title: Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot-Marie-Tooth disease.
abstract: Neurofilament light chain polypeptide (NEFL) is one of the most abundant cytoskeletal components of the neuron. Mutations in the NEFL gene were recently reported as a cause for autosomal dominant Charcot-Marie-Tooth type 2E (CMT2E) linked to chromosome 8p21. In order to investigate the frequency and phenotypic consequences of NEFL mutations, we screened 323 patients with CMT or related peripheral neuropathies. We detected six disease associated missense mutations and one 3-bp in-frame deletion clustered in functionally defined domains of the NEFL protein. Patients have an early onset and often a severe clinical phenotype. Electrophysiological examination shows moderately to severely slowed nerve conduction velocities. We report the first nerve biopsy of a CMT patient with a de novo missense mutation in NEFL, and found an axonal pathology with axonal regeneration clusters and onion bulb formations. Our findings provide further evidence that the clinical variation observed in CMT depends on the gene mutated and the specific type of mutation, and we also suggest that NEFL mutations need to be considered in the molecular evaluation of patients with sporadic or dominantly inherited CMT.
authors.affiliation: Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology, University of Antwerp, Belgium.
authors.forename: A
authors.initials: A
authors.lastname: Jordanova
authors.forename: P
authors.initials: P
authors.lastname: De Jonghe
authors.forename: C F
authors.initials: CF
authors.lastname: Boerkoel
authors.forename: H
authors.initials: H
authors.lastname: Takashima
authors.forename: E
authors.initials: E
authors.lastname: De Vriendt
authors.forename: C
authors.initials: C
authors.lastname: Ceuterick
authors.forename: J-J
authors.initials: JJ
authors.lastname: Martin
authors.forename: I J
authors.initials: IJ
authors.lastname: Butler
authors.forename: P
authors.initials: P
authors.lastname: Mancias
authors.forename: S Ch
authors.initials: SCh
authors.lastname: Papasozomenos
authors.forename: D
authors.initials: D
authors.lastname: Terespolsky
authors.forename: L
authors.initials: L
authors.lastname: Potocki
authors.forename: C W
authors.initials: CW
authors.lastname: Brown
authors.forename: M
authors.initials: M
authors.lastname: Shy
authors.forename: D A
authors.initials: DA
authors.lastname: Rita
authors.forename: I
authors.initials: I
authors.lastname: Tournev
authors.forename: I
authors.initials: I
authors.lastname: Kremensky
authors.forename: J R
authors.initials: JR
authors.lastname: Lupski
authors.forename: V
authors.initials: V
authors.lastname: Timmerman
mesh_terms: D000293:Adolescent; D001369:Axons / Q000473:pathology; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D004594:Electrophysiology; D017353:Gene Deletion; D006801:Humans; D007223:Infant; D008854:Microscopy, Electron; D009154:Mutation; D020125:Mutation, Missense; D016900:Neurofilament Proteins / Q000235:genetics*; D013497:Sural Nerve / Q000473:pathology
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L