Axonal neuropathy with optic atrophy is caused by mutations in mitofusin 2

Stephan Züchner, Peter De Jonghe, Albena Jordanova, Kristl G. Claeys, Velina Guergueltcheva, Sylvia Cherninkova, Steven R. Hamilton, Greg Van Stavern, Karen M. Krajewski, Jeffery Stajich, Ivajlo Tournev, Kristien Verhoeven, Christine T. Langerhorst, Marianne De Visser, Frank Baas, Thomas Bird, Vincent Timmerman, Michael Shy, Jeffery M. Vance

Research output: Contribution to journalArticlepeer-review

302 Scopus citations


Objective: Charcot-Marie-Tooth (CMT) neuropathy with visual impairment due to optic atrophy has been designated as hereditary motor and sensory neuropathy type VI (HMSN VI). Reports of affected families have indicated autosomal dominant and recessive forms, but the genetic cause of this disease has remained elusive. Methods:Here, we describe six HMSN VI families with a subacute onset of optic atrophy and subsequent slow recovery of visual acuity in 60% of the patients. Detailed clinical and genetic studies were performed. Results: In each pedigree, we identified a unique mutation in the gene mitofusin 2 (MFN2). In three families, the MFN2 mutation occurred de novo; in two families the mutation was subsequently transmitted from father to son indicating autosomal dominant inheritance. Interpretation: MFN2 is a mitochondrial membrane protein that was recently reported to cause axonal CMT type 2A. It is intriguing that MFN2 shows functional overlap with optic atrophy 1 (OPA1), the protein underlying the most common form of autosomal dominant optic atrophy, and mitochondrial encoded oxidative phosphorylation components as seen in Leber's hereditary optic atrophy. We conclude that autosomal dominant HMSN VI is caused by mutations in MFN2, emphasizing the important role of mitochondrial function for both optic atrophies and peripheral neuropathies.

Original languageEnglish
Pages (from-to)276-281
Number of pages6
JournalAnnals of neurology
Issue number2
StatePublished - Feb 2006


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