Double Trouble Mutations Underlie Mitochondrial Dynamics Disorders in a Severe Form of Charcot-Marie-Tooth Disease

Charcot-Marie-Tooth disease type 2A (CMT2A) is an inherited axonal peripheral neuropathy mainly caused by mutations in the mitofusin 2 (MFN2) gene encoding for the MFN2 protein, a GTPase involved in the mitochondrial dynamics and bioenergetics. We identified a novel mutation, that was inherited from her mother, in the MFN2 protein (Met234Ile) in a Charcot-Marie-Tooth patient. She has also a variant of uncertain significance (Thr36Ala), in the PMP22 gene, encoding for peripheral myelin protein 22, inherited from her father. The patient presented severe sensorimotor neuropathy with early onset. The mother presented a distal muscle atrophy in the legs, the father was asymptomatic. To show the pathogenicity of these mutations, we characterized the structure, adenosine triphosphate (ATP) content, bioelectric characteristics and functions of mitochondria in cultured primary fibroblasts obtained from the proband and her parents. Under normal culture conditions, mitochondria showed normal morphology. Under oxidative stress conditions, ATP production was reduced and the proband cells showed a decrease of the mitochondrial fusion with small connected networks and a decrease of the mitochondrial volume. The alteration of the mitochondrial network only when cells are challenged in aerobiosis testifies to the fragility of mitochondria, which are unable to meet the metabolic needs of neurons. Interestingly, fibroblasts derived from the two parents did not show any change. These results support the hypothesis that the mutation in the MFN2 gene altering mitochondrial bioenergetics and fusion causes axonal sensory-motor neuropathy. We speculate that PMP22 may promote mitochondrial dysfunction, myelin having a role in mitochondrial metabolism.