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

TLDR

Hereditary motor and sensory neuropathy type VI (HMSN VI) is a Charcot‑Marie‑Tooth variant marked by optic atrophy, yet its genetic cause had remained unclear until this study. The authors examined six HMSN VI families, performing detailed clinical assessments and genetic analyses to identify disease‑causing variants. They discovered a unique MFN2 mutation in every pedigree—de novo in three families and inherited in two—establishing MFN2 as the causative gene for autosomal dominant HMSN VI. Published in Annals of Neurology, 2006;59:276–281.

Abstract

Abstract 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. Ann Neurol 2006;59:276–281