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Brain Advance Access originally published online on May 19, 2006
Brain 2006 129(8):2093-2102; doi:10.1093/brain/awl126
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MFN2 mutation distribution and genotype/phenotype correlation in Charcot–Marie–Tooth type 2

Kristien Verhoeven1,*, Kristl G. Claeys2,4,*, Stephan Züchner12,16, J. Michael Schröder16, Joachim Weis16, Chantal Ceuterick3, Albena Jordanova1,19, Eva Nelis2, Els De Vriendt1, Matthias Van Hul1, Pavel Seeman21, Radim Mazanec22, Gulam Mustafa Saifi13, Kinga Szigeti13, Pedro Mancias14, Ian J. Butler14, Andrzej Kochanski23, Barbara Ryniewicz24, Jan De Bleecker5, Peter Van den Bergh7, Christine Verellen8, Rudy Van Coster6, Nathalie Goemans9, Michaela Auer-Grumbach25, Wim Robberecht10, Vedrana Milic Rasic26, Yoram Nevo27, Ivajlo Tournev19, Velina Guergueltcheva19, Filip Roelens11, Peter Vieregge18, Paolo Vinci28, Maria Teresa Moreno29, H.-J. Christen17, Michael E. Shy15, James R. Lupski13, Jeffery M. Vance12, Peter De Jonghe2,4 and Vincent Timmerman1

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

Correspondence to: Prof. Dr Vincent Timmerman, PhD, Peripheral Neuropathy Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB8), University of Antwerp (UA), Universiteitsplein 1, B-2610 Antwerpen, Belgium E-mail: vincent.timmerman{at}ua.ac.be

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.

Key Words: Charcot–Marie–Tooth type 2; mitofusin 2; genotype–phenotype correlation

Abbreviations: CMAP, compound motor action potentials; CMT, Charcot–Marie–Tooth disease type 1

.

Received February 7, 2006. Revised April 7, 2006. Accepted April 10, 2006.

*These authors contributed equally to this work.


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