X-linked Charcot-Marie-Tooth disease (ORPHA:64747)
A disorder that belongs to the genetically heterogeneous group of CMT peripheral sensorimotor polyneuropathy diseases.
Clinical description
CMTX1 is characterized by a slowly progressive course: muscle wasting and weakness of distal limb muscles mainly involving the feet, legs and hands (particularly the thenar eminence), with proximal muscle weakness occurring in severe cases; distal sensory loss; loss of deep tendon reflexes; pes cavus and more rarely scoliosis. Rare instances of transient central nervous system (CNS) dysfunction have been described, with dysarthria, dysphagia, weakness, ataxia, and even aphasia and somnolence. All forms of CMTX are rare and are characterized by intellectual deficit (CMTX2, CMTX4), spastic paraplegia (CMTX3), hearing loss (CMTX4, CMTX5, rarely CMTX1), and optic atrophy (CMTX5).
Etiology
CMTX1 is associated with mutations in the GJB1 gene (Xq13.1), encoding connexin 32 (Cx32). Cx32 forms gap-junctions in non-compact myelin produced by myelinating Schwann cells. Cx32 is also expressed in oligodendrocytes, explaining the potential CNS involvement. CMTX5 is associated with mutations in the phosphoribosylpyrophosphate synthetase 1 gene (PRPS1). CMTX1 is transmitted as an X-linked dominant trait and males are more severely affected than females, whereas the other CMTX types are X-linked recessive and female carriers are usually unaffected.
Diagnostic methods
Diagnosis is based on family and personal history, clinical examination, nerve conduction studies (NCS), and DNA testing (for CMTX1). NCS show a sensorimotor polyneuropathy with decreased conduction velocities in males (usually in the intermediate range of 30-45 m/s in upper limb motor nerves) and mildly decreased or even normal velocities in females. In contrast with other CMT types, conduction slowing is frequently nonhomogeneous, with temporal dispersion and sometimes conduction blocks, and the median nerve being more severely affected than the ulnar nerve. Nerve biopsy reveals prominent axonal changes, in spite of nerve conduction slowing, with evidence of ultrastructural abnormalities in the paranodal regions. Auditory evoked potentials usually reveal abnormalities of central waves in the brainstem, consistent with frequent subclinical brain involvement in CMTX1.
Differential diagnosis
Differential diagnosis includes other CMT types and acquired dysimmune neuropathies such as chronic inflammatory demyelinating polyradiculoneuropathy (see these terms).
Antenatal diagnosis
Prenatal diagnosis is possible for CMTX1 when the mutation is known.
Genetic counseling
As an X-linked dominant trait, there is no male-to-male transmission; female carriers are usually mildly affected and have a 50% risk of transmitting the disease to their offspring.
Management and treatment
There is no drug treatment available. Rehabilitation therapy and surgical treatment of skeletal deformities are the only options.
Prognosis
CMTX1 is moderately severe for affected males, who may loose ambulation capacity later in life.

                            Last update: 
                            January 2008


                            - Expert reviewer(s): 
                            Dr Davide PAREYSON