Inheritance of Charcot-Marie-Tooth disease 1A with rare nonrecurrent genomic rearrangement.

Rare copy number variations by the nonrecurrent rearrangements involving PMP22 have been recently suggested to be associated with CMT1A peripheral neuropathy. As a mechanism of the nonrecurrent rearrangement, replication-based fork stalling template switching (FoSTeS) by microhomology-mediated break-induced replication (MMBIR) has been proposed. We found three Korean CMT1A families with putative nonrecurrent duplication. The duplications were identified by microsatellite typing and applying a CGH microarray. The breakpoint sequences in two families suggested an Alu-Alu-mediated rearrangement with the FoSTeS by the MMBIR, and a two-step rearrangement of the replication-based FoSTeS/MMBIR and meiosis-based recombination. The two-step mechanism has still not been reported. Segregation analysis of 17p12 microsatellite markers and breakpoint junction analysis suggested that the nonrecurrent rearrangements are stably inherited without alteration of junction sequence; however, they may allow some alteration of the genomic contents in duplication across generations by recombination event. It might be the first study on the pedigree analysis of the large CMT1A families with nonrecurrent rearrangements. It seems that the exact mechanism of the nonrecurrent rearrangements in the CMT1A may have a far more complex process than has been expected.

Charcot-Marie-Tooth 1A concurrent with schwannomas of the spinal cord and median nerve.

We identified Charcot-Marie-Tooth disease type 1A (CMT1A) in a family with schwannomas in the spinal cord and median nerve. The CMT1A in this family showed an autosomal dominant pattern, like other CMT patients with PMP22 duplication, and the family also indicated a possible genetic predisposition to schwannomas by 'mother-to-son' transmission. CMT1A is mainly caused by duplication of chromosome 17p11.2-p12 (PMP22 gene duplication). A schwannoma is a benign encapsulated tumor originating from a Schwann cell. A case of hereditary neuropathy with liability to pressure palsies (HNPP) concurrent with schwannoma has been previously reported. Although it seems that the co-occurrence of CMT1A and schwannomas in a family would be the result of independent events, we could not completely ignore the possibility that the coincidence of two diseases might be due to a shared genetic background.

Distal hereditary motor neuropathy in Korean patients with a small heat shock protein 27 mutation.

Distal hereditary motor neuropathy (dHMN) is a heterogeneous disorder characterized by degeneration of motor nerves in the absence of sensory abnormalities. Recently, mutations in the small heat shock protein 27 (HSP27) gene were found to cause dHMN type II or Charcot-Marie-Tooth disease type 2F (CMT2F). The authors studied 151 Korean axonal CMT or dHMN families, and found a large Korean dHMN type II family with the Ser135Phe mutation in HSP27. This mutation was inherited in an autosomal dominant manner, and was well associated with familial members with the dHMN phenotype. This mutation site is located in the alpha-crystallin domain and is highly conserved between different species. The frequency of this HSP27 mutation in Koreans was 0.6%. Magnetic resonance imaging analysis revealed that fatty infiltrations tended to progressively extend distal to proximal muscles in lower extremities. In addition, fatty infiltrations in thigh muscles progressed to affect posterior and anterior compartments but to lesser extents in medial compartment, which differs from CMT1A patients presenting with severe involvements of posterior and medial compartments but less involvement of anterior compartment. The authors describe the clinical and neuroimaging findings of the first Korean dHMN patients with the HSP27 Ser135Phe mutation. To our knowledge, this is the first report of the neuroimaging findings of dHMN type II.

MPZ mutation in an early-onset Charcot-Marie-Tooth disease type 1B family by genome-wide linkage analysis.

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous peripheral neuropathy. The objective of this study was to find the causative mutation(s) in a demyelinating autosomal dominant CMT family. A high density SNP-based genome-wide linkage scan was performed, and causative mutations were determined by sequencing of candidate genes in the linkage disequilibrium region. Linkage analysis mapped the underlying gene to a region on chromosome 1q22-q23 with a maximum two-point LOD score of 2.036. Sequencing analysis revealed a novel c.243C>G (His81Gln) mutation in the MPZ gene, which encodes the major integral membrane protein of the peripheral nerve system. MPZ is well known as a CMT-causative gene with wide phenotypic spectrum. The clinical symptoms were more similar to those of patients with the His81Arg than patients with the His81Tyr mutation. The novel mutation completely co-segregated with affected members, and was not found in controls. Therefore, we suggest that the identified mutation in MPZ is the underlying cause of CMT in the family. In addition, this study demonstrated that the clinical phenotypes may be variable with different mutations at the same site in the MPZ gene.