Late-onset Charcot-Marie-Tooth disease 4F caused by periaxin gene mutation

We identified the main features of Charcot-Marie-Tooth (CMT) disease, type 4F, caused by a periaxin gene (PRX) mutation in Japanese patients. Periaxin is known as one of the key myelination molecules, forming tight junction between myelin loop and axon. We collected 427 DNA samples from individuals with CMT or CMT-related neuropathy, negative for PMP22 duplication. We investigated PRX mutations using a purpose-built resequencing array screen during the period 2006-2012. We detected two types of PRX mutations in three patients; one patient showed a novel homozygous p.D651N mutation and the other two showed homozygous p.R1070X mutation. All PRX mutations reported so far have been of nonsense or frameshift type. In this study, we found homozygous missense mutation p.D651N. Aspartate 651 is located in a repeat domain; its position might indicate an important function. PRX mutations usually lead to early-onset, autosomal-recessive demyelinating CMT neuropathy 4F (CMT4F) or Dejerine-Sottas disease; their clinical phenotypes are severe. In our three patients, the onset of the disease was at the age of 27 years or later, and their clinical phenotypes were milder compared with those reported in previous studies. We showed a variation of clinical phenotypes for CMT4F caused by a novel, nonsense PRX mutation.