Brain, Vol. 126, No. 3, 590-597,
March 2003
© 2003 Guarantors of Brain
doi: 10.1093/brain/awg059
Mutations in the neurofilament light chain gene (NEFL) cause early onset severe Charcot–Marie–Tooth disease
1 Molecular Genetics Department, Flanders Interuniversity Institute for Biotechnology and 2 Laboratory of Neuropathology and Electronmicroscopy, Born-Bunge Foundation, University of Antwerp, Antwerp, 3 Division of Neurology, University Hospital of Antwerp, Edegem, Belgium, Departments of 4 Molecular and Human Genetics, and 5 Pediatrics, Baylor College of Medicine, Houston, TX, Departments of 6 Neurology and 7 Pathology and Laboratory Medicine, The University of Texas—Houston Medical School, Texas, 8 Department of Genetics, Credit Valley Hospital, Ontario, 9 Department of Neurology, Wayne State University School of Medicine, Detroit, MI, 10 Lutheran General Hospital, Park Ridge, IL, USA, 11 Laboratory of Molecular Pathology and 12 Department of Neurology, Sofia Medical University, Sofia, Bulgaria
Correspondence to: Professor Dr Vincent Timmerman, PhD, Peripheral Neuropathy Group, Molecular Genetics Department (VIB8), University of Antwerp (UIA), Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: vincent.timmerman{at}ua.ac.be
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.
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