title: The novel neurofilament light (NEFL) mutation Glu397Lys is associated with a clinically and morphologically heterogeneous type of Charcot-Marie-Tooth neuropathy.
abstract: Charcot-Marie-Tooth disease comprises a heterogeneous group of hereditary neuropathies which fall into two main groups: demyelinating CMT1 with reduced nerve conduction velocity and axonal CMT2 with normal nerve conduction velocity. The neuropathological features correspond in most cases to this classification. Four genes were recently identified to cause autosomal dominant CMT2, including the neurofilament light gene. Thus far, only few mutations have been reported in neurofilament light involving eight amino acids of the gene. We identified a novel mutation, Glu397Lys, in a conserved motive signaling the end of the rod domain. The affected family members from three generations showed strikingly different clinical phenotypes, including weakness of the lower extremities, foot deformities, and deafness. The mutation was associated with nerve conduction velocities ranging from 27 m/s in a 25-year-old female to 43 m/s in an 82-year-old male in the lower extremity motor nerves. Sural nerve biopsies of two affected subjects were analyzed by light and electron microscopy. The pathological changes consisted of a reduction of predominantly large myelinated nerve fibers and various stages of onion bulb formation as typically seen in CMT1. This correlative study further confirms that neurofilament light gene mutations cause a wide clinical spectrum. Thus, analysis of the neurofilament light gene should not be restricted to pure axonal neuropathies.
authors.affiliation: Institut für Neuropathologie, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 32, 52074 Aachen, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Matthias
authors.initials: M
authors.lastname: Vorgerd
authors.forename: Eckhart
authors.initials: E
authors.lastname: Sindern
authors.forename: J Michael
authors.initials: JM
authors.lastname: Schröder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001369:Axons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D004252:DNA Mutational Analysis; D003638:Deafness / Q000235:genetics / Q000503:physiopathology; D005260:Female; D005820:Genetic Testing; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D018908:Muscle Weakness / Q000235:genetics / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000235:genetics; D016900:Neurofilament Proteins / Q000235:genetics*; D010375:Pedigree; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D017434:Protein Structure, Tertiary / Q000235:genetics; D013497:Sural Nerve / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L; D018698:Glutamic Acid; D008239:Lysine