ArticleAnnals of neurology2009
A novel recessive Nefl mutation causes a severe, early-onset axonal neuropathy.
Article in Annals of neurology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 1 of them a synthesis that pooled it.
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Who cites it
59 citing papers in PubMed, 1 synthesis or guideline pooled it, 110 citations in OpenAlex.
- Intermediate Charcot-Marie-Tooth disease: an electrophysiological reappraisal and systematic review.Journal of neurology · 2017Pooled it
- Neurofilament Light Chain (Nfl) Level in Serum as a Suitable In Vivo Biomaker for Axonal Damage in a Murine Viral Model of Multiple Sclerosis.Journal of cellular and molecular medicine · 2026Article
- Junctions in Jeopardy: the neuromuscular junction is a selective pathological target in Charcot-Marie-Tooth disease.Mammalian genome : official journal of the International Mammalian Genome Society · 2026Review
- The p.(Leu97Ile) variant expands the genetic landscape of NEFL-associated Charcot-Marie-tooth neuropathies.Human molecular genetics · 2026Article
- Haplotype editing with CRISPR-Cas9 as a therapeutic approach for dominant-negative missense mutations in NEFL.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- High Diagnostic Yield of Next-Generation Sequencing in Charcot-Marie-Tooth Patients and a Novel Variant in theMolecular syndromology · 2025Article
- From Cell Architecture to Mitochondrial Signaling: Role of Intermediate Filaments in Health, Aging, and Disease.International journal of molecular sciences · 2025Review
- Haplotype editing with CRISPR/Cas9 as a therapeutic approach for dominant-negative missense mutations inbioRxiv : the preprint server for biology · 2024Article
- Customized antisense oligonucleotide-based therapy for neurofilament-associated Charcot-Marie-Tooth disease.Brain : a journal of neurology · 2024Article
- Novel Genetic and Biochemical Insights into the Spectrum of NEFL-Associated Phenotypes.Journal of neuromuscular diseases · 2024Review
- The role of mechanics in axonal stability and development.Seminars in cell & developmental biology · 2023Review
- Fructose Diet-Associated Molecular Alterations in Hypothalamus of Adolescent Rats: A Proteomic Approach.Nutrients · 2023Article
- Neurofilaments in health and Charcot-Marie-Tooth disease.Frontiers in cell and developmental biology · 2023Review
- Posttranscriptional regulation of neurofilament proteins and tau in health and disease.Brain research bulletin · 2023Review
- Molecular characterization of Turkish patients with demyelinating Charcot-Marie-Tooth disease.Neurogenetics · 2022Article
- Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.Molecular genetics & genomic medicine · 2022Article
- Charcot-Marie-Tooth disease type 2CC due toJournal of neurology, neurosurgery, and psychiatry · 2022Observational
- De novo pathogenic variant in SETX causes a rapidly progressive neurodegenerative disorder of early childhood-onset with severe axonal polyneuropathy.Acta neuropathologica communications · 2021Article
- Article
- A review and analysis of the clinical literature on Charcot-Marie-Tooth disease caused by mutations in neurofilament protein L.Cytoskeleton (Hoboken, N.J.) · 2021Review
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5 authors at 2 institutions in 1 country.
Funding
Abstract
objectiveTo report the first cases of a homozygous recessive mutation in NEFL, the gene that encodes the light subunit of neurofilaments.
methodsClinical 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.
resultsFour 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.
interpretationThis 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.
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