Giant axon and neurofilament accumulation in Charcot–Marie–Tooth disease type 2E

Abstract

The axonal type 2 Charcot-Marie-Tooth disease (CMT2) is phenotypically poorly characterized. Here the authors report a family with a Pro22Ser mutation in the neurofilament-light gene (NF-L; CMT2E) manifesting electrophysiologically as the demyelinating type 1 CMT (CMT1) and pathologically as an axonopathy with giant axons and accumulation of disorganized NF. NF-L should be investigated in CMT2 as well as in CMT1 not associated with the usual genes PMP22, Cx32, and P0.

NEFL Pro22Arg mutation in Charcot-Marie-Tooth disease type 1

“…We believed that this mutation was the underlying cause of the CMT1 phenotype in the FC99 family for the following reasons: cosegregation of the mutation with affected members of the pedigree, no similar mutation in controls (n = 210), well-conserved Pro22 among different species, and the findings of previous reports on the effect of different mutations at the Pro22 site. It seems that codon 22 is one of the mutational hot spots in the NEFL gene because three different Pro22 mutations, including the one found in this study, have been reported (Fabrizi et al 2004;Georgiou et al 2002;Yoshihara et al 2002). Three different families have been reported to have Pro22 mutations: Pro22Ser in a Slovenian family (Georgiou et al 2002) and an Italian family (Fabrizi et al 2004), and Pro22Thr in a Japanese family (Yoshihara et al 2002).…”

“…1b). This mutation was found in the (Yoshihara et al 2002) and c.64C [ T resulting in Pro22Ser (Fabrizi et al 2004;Georgiou et al 2002), but this Pro22Arg mutation was not reported in the inherited peripheral neuropathies mutation database. Amino acids at the mutated site are highly conserved in different species (Fig.…”

“…Three mutations (Pro22Ser, Leu268Pro and del322Cys-326Asn) have been reported to be associated with giant axonal neuropathies and secondary demyelination (Fabrizi et al 2004(Fabrizi et al , 2007, whereas the other mutations (Glu89Lys and Glu397Lys) were found to be associated with onion bulb formations and loss of large myelinated fibers, but not giant axonal neuropathy (Jordanova et al 2003;Züchner et al 2004).…”

“…Several missense mutations in the NEFL gene have been reported, and a number of these have been predicted to produce alterations in the formation of the intermediate filament network in neurons (Pérez-Ollé et al 2005;Sasaki et al 2006). Mutations in the NEFL gene were originally reported to be associated with CMT2E (De Jonghe et al 2001;Fabrizi et al 2004). However, because some patients had markedly reduced NCVs, it was suggested that NEFL neuropathy was also relevant with CMT1F (Jordanova et al 2003).…”

“…Particularly, two Pro22 mutations have been reported: Pro22Ser was found in CMT2E with giant axons in the sural nerve (Fabrizi et al 2004;Georgiou et al 2002), and Pro22Thr was found to be associated with CMT1F (Yoshihara et al 2002). It has been suggested that Pro22 mutations abolish the Thr-Pro phosphorylation sequence of the head domain of NEFL by proline-directed protein kinases (PDPKs) (Sasaki et al 2006).…”