Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin‐associated ocular toxicity?
Despite VGB's unique mechanism of action that directly elevates cerebral GABA (Figure1), its use may be compromised by the development of peripheral visual field defects (pVFD), the origins of which remain largely undefined. In a study of school‐age children who had received VGB as infants, pVFDs were detected in one‐third, and the rate of VFDs increased from 9–63% as VGB treatment duration increased, although other studies have noted that bilateral visual field deficits are common in the treated epilepsy population. To track the retinal toxicity associated with VGB, pediatric neurologists variably rely on either serial funduscopic exams, electroretinogram (ERG), or optical coherence tomography (OCT).1 Nonetheless, there is no consensus as to what testing is sensitive enough to detect early‐onset pVFDs, since normal findings evolve with development, and the robustness of the findings in infants remains questionable. The potential occurrence of pVFD in patients receiving VGB requires clinicians to cautiously balance the potential risk of visual field disruption against the risk of catastrophic cognitive compromise associated with uncontrolled spasms.
There is no consensus regarding the pathomechanisms of pVFD associated with VGB intervention. Adults and infants treated with long‐term VGB intervention manifest peripheral atrophy of the retinal nerve fiber layer. Rodents similarly treated manifest disorganization of the photoreceptor nuclear layer and damage to cone photoreceptors. Additional studies suggest that supraphysiologic GABA in the eye results in excitotoxicity associated with overstimulation of GABAergic receptors. A pathological role for amino acids with structural and biochemical properties similar to that of GABA (ornithine, taurine) has also been suggested in the etiology of retinal toxicity. Although there is no consensus, the preponderance of current data suggests that VGB may induce oxidative retinal damage, but the precise mechanisms by which such damage results in retinal cell loss and pVFDs remain unconfirmed. The fundamental unresolved question is whether VGB or elevated GABA (or both) are mechanistically linked to pVFDS.
Recent studies have begun to provide potential insights into the potential basis of pVFDs associated with VGB intervention. Lakhani et al.2 unmasked a novel link between GABA metabolism, mammalian target of rapamycin (mTOR)‐C1 activity (Figure2), and mitophagy in mammals, and a more recent publication3 indicates that this link may well extend to the capacity of VGB to elevate GABA. In yeast, elevated GABA inhibited mitophagy, resulting in elevated mitochondrial number and associated oxidant stress, all of which could be suppressed with rapamycin, a classic inhibitor of mTOR. These studies were extended to aldh5a1‐/‐ mice, a phenocopy of the heritable Mendelian disorder succinic semialdehyde dehydrogenase deficiency (SSADHD) which also features accumulation of GABA and ablates the function of the second enzyme of GABA metabolism (Figure1). Elevated mitochondrial numbers in both brain and liver of aldh5a1‐/‐ mice were observed, associated with increased markers of oxidative stress. As for yeast, rapamycin could override these effects in aldh5a1‐/‐ mice. Immunoblotting studies of the ribosomal protein S6 in mice verified that mTORC1 was mechanistically in play in this pathology.
Since VGB enhances GABA production (Figure1), it was hypothesized that rodents undergoing VGB intervention would yield similar results to those found in aldh5a1‐/‐ mice.