Paternal gender specificity and mild phenotypes in Charcot-Marie-Tooth type 1A patients with de novo 17p12 rearrangements.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) are developed by duplication and deletion of the 17p12 (PMP22) region, respectively. METHODS: De novo rates were determined in 211 CMT1A or HNPP trio families, and then, analyzed gender-specific genetic features and clinical phenotypes of the de novo cases. RESULTS: This study identified 40 de novo cases (19.0%). Paternal origin was highly frequent compared to maternal origin (p = .005). Most de novo CMT1A rearrangements occurred between non-sister chromatids (p = .003), but it was interesting that three of the four sister chromatids exchange cases were observed in the less frequent maternal origin. Paternal ages at the affected child births were slightly higher in the de novo CMT1A group than in the non-de novo CMT1A control group (p = .0004). For the disability score of CMTNS, the de novo CMT1A group had a slightly lower value compared to the control group (p = .005). Electrophysiological studies showed no significant differences between the two groups. CONCLUSION: This study suggests that de novo CMT1A patients tend to have milder symptoms and that the paternal ages at child births in the de novo group are higher than those of the non-de novo group.

Small heat shock protein B3 (HSPB3) mutation in an axonal Charcot-Marie-Tooth disease family.

Heat shock protein B3 (HSPB3) gene encodes a small heat-shock protein 27-like protein which has a high sequence homology with HSPB1. A mutation in the HSPB3 was reported as the putative underlying cause of distal hereditary motor neuropathy 2C (dHMN2C) in 2010. We identified a heterozygous mutation (c.352T>C, p.Tyr118His) in the HSPB3 from a Charcot-Marie-Tooth disease type 2 (CMT2) family by the method of targeted next generation sequencing. The mutation was located in the well conserved alpha-crystalline domain, and several in silico predictions indicated a pathogenic effect of the mutation. Clinical and electrophysiological features of the patients indicated the axonal type of CMT. Clinical symptoms without sensory involvements were similar between the present family and the previous family. Mutations in the HSPB1 and HSPB8 genes have been reported to be relevant with both types of CMT2 and dHMN. Our findings will help in the molecular diagnosis of CMT2 by expanding the phenotypic range due to the HSPB3 mutations.

Clinical characterization and genetic analysis of Korean patients with X-linked Charcot-Marie-Tooth disease type 1.

Mutations in the gap junction protein beta 1 gene (GJB1) cause X-linked Charcot-Marie-Tooth disease type 1 (CMTX1). CMTX1 is representative of the intermediate type of CMT, having both demyelinating and axonal neuropathic features. We analyzed the clinical and genetic characterization of 128 patients with CMTX1 from 63 unrelated families. Genetic analysis revealed a total of 43 mutations including 6 novel mutations. Ten mutations were found from two or more unrelated families. p.V95M was most frequently observed. The frequency of CMTX1 was 9.6% of total Korean CMT family and was 14.8% when calculated within genetically identified cases. Among 67 male and 61 female patients, 22 females were asymptomatic. A high-arched foot, ataxia, and tremor were observed in 87%, 41%, and 35% of the patients, respectively. In the male patients, functional disability scale, CMT neuropathy score, and compound muscle action potential of the median/ulnar nerves were more severely affected than in the female patients. This study provides a comprehensive summary of the clinical features and spectrum of GJB1 gene mutations in Korean CMTX1 patients.