Charcot-Marie-Tooth Disease, Dominant Intermediate A

Description

Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1 is a demyelinating neuropathy, whereas CMT2 is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Davis et al. (1978) proposed that this form be designated 'intermediate' CMT.

For a phenotypic description and a discussion of genetic heterogeneity of dominant intermediate CMT neuropathy, see CMTDIB (606482).

Clinical Features

Rossi et al. (1985) and Villanova et al. (1998) reported a large kinship in which 15 individuals, ranging in age from 7 to 72 years, had onset of slowly progressive CMT in the first or second decades of life. Patients presented with lower limb weakness, resulting in muscle cramps and difficulty walking and running. Later in life, they developed severe weakness and atrophy of distal leg and intrinsic hand muscles, steppage gait, pes cavus, areflexia, and mild distal sensory loss. However, none of the patients became wheelchair-bound. Sural nerve biopsy showed chronic axonal degeneration with regeneration, secondary segmental de- and remyelination, and occasional onion bulbs. Electrophysiologic studies of the median motor nerve showed intermediate values between 25 and 45 m/s.

Inheritance

The transmission pattern of CMTDIA in the family reported by Rossi et al. (1985) was consistent with autosomal dominant inheritance.

Mapping

In an Italian family with dominant intermediate CMT, described earlier by Rossi et al. (1985) and Villanova et al. (1998), Verhoeven et al. (2001) demonstrated linkage to chromosome 10q24.1-q25.1. Sural nerve biopsy in affected members of this family showed axonal degeneration, loss of large diameter fibers, rare segmental demyelination, and remyelination with onion bulb formation.