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Ann Neurol. 2019 Jul;86(1):55-67. doi: 10.1002/ana.25500. Epub 2019 May 27.

A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).

Author information

1
Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
2
Hôpital Pitié-Salpêtrière, AP-HP, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Paris, France.
3
MRC Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom.
4
Department of Clinical Neurophysiology, Norfolk and Norwich University Hospital, Norfolk, United Kingdom.
5
Istanbul University, Istanbul Faculty of Medicine, Neurology Dep. Istanbul, Turkey.
6
Bogazici University, Department of Molecular Biology and Genetics, Istanbul, Turkey.
7
Laboratoire de Recherche en Neurosciences Service de Neurologie, CHU, Alger, Algeria.
8
Department of Medical Genetics, Timone Hospital, Marseille, France.2, Aix-Marseille University, INSERM, MMG, U1251, Marseille, France.
9
Université Côte d'Azur, Service Système Nerveux Périphérique, Muscle et SLA, Centre Hospitalier Universitaire de Nice, Nice, France.
10
Reference center for neuromuscular disorders and ALS, CHU La Timone, Aix-Marseille University, Marseille, France.
11
Center of Biology and Pathology Laboratory of Molecular Neurogenetics, Hospices Civils, Lyon, France.
12
Reference center for neuromuscular disorders AOC (Atlantique Occitanie Caraibes), CHU de Bordeaux, Bordeaux, France.
13
Institut Jérôme Lejeune, Paris, France.
14
INOVIE, Beirut, Lebanon.
15
Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
16
Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom.
17
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
18
Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
19
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and MATERNAL Infantile Sciences, University of Genoa, and IRCCS Policlinico San Martino, Genoa, Italy.
20
Fondazione Policlinico Universitario Agostino Gemelli IRCCS. Centro Clinico Nemo Adulti Rome, Rome, Italy.
21
Università Cattolica del Sacro Cuore. Sede di Roma, Rome, Italy.
22
UOC Neurologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
23
Department of Neurosciences, Reproductive Sciences and Odontostomatology, University Federico II of Naples, Naples, Italy.
24
Department of Neurology, Università Magna Graecia di Catanzaro, Catanzaro, Italy.
25
Department of Neurology, Kawasaki Medical School, Kurashiki, Japan.
26
Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
27
Department of Neurology, University of Iowa Hospitals and Clinics, Iowa, IA.
28
Department of Neurology, University of Rochester, Rochester, NY.
29
Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.
30
Department of Research and Clinical Development, Scientific Directorate, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
31
Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Abstract

OBJECTIVE:

Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B.

METHODS:

We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score.

RESULTS:

There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations.

INTERPRETATION:

This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019.

PMID:
31070812
DOI:
10.1002/ana.25500

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