Charcot-Marie-Tooth disease type 1 (ORPHA:65753)
Charcot-Marie-Tooth disease type 1 (CMT1) is a group of autosomal dominant demyelinating peripheral neuropathies characterized by distal weakness and atrophy, sensory loss, foot deformities, and slow nerve conduction velocity.
Epidemiology
The prevalence of CMT1 is estimated to be between 1/7,000 and 1/5,000, with CMT1A representing 70% of cases.
Clinical description
Age of onset of CMT1 varies widely and ranges from infancy to the fourth or subsequent decades of life. Typically, patients become symptomatic between the first and the second decade of life; however, the full clinical picture may appear later. Clinical severity is variable, ranging from extremely mild disease, which goes unrecognized, to considerable weakness and disability. Affected individuals typically develop distal weakness, symmetric atrophy of muscles (mainly peroneal), and reduced-to-absent tendon reflexes. Sensory deficits of position, vibration, and pain/temperature commonly occur in the feet and later in the hands. Pes cavus (or planus) with hammer toes is often present since childhood. Variable scoliosis may develop during adolescence.
Etiology
CMT1A can be caused by 1.4 Mb duplications or by point mutations in the PMP22 gene (17p12). CMT1E is caused by point mutations in the PMP22 gene (17p12). CMT1B is associated with MPZ (1q22) gene mutations. CMT1C, CMT1D and CMT1F (see these terms) are associated with pathogenic variants in LITAF (16p13.3), EGR2 (10q21.1) and NEFL (8p21.2), respectively.
Diagnostic methods
Diagnosis of CMT1 is based on progressive peripheral motor and sensory neuropathy; slow nerve conduction velocity (NCV) with motor NCV <38 m/s in upper limbs; and positive family history (however, sporadic presentations may occur, due to de novo mutations). Genetic testing is the gold standard for diagnosis.
Differential diagnosis
Differential diagnosis includes other genetic neuropathies, especially X-linked CMT, autosomal dominant CMT2, CMT4, and hereditary neuropathy with liability to pressure palsies (see these terms). CMT1 identification may be challenging when there is no family history and acquired demyelinating neuropathies must also be taken into account.
Antenatal diagnosis
Preimplantation genetic diagnosis may be an option for families in which the pathogenic variant has been identified.
Genetic counseling
Transmission is autosomal dominant with complete penetrance and genetic counseling is recommended.
Management and treatment
Treatment is multidisciplinary and includes use of special shoes, inserts and/or ankle foot orthoses; forearm crutches, canes, and wheelchairs for the most severe cases, as needed for mobility; surgery for severe pes cavus, as needed; exercise for muscle strengthening, as tolerated; stretching to prevent Achilles' tendon shortening; and regular foot examination for pressure sores. Occupational therapy focused on strategies/tools to help patients with daily living activities is useful, especially for those with hand weakness.
Prognosis
CMT1 is slowly progressive and affected individuals experience long plateau periods without obvious deterioration. Most patients remain ambulatory throughout life and have a normal lifespan.

                            Last update: 
                            March 2016


                            - Expert reviewer(s): 
                            Dr Davide PAREYSON  - Dr Chiara PISCIOTTA