The neurofilament light chain (NF-L) is a major constituent of intermediate 
filaments and plays a pivotal function in the assembly and maintenance of axonal 
cytoskeleton. Mutations in the NF-L gene (NEFL) cause autosomal dominant 
neuropathies that are classified either as axonal Charcot-Marie-Tooth (CMT) type 
2E (CMT2E) or demyelinating CMT type 1F (CMT1F). The pathophysiological bases of 
the disorder(s) are elusive. We performed a mutational analysis of NEFL in a 
series of 177 index cases with CMT and without mutations in the genes for 
peripheral myelin protein zero (MPZ), peripheral myelin protein 22 (PMP22) and 
connexin 32 (GJB1); the motor nerve conduction velocity (MNCV) at the median 
nerve was below 38 m/s in 76 cases and above 38 m/s in 101. We identified five 
new pedigrees with four mutations in the head and rod domains of NF-L, including 
a novel Leu268Pro substitution and a novel del322Cys_326Asn deletion. Several 
examined affected members exhibited marked variability in the severity of 
disease and age at onset. Nerve conduction alterations were consistent with an 
axonal neuropathy often associated with demyelinating features, such as 
prolonged distal latencies (DL). Pathological examination of sural nerve 
biopsies in the probands detected in four cases a chronic axonal neuropathy 
dominated by focal accumulations of NF with axonal swellings (giant axons) and 
significant secondary demyelination; in the fifth case no NFs accumulations were 
evident but many myelinated fibres consisted exclusively of microtubules with 
few or absent NF. The pathological phenotype correlated with the pattern of 
nerve conduction alterations and indicated that NEFL mutations cause a profound 
alteration of the cytoskeleton possibly related to defective targeting of NF.