The Genetics of Ethambutol-Induced Optic Neuropathy: A Narrative Review

Abstract

Tuberculosis (TB) is a global health problem with the major brunt of disease occurring in developing countries. The cornerstone of treatment of TB is anti-tubercular therapy (ATT), which includes rifampicin, isoniazid, pyrazinamide and ethambutol. Because of emerging drug resistance, treatment failures, defaulters and increasing incidence of disseminated and extrapulmonary TB, the guidelines have been modified in some countries. Ethambutol is prescribed for longer times (in some cases >8 months) and hence the incidence of ethambutol-induced optic neuropathy (EtON) is expected to rise. The fundamental question which needs explanation is why only a small subset of patients on ethambutol are prone to develop loss of vision. This review focuses on available genetic studies which provide evidence that mitochondria are the likely substrates involved in the final pathway of reactive oxidative damage of the papillo-macular bundle. Genetic analysis of mitochondrial mutations encoding genes involved in oxidative phosphorylation pathways may help in isolating the subset of patients who are genetically susceptible. If the groups having high risk of developing EtON are recognised then prolonged duration of ethambutol treatment can be avoided in these susceptible individuals. A better understanding of the pathophysiology will also pave the way for the development of management strategies in this condition.

Keywords: Tuberculosis; ethambutol; mitochondria; optic neuropathy; pharmacogenomics.

Figure 1.

The role of mitochondria in ethambutol-induced optic neuropathy (EtON). Oxidative phosphorylation is carried out by five multimeric enzymes: reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase–ubiquinone oxidoreductase (complex I); succinate dehydrogenase–ubiquinone oxidoreductase (complex II); ubiquinone–cytochrome c oxidoreductase (complex III); cytochrome c oxidase (complex IV); and ATP synthase (complex V) along with two small electron carriers: ubiquinone (coenzyme Q10) and cytochrome c (cyt c). The two processes i.E., transfer of electrons along the process to molecular oxygen, thereby producing water, and pumping of protons from the matrix to the inter-membrane space to generate an electrochemical gradient combine together to complete the oxidative phosphorylation process.

Figure 2.

Role of mitochondria and its genetics in ethambutol-induced optic neuropathy. The three mutations (nt-11778, nt-14484 and nt-3460) are present in mitochondrial deoxyribonucleic acid (DNA) and are responsible for causing Leber’s hereditary optic neuropathy. The OPA1 and MFN2 genes are present in nuclear DNA but encode enzymes responsible for mitochondrial fusion and their mutations affect mitochondrial production and hence might be involved in the aetiology of ethambutol-induced optic neuropathy.