ClinVar Genomic variation as it relates to human health

Distal lower limb muscle weakness (present) , Distal upper limb muscle weakness (present) , Proximal muscle weakness in lower limbs (present) , Reduced tendon reflexes (present) , Distal amyotrophy (present) , Hypotrophy of the small hand muscles (present) (less)

Among 20 unrelated French Charcot-Marie-Tooth disease type 1B (CMT1B; 118200) patients without 17p11.2 duplications, Rouger et al. (1996) found 3 different mutations at codon 98. No other mutation in exon 3 of the MPZ gene was detected. The mutation was demonstrated to be de novo in 1 of the cases and suspected of being de novo in the other 2, suggesting that mutations occur with a high rate at codon 98. In 1 patient an arg98-to-pro (R98P; 159440.0009) mutation was caused by a 293G-C transversion, whereas in another patient an arg98-to-cys substitution (R98C; 159440.0010) was caused by a 292C-T transition. The third mutation was a 293G-A transition, resulting in an arg98-to-his substitution. Rouger et al. (1996) noted that this mutation had previously been reported in a Japanese family by Hayasaka et al. (1993). The patient with the R98C mutation showed a more severe clinical and electrophysiologic phenotype than the others with a codon 98 mutation, partly compatible with Dejerine-Sottas syndrome with very early onset (1 year), and a very low nerve conduction velocity, but only mild functional disability at age 8 years. All 3 mutations in codon 98 implied a C-to-T transition (1 on the sense and 2 on the antisense strand), suggesting that they may result from the deamination of a methylcytosine to a thymine. The authors stated that this could explain the high rate of mutations on codon 98. The R98H mutation, characterized by direct sequencing in 2 cases, was not detected by the SSCP technique. Since SSCP analysis was used as the initial screening technique in most previous studies, the frequency of mutations at codon 98 may have been underestimated. The 3 codon 98 mutations represented 20% of the CMT1 patients without duplications and probably a much higher proportion of those with MPZ mutations. These mutations can be picked up by CfoI restriction of exon 3 of the MPZ gene; this approach should be the first step in screening CMT1 patients without duplications. Watanabe et al. (2002) reported partial symptom relief with corticosteroid treatment in a patient with demyelinating CMT1B and a heterozygous R98H mutation in the MPZ gene. Although this response is rare in such patients, Watanabe et al. (2002) hypothesized that poor myelin compaction by the MPZ protein, caused by the mutation, may have allowed circulating immune elements access to normally sequestered endoneurial components, thus accounting for the response to corticosteroid treatment. (less)