CMT Type 6: Axonal neuropathy with optic atrophy is caused by mutations in mitof

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Ann Neurol. 2006 Jan 25;59(2):276-281

Axonal neuropathy with optic atrophy is caused by mutations in

mitofusin 2.

Zuchner S, De Jonghe P, Jordanova A, Claeys KG, Guergueltcheva V,

Cherninkova S, Hamilton SR, Van Stavern G, Krajewski KM, Stajich J,

Tournev I, Verhoeven K, Langerhorst CT, de Visser M, Baas F, Bird T,

Timmerman V, Shy M, Vance JM.

Center for Human Genetics, and Department of Psychiatry and

Behavioral Sciences, Duke University Medical Center, Durham, NC.

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.