Brain Advance Access originally published online on October 18, 2006
Brain 2007 130(2):394-403; doi:10.1093/brain/awl284
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Charcot–Marie–Tooth disease type 2E, a disorder of the cytoskeleton
1 Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona Italy 2 Section of Biology and Genetics, Department of Mother and Child and Biology-Genetics, University of Verona Italy
Correspondence to: Dr Gian Maria Fabrizi, Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona. Policlinico "G.B. Rossi", P.le L.A. Scuro 10, 37134 Verona, Italy E-mail: gianmaria.fabrizi{at}univr.it
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.
Key Words: Charcot–Marie–Tooth disease; neurofilament light chain subunit; giant axons; secondary demyelination; phenotype and genotype correlations
Abbreviations: CMT, Charcot–Marie–Tooth; MNCV, motor nerve conduction velocity; NF-L, neurofilament light; SNP, single nucleotide polymorphism
Received June 17, 2006. Revised August 19, 2006. Accepted August 23, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. W. Cleveland, K. Yamanaka, and P. Bomont Gigaxonin controls vimentin organization through a tubulin chaperone-independent pathway Hum. Mol. Genet., April 15, 2009; 18(8): 1384 - 1394. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhai, H. Lin, J.-P. Julien, and W. W. Schlaepfer Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot Marie Tooth disease-linked mutations in NFL and HSPB1 Hum. Mol. Genet., December 15, 2007; 16(24): 3103 - 3116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Miltenberger-Miltenyi, A. R. Janecke, J. V. Wanschitz, V. Timmerman, C. Windpassinger, M. Auer-Grumbach, and W. N. Loscher Clinical and Electrophysiological Features in Charcot-Marie-Tooth Disease With Mutations in the NEFL Gene Arch Neurol, July 1, 2007; 64(7): 966 - 970. [Abstract] [Full Text] [PDF]
|
|