Leigh syndrome (subacute necrotizing encephalomyelopathy) is a mitochondrial disease often caused by mutations in Complex I subunits or SURF1 (cytochrome c oxidase assembly factor). Why does brain necrosis occur in areas of high energy demand (basal ganglia, brainstem) rather than uniformly?

• A Basal ganglia and brainstem have higher lactate thresholds and accumulate lactic acid from anaerobic glycolysis earlier than cortex
• B The blood-brain barrier is more permeable in these regions, allowing toxic metabolites to concentrate
• C Mitochondrial fission/fusion imbalance specifically affects dopaminergic neurons in the basal ganglia
• D High-energy-demand brain regions rely almost exclusively on oxidative phosphorylation; mitochondrial ETC defects disproportionately deplete ATP in these areas, triggering energy failure-induced excitotoxicity and necrosis ✓

Explanation

The brain accounts for ~20% of total body O2 consumption despite being 2% of body mass. High-energy-demand areas like the basal ganglia (rich in dopaminergic neurons with high metabolic requirements) and brainstem respiratory centers are most sensitive to oxidative phosphorylation failure because they have limited glycolytic capacity relative to their ATP demand. Mitochondrial dysfunction reduces ATP production, causes Ca2+ dyshomeostasis, and triggers NMDA receptor-mediated excitotoxicity. The resulting bilateral, symmetric necrosis in these regions on MRI (T2 hyperintensities) is the hallmark of Leigh syndrome.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.