Ocular Pathology and Genetics
Ocular pathology and genetics
This domain tests neoplastic, degenerative, and inherited ocular disease, with emphasis on mechanisms and inheritance patterns. Genetics questions often ask you to infer risk from a pedigree or a molecular finding.
Core rules
- Retinoblastoma is caused by biallelic RB1 inactivation. Germline RB1 mutations produce bilateral or multifocal disease and autosomal dominant inheritance with incomplete penetrance.
- The two-hit hypothesis explains why hereditary retinoblastoma presents earlier and is often bilateral.
- Marfan syndrome is FBN1-related, autosomal dominant, with ectopia lentis and aortic risk. Stickler syndrome involves collagen genes and retinal detachment risk.
- Leber hereditary optic neuropathy is mitochondrial, maternally inherited, and often causes painless sequential vision loss in young men.
- Diabetic retinopathy is microvascular; proliferative disease is driven by VEGF. AMD has drusen, RPE dysfunction, and complement pathway associations.
Worked example
A child has bilateral retinoblastoma. What does this imply about the RB1 mutation? Bilateral disease strongly suggests a germline mutation: one mutant allele is inherited, and a second somatic hit occurs in retinal cells. Each offspring has a 50% chance of inheriting the mutant allele, so genetic counselling is indicated. A unilateral, unifocal tumour is more often due to two somatic hits and carries a lower hereditary risk.
Traps
- Assuming all retinoblastoma is hereditary.
- Forgetting mitochondrial inheritance has no male transmission.
- Mixing Marfan (FBN1) with homocystinuria (downward lens dislocation).
- Treating genotype as perfectly predictive; penetrance and mosaicism matter.