title: Clinical and morphological variability of the E396K mutation in the neurofilament light chain gene in patients with Charcot-Marie- Tooth disease type 2E.
abstract: Mutations in the neurofilament light chain (NEFL) gene mostly cause autosomal dominant axonal Charcot-Marie- Tooth neuropathy (CMT2E). The mutation c.1186G>A, p.E396K has been reported in seven unrelated families so far, however, the phenotypic spectrum has not been fully elucidated. Here we describe nine patients with the E396K mutation who had a strikingly discordant clinical severity. The clinical picture in family I (patients I,1-II,8) was characterized by childhood onset, distal and proximal pareses, and loss of ambulation in the 6th decade of life, whereas onset was at age 50 years in patient 9, who had no affected relatives. Electrophysiology and sural nerve biopsy revealed a mixed axonal and demyelinating neuropathy, along with probably coincidental inflammatory small vessel disease in patient 9. Biopsy results in family I suggest that not only axons but also Schwann cells may be primary disease targets in CMT2E. Considerably elevated CK levels in all affected adults of family I as well as pronounced myopathic changes in skeletal muscle biopsies point towards an accompanying muscle involvement as a primary target. Our findings reveal an extended phenotype of CMT2E caused by an identical missense mutation of the NEFL gene.
authors.forename: Miriam
authors.initials: M
authors.lastname: Elbracht
authors.forename: Jan
authors.initials: J
authors.lastname: Senderek
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Kay
authors.initials: K
authors.lastname: Nolte
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Andreas
authors.initials: A
authors.lastname: Roos
authors.forename: Jens
authors.initials: J
authors.lastname: Reimann
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
mesh_terms: D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D020125:Mutation, Missense; D016900:Neurofilament Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D013497:Sural Nerve / Q000473:pathology
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L