Mechanisms of disease and clinical features of mutations of the gene for mitofusin 2: an important cause of hereditary peripheral neuropathy with striking clinical variability in children and adults.

Mitofusin 2, a large transmembrane GTPase located in the outer mitochondrial membrane, promotes membrane fusion and is involved in the maintenance of the morphology of axonal mitochondria. Mutations of the gene encoding mitofusin 2 (MFN2) have recently been identified as the cause of approximately one-third of dominantly inherited cases of the axonal degenerative forms of Charcot-Marie-Tooth disease (CMT type 2A) and of rarer variants. The latter include a severe, early-onset axonal neuropathy, which may occur in autosomal dominant or recessive forms, as well as some instances associated with pyramidal tract involvement (CMT type 5), with optic atrophy (CMT type 6), and, occasionally, with alterations of cerebral white matter. All individuals with a dominantly or recessively inherited or otherwise unexplained, chronic progressive axonal degenerative polyneuropathy should be tested for mutations of MFN2.