In Leber's hereditary optic neuropathy (LHON), the primary mitochondrial DNA point mutation at position 11778 (ND4 subunit) results in impaired complex I function. The mechanism by which this causes selective retinal ganglion cell death is:
- A Increased reactive oxygen species (ROS) production from dysfunctional complex I leading to selective vulnerability of small-calibre unmyelinated RGC axons in the papillomacular bundle ✓
- B Impaired ATP synthesis leading to failure of RGC axonal transport and synaptic transmission in the lateral geniculate nucleus
- C Accumulation of NADH causing cytoplasmic acidosis selectively lethal to RGC layer
- D Mitochondrial aggregation in the perinuclear zone of RGCs preventing nuclear export of pro-survival mRNA
Explanation
LHON mutations (11778, 3460, 14484 — in ND4, ND1, and ND6 subunits of complex I respectively) impair NADH dehydrogenase, leading to excessive ROS generation from electrons leaking to oxygen within the respiratory chain. The papillomacular bundle RGC axons are particularly vulnerable because they are small-calibre, have high metabolic demands, and are unmyelinated within the eye (myelination begins at the lamina cribrosa). Increased oxidative stress exceeds the antioxidant capacity of these cells specifically. The sex-linked carrier females are partially protected by higher mitochondrial membrane potential in heteroplasmy. Idebenone, a short-chain quinone antioxidant, has been approved (EMA) for LHON to scavenge ROS and partially restore complex I function.
Reference: Khurana Comprehensive Ophthalmology, 7th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.