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NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype.
J Neurol. 2016 Feb; 263(2):361-369.JN

Abstract

The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia.

Authors+Show Affiliations

Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria (UC), Santander, Spain. joseberciano51@hotmail.com. "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain. joseberciano51@hotmail.com.Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium."Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain. Service of Clinical Neurophysiology, University Hospital "Marqués de Valdecilla (IDIVAL)", UC, Santander, Spain.Service of Neurology, University Hospital of Salamanca, Salamanca, Spain."Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain. Service of Radiology, University Hospital "Marqués de Valdecilla (IDIVAL)", UC, Santander, Spain.Service of Pediatric Neurology, University Hospital of Salamanca, Salamanca, Spain.Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria (UC), Santander, Spain. "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.Service of Neurology, University Hospital "Marqués de Valdecilla (IDIVAL)", University of Cantabria (UC), Santander, Spain. "Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED)", Santander, Spain.Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium. Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26645395

Citation

Berciano, José, et al. "NEFL N98S Mutation: Another Cause of Dominant Intermediate Charcot-Marie-Tooth Disease With Heterogeneous Early-onset Phenotype." Journal of Neurology, vol. 263, no. 2, 2016, pp. 361-369.
Berciano J, Peeters K, García A, et al. NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype. J Neurol. 2016;263(2):361-369.
Berciano, J., Peeters, K., García, A., López-Alburquerque, T., Gallardo, E., Hernández-Fabián, A., Pelayo-Negro, A. L., De Vriendt, E., Infante, J., & Jordanova, A. (2016). NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype. Journal of Neurology, 263(2), 361-369. https://doi.org/10.1007/s00415-015-7985-z
Berciano J, et al. NEFL N98S Mutation: Another Cause of Dominant Intermediate Charcot-Marie-Tooth Disease With Heterogeneous Early-onset Phenotype. J Neurol. 2016;263(2):361-369. PubMed PMID: 26645395.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - NEFL N98S mutation: another cause of dominant intermediate Charcot-Marie-Tooth disease with heterogeneous early-onset phenotype. AU - Berciano,José, AU - Peeters,Kristien, AU - García,Antonio, AU - López-Alburquerque,Tomás, AU - Gallardo,Elena, AU - Hernández-Fabián,Arantxa, AU - Pelayo-Negro,Ana L, AU - De Vriendt,Els, AU - Infante,Jon, AU - Jordanova,Albena, Y1 - 2015/12/08/ PY - 2015/09/03/received PY - 2015/11/24/accepted PY - 2015/12/10/entrez PY - 2015/12/10/pubmed PY - 2016/12/15/medline KW - Cerebellar ataxia KW - Charcot–Marie–Tooth disease types 2E and 1F KW - Dominant intermediate Charcot–Marie–Tooth disease KW - Muscle edema KW - Muscle fatty atrophy KW - NEFL N98S mutation SP - 361 EP - 369 JF - Journal of neurology JO - J. Neurol. VL - 263 IS - 2 N2 - The purpose of this study was to describe a pedigree with NEFL N98S mutation associated with a dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and heterogeneous early-onset phenotype. The pedigree comprised two patients, the proband and her son, aged 38 and 5 years. The proband, evaluated at age 31, showed delayed motor milestones that, as of the second decade, evolved into severe phenotype consisting of sensorimotor neuropathy, pes cavus, clawing hands, gait and kinetic cerebellar ataxia, nystagmus and dysarthria, she being wheelchair bound. By then, a working diagnosis of sporadic early onset cerebellar ataxia with peripheral neuropathy was established. Screening of mutations associated with SCA and autosomal recessive cerebellar ataxias was negative. Her son showed a mild phenotype characterized by delayed motor milestones, and lower-limb hypotonia and areflexia. Electrophysiology in both patients showed nerve conduction slowing in the intermediate range, both in proximal and distal nerve segments, but where compound muscle action potentials exhibited severe attenuation there was conduction slowing down to the demyelinating range. In the proband, cranial magnetic resonance imaging (MRI) showed cerebellar atrophy, electromyography disclosed active denervation in tibialis anterior, and MRI of lower-limb musculature demonstrated widespread and distally accentuated muscle fatty atrophy; furthermore, on water sensitive MRI sequences there was edema of calf muscles. We conclude that the NEFL N98S mutation is associated with a DI-CMT phenotype characterized by early-onset sensorimotor neuropathy delaying motor milestones, which may evolve into a severe and complex clinical picture including cerebellar ataxia. SN - 1432-1459 UR - https://www.unboundmedicine.com/medline/citation/26645395/NEFL_N98S_mutation:_another_cause_of_dominant_intermediate_Charcot_Marie_Tooth_disease_with_heterogeneous_early_onset_phenotype_ L2 - https://dx.doi.org/10.1007/s00415-015-7985-z DB - PRIME DP - Unbound Medicine ER -