Ethambutol toxicity exacerbating the phenotype of CMT2A2

Introduction: CMT2A2 is associated with mutations in the mitofusin 2 gene, which encodes a protein involved in mitochondrial fusion. Ethambutol is an antimycobacterial agent associated with toxic optic neuropathies. Ethambutol-induced optic neuropathy occurs in patients with mutations in a related fusion gene, OPA1, which is responsible for autosomal dominant optic atrophy.

Methods: We describe a patient with CMT2A2 (MFN2 mutation: T669G, F223L) who developed accelerated weakness, vocal cord paralysis, and optic atrophy after receiving ethambutol.

Results: Deterioration began within months of initiating ethambutol therapy. After discontinuation of ethambutol, neurologic deterioration stabilized with subsequent improvement in visual fields.

Conclusions: CMT2A2 is part of a group of genetic disorders which share an association with the process of mitochondrial fusion. This case shows that patients with CMT2A2, and possibly other mitochondrial fusion defects, may be uniquely susceptible to ethambutol-induced neurotoxicity. This has implications regarding the underlying pathophysiology of mitochondrial fusion defects.