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


CONCLUSIONS
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.
Züchner
Stephan
S
Center for Human Genetics, Duke University Medical Center, Durham, NC 27710, USA. szuchner@duke.edu
De Jonghe
Peter
P
Jordanova
Albena
A
Claeys
Kristl G
KG
Guergueltcheva
Velina
V
Cherninkova
Sylvia
S
Hamilton
Steven R
SR
Van Stavern
Greg
G
Krajewski
Karen M
KM
Stajich
Jeffery
J
Tournev
Ivajlo
I
Verhoeven
Kristien
K
Langerhorst
Christine T
CT
de Visser
Marianne
M
Baas
Frank
F
Bird
Thomas
T
Timmerman
Vincent
V
Shy
Michael
M
Vance
Jeffery M
JM
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis / Q000379:methods; D005192:Family Health; D020558:GTP Phosphohydrolases; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000235:genetics*; D008954:Models, Biological; D009154:Mutation; D009431:Neural Conduction / Q000502:physiology; D009896:Optic Atrophy / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D014792:Visual Acuity / Q000502:physiology
D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human