Abstract and Commentary
Synopsis: The present findings raise the possibility that new effective therapies may be developed for CMT2A, which target the underlying pathophysiology.
Source: Zuchner S, et al. Mutations in the Mitochondrial GTPase Mitofusin 2 Cause Charcot-Marie-Tooth Neuropathy Type 2A. Nat Genet. 2004,36:449-451.
Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy which leads to characteristic features of peroneal atrophy, weakness pes cavus, and sensory loss. Symptoms often begin in the first or second decade of life. However, in some cases, they can occur much later According to electrophysiological criteria, CMT falls into 2 main categories. The first is the demyelinating CMT type 1. This is associated with decreased nerve conduction velocities. It has been shown to be due to a duplication of the human peripheral myelin protein 22, which results in 3 copies of the gene. This duplication is found in 70-85% of both autosomal dominant and isolated CMT-1 cases.
The second major category of CMT is type 2, or the axonal form. There are a number of subcategories of CMT type 2. It manifests either normal or minimally reduced nerve conduction velocities. A mutation in the gene KIF1B was previously reported in 1 Japanese family with CMT2A. No further mutations in this gene, however, have been identified by linkage studies in a large number of families with CMT2A.
In the present report, 7 families with CMT2A were defined with the classical phenotype, and in different ethnic backgrounds. It was found by direct sequencing and lod scores that the primary gene mutated was the mitochondrial fusion protein mitofusin 2 (MFN2). This was shown to be caused by a number of point mutations in this gene. A large number of other genes were excluded, including KIF1B. MFN2 is localized to the outer mitochondrial membrane, where it regulates the mitochondrial network architecture by fusion of mitochondria. All the mutations which were identified, co-segregated with the disease phenotype in the respective families. The mutations were in regions which are highly conserved across numerous species.
Mitochondria normally undergo a dynamically-regulated balance between fusion and fission reactions. It is likely that disruption of this network will lead to impaired mitochondrial function. It is known that mitochondria need to be moved up and down the axons in order to replenish their proteins and acquire nuclear proteins in the perinuclear region. It has been demonstrated that MFN2 knockout mice have a lethal phenotype. A virally transported MFN2 construct however, rescues the MFN2 deficient mouse cell line. This restores a normal phenotype. It corrects the fusion fission imbalance, which suggests the possibility that CMT2A may be amenable to some type of gene therapy in the future.
The present findings are the first to link a defect in the nuclear encoded mitochondrial gene to a peripheral neuropathy. Previous studies have shown that defects in mitochondrial DNA, such as the T8993G mutation, result in the syndrome of NARP, which consists of neuropathy, ataxia, and retinitis pigmentosa. Cell lines with this mutation show defects in oxidative phosphorylation that can be corrected by antioxidants. This raises the possibility that antioxidants might also show some benefits for patients with CMT2A. The present findings raise the possibility that new effective therapies may be developed for CMT2A, which target the underlying pathophysiology. — M. Flint Beal
Dr. Beal, Professor and Chairman; Department of Neurology; Cornell University Medical College New York, NY, is Editor of Neurology Alert.