Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton.
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.
Fabrizi
Gian Maria
GM
Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Italy. gianmaria.fabrizi@univr.it
Cavallaro
Tiziana
T
Angiari
Chiara
C
Cabrini
Ilaria
I
Taioli
Federica
F
Malerba
Giovanni
G
Bertolasi
Laura
L
Rizzuto
Nicoló
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000648:ultrastructure; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D003599:Cytoskeleton / Q000648:ultrastructure*; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009431:Neural Conduction; D016900:Neurofilament Proteins / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D013497:Sural Nerve / Q000378:metabolism / Q000648:ultrastructure
D016900:Neurofilament Proteins; C044882:neurofilament protein L