Genetic Eye Diseases Overview - Gene Scene Basics
- Modes of Inheritance:
- Autosomal Dominant (AD): Vertical transmission; 50% offspring risk.
- Autosomal Recessive (AR): Horizontal transmission; 25% offspring risk; consanguinity ↑ risk.
- X-linked Recessive (XLR): Males primarily affected; females are carriers. 📌 "X-Gents affected, Carrier Ladies."
- X-linked Dominant (XLD): Affects both males & females; often lethal in males.
- Mitochondrial: Exclusively maternal inheritance.
- Key Genetic Terms:
- Penetrance: Percentage (%) of individuals with a specific genotype who express the associated phenotype.
- Expressivity: Variable severity or range of manifestations of a phenotype among individuals with the same genotype.
- Locus Heterogeneity: Same disease/phenotype caused by mutations at different gene loci.
- Allelic Heterogeneity: Different mutations (alleles) at the same gene locus cause the same or similar phenotype.
- Pleiotropy: A single gene influences multiple, seemingly unrelated phenotypic traits.
⭐ Mitochondrial inheritance is exclusively maternal to all offspring.
Phakomatoses & Systemic Syndromes - Dots, Spots, Eye Troubles
Key genetic disorders with ocular and systemic manifestations:
| Syndrome | Ocular Findings | Systemic Findings |
|---|---|---|
| Neurofibromatosis 1 (NF1) | Lisch nodules (iris hamartomas), Optic nerve glioma | Café-au-lait macules, Neurofibromas |
| Neurofibromatosis 2 (NF2) | Posterior Subcapsular Cataracts (PSC) | Bilateral vestibular schwannomas |
| Tuberous Sclerosis (TSC) | Retinal astrocytic hamartomas, Achromic patches | Ash-leaf spots (hypopigmented), Facial angiofibromas |
| Sturge-Weber Syndrome | Congenital glaucoma (often unilateral), Choroidal hemangioma | Facial port-wine stain (V1/V2), Leptomeningeal angioma |
| Von Hippel-Lindau (VHL) | Retinal capillary hemangioblastoma | CNS hemangioblastomas, Renal cell carcinoma, Pheochromocytoma |
⭐ Lisch nodules (iris hamartomas) are present in >90% of adult patients with NF1.
Retinoblastoma - Glow Worm Alert
- Pathogenesis: Mutation in RB1 tumor suppressor gene. Explained by Knudson's "two-hit" hypothesis.
- Classic Presentation: Leukocoria (📌 "cat's eye reflex" - most common sign), strabismus (second most common).
- Forms & Implications:
- Key Concern: Significant risk of secondary primary malignancies, especially osteosarcoma with heritable RB.
⭐ The most common intraocular malignancy in children is Retinoblastoma.
Anterior Segment Genetic Disorders - Cloudy & Pressured Views
| Feature | Congenital Cataract | Aniridia | Primary Congenital Glaucoma (PCG) |
|---|---|---|---|
| Presentation | Cloudy lens (leukocoria), ↓vision. Often bilateral. | Absent/partial iris, photophobia, nystagmus. Often bilateral. | Buphthalmos ('ox eye'), corneal haze/edema, tearing, photophobia. |
| Key Genes | GJA3, GJA8, CRYAA (connexins, crystallins) | PAX6 (master control gene) | CYP1B1, LTBP2 |
| Associations | Galactosemia, Lowe syndrome, TORCH (e.g., Rubella) | WAGR syn. (Wilms, Aniridia, GU, Retard.), glaucoma risk (50-75%) | Haab's striae (breaks in Descemet's), ↑IOP >21 mmHg. |
| Image |  |  |  |
Retinal Dystrophies & Albinism - Night Blind & Sun Shy
- Leber Congenital Amaurosis (LCA):
- Severe visual loss from birth, nystagmus, amaurotic pupils.
- Key genes: RPE65, CEP290.
- Retinitis Pigmentosa (RP):
- Early onset forms; progressive night blindness, peripheral vision loss.
- Fundus: Classic bone spicule pigmentation, attenuated vessels.
- Albinism (Oculocutaneous & Ocular):
- Photophobia ("Sun Shy"), nystagmus, often ↓ visual acuity.
- Foveal hypoplasia (key for ↓VA), transillumination iris defects.
- Key genes: TYR, OCA2.
⭐ Foveal hypoplasia is a characteristic feature of albinism, leading to reduced visual acuity.
High-Yield Points - ⚡ Biggest Takeaways
- Retinoblastoma: RB1 gene, leukocoria, strabismus; most common childhood intraocular malignancy.
- Congenital Cataract: Often AD; linked to galactosemia, rubella (TORCH).
- Aniridia: PAX6 gene; associated with WAGR syndrome (Wilms tumor risk).
- LCA: Severe neonatal vision loss, AR; RPE65 gene is a common cause.
- Albinism: Nystagmus, foveal hypoplasia, iris transillumination, photophobia.
- Retinitis Pigmentosa: Night blindness, peripheral vision loss (tunnel vision); progressive.
- Ectopia Lentis: Upward in Marfan (FBN1); downward in Homocystinuria.
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