Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype

Ilaria Callegari; C Gemelli; A Geroldi; F Veneri; P Mandich; M D’Antonio; D Pareyson; M Shy; A Schenone; V Prada; M Grandis

doi:10.1007/s00415-019-09453-3

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Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype

Journal article

Peer reviewed

Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype

Ilaria Callegari, C Gemelli, A Geroldi, F Veneri, P Mandich, M D’Antonio, D Pareyson, M Shy, A Schenone, V Prada, …

Journal of neurology, Vol.266(11), pp.2629-2645

11/2019

DOI: 10.1007/s00415-019-09453-3

PMID: 31278453

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Abstract

Mutations of myelin protein zero gene (MPZ) are found in 5% of Charcot–Marie–Tooth patients. In 2004, Shy et al. identified two main phenotypes associated with them: an early-onset subtype with mainly demyelinating features and a late-onset subgroup with prominent axonal impairment. We evaluated whether novel MPZ mutations described in literature during the last 14 years could still fit with this classification. We collected and revised reports of 69 novel MPZ mutations. Almost 90% of them could be alternatively classified as responsible for: (a) an early-onset phenotype, with first limitations starting before 3 years (2.5 ± 0.50 years), motor milestones delays, frequently severe course and upper limb MNCVs below 15 m/s; (b) late-onset neuropathy, with mean age of onset of 42.8 ± 1.5 years and mean upper limbs motor nerve conduction velocities (MNCVs) of 47.2 ± 1.4 m/s; (c) a phenotype more similar to typical CMT1A neuropathy, with onset during the 2nd decade, MNCV in the range of 15–30 m/s and slowly progressive course. The present work confirms that P0-related neuropathies may be separated into two main distinct phenotypes, while a third, relatively small, group comprehend patients carrying MPZ mutations and a childhood-onset disease, substantiating the subdivision into three groups proposed by Sanmaneechai et al. (Brain 138:3180–3192, 2015). Interestingly, during the last years, an increasing number of novel MPZ mutations causing a late-onset phenotype has been described, highlighting the clinical relevance of late-onset P0 neuropathies. Since the family history for neuropathy is often uncertain, due to the late disease onset, the number of patients carrying this genotype is probably underestimated.

Myelin protein zero

Neurology

Neurosciences

Medicine & Public Health

Phenotype classification

Charcot–Marie–Tooth

Genotype–phenotype correlation

Neuroradiology

Details

Title: Subtitle: Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype
Creators: Ilaria Callegari - IRCCS Mondino Foundation Pavia Italy
C Gemelli - grid.5606.5 0000 0001 2151 3065 Department of Neuroscience Rehabilitation Ophthalmology Genetics, Maternal and Child Health (DiNOGMI) University of Genova Genoa Italy
A Geroldi - grid.5606.5 0000 0001 2151 3065 Department of Neuroscience Rehabilitation Ophthalmology Genetics, Maternal and Child Health (DiNOGMI) University of Genova Genoa Italy
F Veneri - grid.5606.5 0000 0001 2151 3065 Department of Neuroscience Rehabilitation Ophthalmology Genetics, Maternal and Child Health (DiNOGMI) University of Genova Genoa Italy
P Mandich - grid.414603.4 Ospedale Policlinico San Martino IRCCS Largo P. Daneo 3 16132 Genoa Italy
M D’Antonio - grid.18887.3e 0000000417581884 Division of Genetics and Cell Biology San Raffaele Scientific Institute Milan Italy
D Pareyson - grid.417894.7 0000 0001 0707 5492 Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences Fondazione IRCCS Istituto Neurologico Carlo Besta Milan Italy
M Shy - grid.412584.e 0000 0004 0434 9816 Department of Neurology University of Iowa Hospitals & Clinics Iowa City USA
A Schenone - grid.414603.4 Ospedale Policlinico San Martino IRCCS Largo P. Daneo 3 16132 Genoa Italy
V Prada - grid.5606.5 0000 0001 2151 3065 Department of Neuroscience Rehabilitation Ophthalmology Genetics, Maternal and Child Health (DiNOGMI) University of Genova Genoa Italy
M Grandis - grid.414603.4 Ospedale Policlinico San Martino IRCCS Largo P. Daneo 3 16132 Genoa Italy
Resource Type: Journal article
Publication Details: Journal of neurology, Vol.266(11), pp.2629-2645
Publisher: Springer Berlin Heidelberg; Berlin/Heidelberg
DOI: 10.1007/s00415-019-09453-3
PMID: 31278453
ISSN: 0340-5354
eISSN: 1432-1459
Language: English
Date published: 11/2019
Academic Unit: Neurology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute
Record Identifier: 9984070694502771

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