve in the lower limbs, followed by weakness and atrophy of hands, sensory loss, and characteristic foot abnormalities. CMT4 is usually more severe than other forms of CMT and onset occurs earlier. The disease may arise in early infancy with hypotonia or may manifest in later infancy with toe walking. The most common symptoms are walking difficulties with steppage gait or pes cavus. Hammer toes are frequent and other skeletal deformities, such as scoliosis, are often observed. Sensory signs are usually less prominent than motor signs. The most frequent finding is distal loss of sensation to touch, pain, and vibration in the lower limbs. Deep tendon reflexes are reduced or absent in most patients with demyelinating CMT4. To date, 15 forms of CMT4 have been described, including eleven demyelinating (CMT4 types A, 4B1, 4B2, 4C, 4D, 4E, 4F, 4G, 4H, 4J and CCFDN; see these terms) and four axonal forms (CMT4 types 4C1, 4C2, 4C3 and 4C4; see these terms).

So far, fourteen genes and two loci have been described associated with these fifteen CMT variants and the roles and functions of the proteins encoded by these CMT4 genes are diverse.

The diagnostic approach includes clinical examinations (natural history of the disease, and neurological and systemic examinations), together with definition of the inheritance pattern, electrophysiological studies and a nerve biopsy for selected patients. Identification of the disease-causing mutation supports the clinical and electrophysiological diagnosis. Definitive diagnosis is extremely difficult because the phenotype is similar throughout the spectrum of clinical types, both demyelinating and axonal.

Genetic counseling should be offered to the parents of an affected individual and prenatal diagnosis should be proposed when the disease is well diagnosed and the disease-causing mutation in the family has been identified.

There is currently no cure for CMT and treatment is only symptomatic: physical therapy and orthopedic management for musculoskeletal dysfunction; pulmonary evaluation, ventilatory support, and scoliosis correction for respiratory dysfunction; and pain control, antidepressants and anticonvulsants for sensory dysfunction.

The prognosis for the different types of CMT4 varies and depends on the clinical severity. In general CMT is a slowly progressive neuropathy, causing eventual disability but, in the absence of secondary complications, does not generally reduce life expectancy. However, early-onset and severe respiratory complications associated with some forms of CMT4 (notably CMT4C4, CMT4B1, CMT4B2 and CMT4E) may lead to a poorer prognosis with early death in some cases.

Expert reviewer(s)

  • Dr Carmen ESPINÓS
  • Pr Francesc PALAU

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Detailed information

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  • EN (2014,pdf)
Guidance for genetic testing
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Clinical genetics review
  • EN (2014)
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