Late-onset Charcot-Marie-Tooth type 2 disease with hearing impairment associated with a novel Pro105Thr mutation in the MPZ gene†

Charcot-Marie-Tooth disease (CMT) is a heterogenous group of disorders of peripheral nervous system with a prevalence of 1:2,500. The frequency of axonal form of Charcot-Marie-Tooth disease (CMT2) remains unknown. To date 17 loci in autosomal dominant (14) and in autosomal recessive (3) CMT2 have been mapped [Bernard et al., 2006; Zuchner and Vance, 2006]. Among 11 genes identified in AD-CMT2, the Mitofusin 2 gene has been shown to be mutated in 11% of CMT2 cases [Verhoeven et al., 2006]. SomeAD-CMT2 forms are characterizedby specific clinical features, whereas to distinguish between other types linkage analysis is necessary. The firstMPZmutation in the hypertrophic form of CMT disease was reported in 1993 [Hayasaka et al., 1993]. The congenital hypomyelination neuropathy (CHN) was a second phenotype which was shown to be associated with mutations in the MPZ gene [Warner et al., 1996; Szigeti et al., 2003; Kochanski et al., 2004]. Interestingly, CMT2 disease associated with mutations in the myelin protein zero gene (MPZ) was not recognized until 1997. In 1997, a novel mutation in the MPZ gene was identified in a large CMT2 Sardinian family consisting of five generations [Marrosu et al., 1998]. In this study we report on two affected patients from a CMT2 family, in which a novel p.Pro105Thr mutation in the MPZ gene has been found. The family consists of three generations (Fig. 1). The proband (III:2) had been admitted to Neurology Department at age 54 due to clumsy gait and sensory loss in the distal parts of the upper and lower limbs since the age of 46.Onneurological examination hehadweakness of the distal muscles of the lower limbs and hypertrophy of calf muscles. Achilles tendon reflexes were bilaterally absent. A sensory loss within all modalities was prominent in the lower limbs distally and extended proximally to the knees. The patient showed marked ataxia when walking with closed eyes. There was a prominent steppage gait and he was unable to walk on his heels and toes. Audiometry showed left-sided severe sensorineural hearing loss of 20 progressing to 60 dB hearing level (HL) in the high frequencies. The brother of the proband (III:1), a 60-year-old man, first noticed foot drop at age 54. The disease was progressing within the next years, leading to marked wasting of the calf muscles. He complained of pains and paraesthesia in the lower limbs. On neurological examination at the age of 60 years he had pes cavus deformity, weakness, and wasting of the distal muscles of the lower limbs. Tendon reflexes in the lower limbs were absent. There was hypesthesia in the distal parts of the lower limbs. Similar to his brother he had marked ataxia when walking with closed eyes. In spite of denying any