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Brain Advance Access published online on May 19, 2006
Brain, doi:10.1093/brain/awl126
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org. The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org
Received February 7, 2006
Revised April 7, 2006
Accepted April 10, 2006

Article

MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie- Tooth type 2

Kristien Verhoeven 1 *, Kristl G. Claeys 2 *, Stephan Züchner 3, J. Michael Schröder 4, Joachim Weis 4, Chantal Ceuterick 5, Albena Jordanova 6, Eva Nelis 7, Els De Vriendt 1, Matthias Van Hul 1, Pavel Seeman 8, Radim Mazanec 9, Gulam Mustafa Saifi 10, Kinga Szigeti 10, Pedro Mancias 11, Ian J. Butler 11, Andrzej Kochanski 12, Barbara Ryniewicz 13, Jan De Bleecker 14, Peter Van den Bergh 15, Christine Verellen 16, Rudy Van Coster 17, Nathalie Goemans 18, Michaela Auer-Grumbach 19, Wim Robberecht 20, Vedrana Milic Rasic 21, Yoram Nevo 22, Ivajlo Tournev 23, Velina Guergueltcheva 23, Filip Roelens 24, Peter Vieregge 25, Paolo Vinci 26, Maria Teresa Moreno 27, H.-J. Christen 28, Michael E. Shy 29, James R. Lupski 10, Jeffery M. Vance 30, Peter De Jonghe 2, and Vincent Timmerman 1 *

1 Peripheral Neuropathy Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Belgium
2 Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Belgium; Division of Neurology, University Hospital of Antwerp (UZA), Antwerpen, Belgium
3 Center for Human Genetics, Duke University Medical Center, Durham, NC, USA; Department of Neuropathology, University Hospital, RWTH Aachen, Aachen, Germany
4 Department of Neuropathology, University Hospital, RWTH Aachen, Aachen, Germany
5 Laboratory of Neuropathology, Institute Born Bunge, University of Antwerp, Antwerpen, Belgium
6 Peripheral Neuropathy Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Belgium; Department of Molecular Pathology, Sofia Medical University, Sofia, Bulgaria, Poland
7 Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Belgium
8 DNA Laboratory, Department of Child Neurology, Second School of Medicine, Charles University Prague, Prague, Czech Republic
9 Department of Neurology, Second School of Medicine, Charles University Prague, Prague, Czech Republic
10 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
11 Department of Neurology, The University of Texas Health Science Centre at Houston Medical School, Houston, TX, USA
12 Neuromuscular Unit, Mossakowski Medical Research Center, Warszawa, Poland
13 Department of Neurology, Medical University, Warszawa, Poland
14 Department of Neurology, University Hospital of Gent, Gent, Brussels
15 Division of Neurology, University Hospital Saint-Luc, Brussels
16 Center of Human Genetics, Catholic University of Louvain, Brussels
17 Department of Child Neurology, University Hospital of Gent, Gent, Brussels
18 Child Neurology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
19 Institute of Medical Biology and Human Genetics, Department of Internal Medicine, Diabetes and Metabolism, Medical University Graz, Graz, Austria
20 Laboratory for Neurobiology, University of Leuven, Campus Gasthuisberg, Leuven, Belgium
21 Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia and Montenegro
22 Department of Child Neurology, Tel Aviv University, Tel Aviv, Israel
23 Department of Molecular Pathology, Sofia Medical University, Sofia, Bulgaria
24 Division of Pediatric Neurology, ‘Heilig-Hart’ Hospital Roeselare, Roeselare, Belgium
25 Department of Neurology, Klinikum Lippe-Lemgo, Germany
26 Department of Rehabilitation of Charcot-Marie-Tooth Disease and Other Neuromuscular Disorders, Specialized Rehabilitation Hospital L. Spolverini, Rome, Italy
27 Division of Infectious Diseases, Hospital del Nino, University of Panama, Panama City, Panama
28 Department of Neuropediatrics, Children's Hospital ‘Auf der Bult’, Hannover, Germany
29 Department of Neurology, Center for Molecular Medicine and Genetics, Wayne State University, Detroit, USA
30 Center for Human Genetics, Duke University Medical Center, Durham, NC, USA

* To whom correspondence should be addressed.
Vincent Timmerman, E-mail: vincent.timmerman{at}ua.ac.be


  Abstract

Mutations in mitofusin 2 (MFN2) have been reported in Charcot-Marie-Tooth type 2 (CMT2) families. To study the distribution of mutations in MFN2 we screened 323 families and isolated patients with distinct CMT phenotypes. In 29 probands, we identified 22 distinct MFN2 mutations, and 14 of these mutations have not been reported before. All mutations were located in the cytoplasmic domains of the MFN2 protein. Patients presented with a classical but rather severe CMT phenotype, since 28% of them were wheelchair-dependent. Some had additional features as optic atrophy. Most patients had an early onset and severe disease status, whereas a smaller group experienced a later onset and milder disease course. Electrophysiological data showed in the majority of patients normal to slightly reduced nerve conduction velocities with often severely reduced amplitudes of the compound motor and sensory nerve action potentials. Examination of sural nerve specimens showed loss of large myelinated fibres and degenerative mitochondrial changes. In patients with a documented family history of CMT2 the frequency of MFN2 mutations was 33% indicating that MFN2 mutations are a major cause in this population.

Keywords: Charcot-Marie-Tooth type 2; mitofusin 2; genotype-phenotype correlation.
*These authors contributed equally to this work.
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