CMT 2E: A disorder of the cytoskeleton

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Brain. 2006 Oct 18

Charcot-Marie-Tooth disease type 2E, a disorder of the cytoskeleton.

Fabrizi GM, Cavallaro T, Angiari C, Cabrini I, Taioli F, Malerba G,

Bertolasi L, Rizzuto N.

Section of Clinical Neurology, Department of Neurological and Visual

Sciences, University of Verona, Italy.

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.