title: A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy.
abstract: OBJECTIVE
  To report the first cases of a homozygous recessive mutation in NEFL, the gene that encodes the light subunit of neurofilaments.
  
  
  METHODS
  Clinical and electrophysiologic data were evaluated, and a sural nerve biopsy from one affected child was examined by immunohistochemistry and electron microscopy. The ability of the mutant protein to form filaments was characterized in an established cell culture system.
  
  
  RESULTS
  Four of five siblings developed of a severe, progressive neuropathy beginning in early childhood. Serial nerve conduction studies showed progressively reduced amplitudes with age and pronounced slowing at all ages. Visual-evoked responses were slowed in three children, indicating that central nervous system axons were subclinically involved. All four affected children were homozygous for a nonsense mutation at glutamate 210 (E210X) in the NEFL gene; both parents were heterozygous carriers. A sural nerve biopsy from an affected patient showed markedly reduced numbers of myelinated axons; the remaining myelinated axons were small and lacked intermediate filaments. The E210X mutant protein did not form an intermediate filament network and did not interfere with the filament formation by wild-type human light subunit of neurofilaments in SW-13 vim(-) cells.
  
  
  CONCLUSIONS
  This is the first demonstration of a recessive NEFL mutation, which appears to cause a simple loss of function, resulting in a severe, early-onset axonal neuropathy with unique features. These results confirm that neurofilaments are the main determinant of axonal caliber and conduction velocity, and demonstrate for the first time that neurofilaments are required for the maintenance of myelinated peripheral nervous system axons.
authors.affiliation: Section of Neurology, St. Christopher's Hospital for Children, Drexel University College of Medicine, Philadelphia, PA 19134, USA. sabrina.yum@drexelmed.edu
authors.forename: Sabrina W
authors.initials: SW
authors.lastname: Yum
authors.forename: Junxian
authors.initials: J
authors.lastname: Zhang
authors.forename: Katie
authors.initials: K
authors.lastname: Mo
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018450:Disease Progression; D005192:Family Health; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D016297:Mutagenesis, Site-Directed / Q000379:methods; D009154:Mutation / Q000235:genetics*; D009431:Neural Conduction / Q000502:physiology; D016900:Neurofilament Proteins / Q000172:deficiency / Q000235:genetics*; D010523:Peripheral Nervous System Diseases / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D012720:Severity of Illness Index; D013497:Sural Nerve / Q000473:pathology / Q000503:physiopathology / Q000648:ultrastructure; D055815:Young Adult
chemical_list: D016900:Neurofilament Proteins; C044882:neurofilament protein L; D018698:Glutamic Acid