In a patient with tuberous sclerosis complex (TSC), bilateral astrocytic hamartomas of the retina present as mulberry-shaped calcified lesions near the optic disc. TSC is caused by mutations in TSC1 (hamartin) or TSC2 (tuberin). The molecular pathway disrupted is:

• A Von Hippel-Lindau/HIF-1α/VEGF pathway
• B Sonic hedgehog signaling pathway
• C NF1/Ras/MAPK pathway
• D mTORC1 (mechanistic Target of Rapamycin Complex 1) pathway activation due to loss of TSC1/TSC2 Rheb-GTPase inhibition ✓

Explanation

TSC1 (hamartin) and TSC2 (tuberin) form a complex that inhibits Rheb GTPase, which in turn suppresses mTORC1. Loss of TSC1/TSC2 leads to constitutive mTORC1 activation, driving protein synthesis, cell growth, and proliferation — causing hamartoma formation in multiple organs (brain tubers, cardiac rhabdomyoma, renal angiomyolipoma, pulmonary lymphangioleiomyomatosis, retinal astrocytic hamartomas). This molecular understanding led to mTOR inhibitor therapy (everolimus, sirolimus) for TSC-related tumors. Von Hippel-Lindau disease involves HIF/VEGF and causes retinal hemangioblastoma, not astrocytic hamartoma.

Reference: Khurana Comprehensive Ophthalmology, 7th ed.

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Written and medically reviewed by the StethoPrep medical team.