Journal article
Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease
Journal of neurology, neurosurgery and psychiatry, Vol.88(7), pp.575-585
07/2017
DOI: 10.1136/jnnp-2016-315077
PMCID: PMC5580821
PMID: 28501821
Abstract
To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (
).
Combined analysis of newly identified patients with
-related CMT and all previously reported cases from the literature.
Five new unrelated patients with CMT carrying the
mutations P8R and N98S and the novel variant L311P were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively. Eight patients had de novo mutations. Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and 'onion bulb' formations and/or thin myelin sheaths were observed in 14 (67%) of them. The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases. Pyramidal tract signs were described in 13 patients and 7 patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia and/or cerebellar atrophy on brain MRI.
-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of
sequence variants and the differential diagnosis with other forms of CMT.
Details
- Title: Subtitle
- Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease
- Creators
- Alejandro Horga - Department of Neurology, Hospital Clinico Universitario San Carlos, Madrid, SpainMatilde Laurà - UCL Institute of Neurology, MRC Centre for Neuromuscular Diseases, National Hospital for Neurology and Neurosurgery, London, UKZane Jaunmuktane - Division of Neuropathology and Department of Neurodegenerative Disease, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, London, UKNivedita U Jerath - Department of Neurology, University of Iowa, Iowa City, Iowa, USAMichael A Gonzalez - The Genesis Project Foundation, The Genesis Project Foundation, Miami, Florida, USAJames M Polke - Neurogenetics Unit, National Hospital for Neurology and Neurosurgery, London, UKRoy Poh - Department of Neurogenetics, The National Hospital for Neurology and Neurosurgery and UCL Institute of Neurology, London, UKJulian C Blake - Department of Clinical Neurophysiology, National Hospital for Neurology and Neurosurgery (and Norfolk and Norwich University Hospital), London, UKYo-Tsen Liu - Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, TaiwanSarah Wiethoff - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKConceição Bettencourt - Department of Molecular Neuroscience, UCL Institute of Neurology, London, UKMichael Pt Lunn - Department of Neurology, National Hospital for Neurology and Neurosurgery, London, UKHadi Manji - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UKMichael G Hanna - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UKHenry Houlden - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UKSebastian Brandner - Division of Neuropatholgoy, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UKStephan Züchner - University of Miami, Miami, Florida, USAMichael Shy - Wayne State University, Michigan, Michigan, USAMary M Reilly - MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery, London, UK
- Resource Type
- Journal article
- Publication Details
- Journal of neurology, neurosurgery and psychiatry, Vol.88(7), pp.575-585
- DOI
- 10.1136/jnnp-2016-315077
- PMID
- 28501821
- PMCID
- PMC5580821
- NLM abbreviation
- J Neurol Neurosurg Psychiatry
- ISSN
- 0022-3050
- eISSN
- 1468-330X
- Publisher
- England
- Grant note
- G108/638 / Medical Research Council\r\nMR/J004758/1 / Medical Research Council\r\nG1001253 / Medical Research Council\r\nG0802760 / Medical Research Council\r\nU54 NS065712 / NINDS NIH HHS\r\nR01 NS075764 / NINDS NIH HHS
- Language
- English
- Date published
- 07/2017
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
- Record Identifier
- 9984070894202771
Metrics
18 Record Views