Charcot-Marie-Tooth Disease And Deafness

A number sign (#) is used with this entry because this syndrome, at least in some cases, is caused by mutation in the peripheral myelin protein-22 gene (PMP22; 601097). In these cases, inheritance is autosomal dominant.

Mild deafness is sometimes coupled with the X-linked form of CMT (302800). See 214370 for a possibly autosomal recessive form of CMT-deafness syndrome and 311070 for an X-linked disorder that includes optic atrophy also.

For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant demyelinating CMT, see CMT1B (118200).

Clinical Features

Pyeritz (1979) examined 3 affected members of 2 generations of a western Maryland kindred, and Gummerson (1981) examined several members of a southern Pennsylvania kindred. In both pedigrees, classic CMT was always associated with sensorineural deafness. No instance of renal disease occurred in either pedigree. A common surname suggested that the kindreds were distantly related.

Kousseff et al. (1982) and Kousseff (1982) described a family in which 82 persons in 7 generations appeared to have had this disorder. Male-to-male transmission was observed 13 times. Onset occurred in childhood with weakness of peroneal muscles, followed by atrophy, pes calcaneovarus, steppage gait, poor balance, and diminished sensation in the legs. Other distal muscles of the arms and legs became involved, resulting in claw hands, pes cavus, hammertoes, and absent deep tendon reflexes. Neuropathy was demonstrated by electromyography. Sensorineural hearing loss, which became apparent in the second decade, was severe to profound in most affected persons after the third decade.

Hamiel et al. (1993) described as a 'new variant' a 3-generation family in which hereditary motor-sensory neuropathy with sensorineural deafness became apparent in early childhood and infancy. Linkage to Duffy blood group on chromosome 1, where CMT1B maps, was excluded. Duplication of the PMP22 gene (601097) found in CMT1A (118220) was also excluded. Male-to-male transmission was observed.

Molecular Genetics

In the family originally reported by Kousseff et al. (1982), Kovach et al. (1999) identified an ala67-to-pro mutation in the PMP22 gene (601097.0010).

Deafness appears to be a rare association with CMT in those cases in which mutation in the PMP22 gene is responsible. Boerkoel et al. (2002) noted that only 2 mutations in the PMP22 gene had been identified as the cause of CMT and deafness: A67P (601097.0010) and W28R (601097.0014).

In 3 affected members of a family with autosomal dominant CMT with deafness, Sambuughin et al. (2003) identified a 12-bp deletion in exon 4 of the PMP22 gene (601097.0015).

Nomenclature

In keeping with the most common designations used in the medical community, 'CMT1' referring to autosomal dominant demyelinating CMT and 'CMT2' referring to axonal CMT, we have chosen to designate this form of demyelinating CMT with hearing loss as 'CMT1E.'