Retinitis pigmentosa and inherited degeneration

Retinitis Pigmentosa (RP)

Retinitis pigmentosa (RP) encompasses a clinically and genetically heterogeneous group of inherited rod-cone dystrophies characterized by primary progressive degeneration of rod photoreceptors, followed inevitably by secondary apoptotic death of cone photoreceptors. It represents the single most common inherited retinal dystrophy, with an estimated prevalence of 1 in 3,500 to 1 in 4,000 individuals (~1.5 million people worldwide).

Inheritance Modes & Molecular Genetics

RP demonstrates extensive genetic heterogeneity, with over 80 causative genes identified across all modes of Mendelian inheritance:

1. Autosomal Dominant RP (AD-RP): Typically displays the mildest clinical course, slowest progression, and best visual prognosis, with central vision often preserved beyond the sixth decade. The most common genetic causes are mutations in RHO (rhodopsin, accounting for 25–30% of AD-RP), PRPF31 (pre-mRNA processing factor 31; exhibits non-penetrance), and RP1.
2. Autosomal Recessive RP (AR-RP): Displays intermediate clinical severity. Mutations in USH2A represent the most common cause of both non-syndromic AR-RP and Usher syndrome type 2. Other common genes include PDE6A, PDE6B (phosphodiesterase 6 subunits), and CNGA1.
3. X-Linked RP (XL-RP): Represents the most aggressive and devastating form. Hemizygous males manifest severe night blindness in early childhood and rapid peripheral field constriction, frequently progressing to legal blindness by their third or fourth decade. Mutations in RPGR (retinitis pigmentosa GTPase regulator) account for $>70\%$ of all XL-RP, with RP2 accounting for 10–20%. Heterozygous carrier females often exhibit a characteristic, reflective, golden-metallic tapetal-like retinal sheen in the posterior pole.
4. Simplex RP describes an isolated family presentation, not a separate mode of inheritance. Recessive disease, new dominant variants, X-linked disease and incomplete family information can all produce this pattern. Confirm genotype and pedigree before recurrence-risk counselling.

Pathophysiological Cascade: From Rod to Cone Death

The pathogenic mutations primarily affect rod-specific phototransduction proteins, cilia structural components, or retinal pigment epithelium (RPE) phagocytic mechanisms. Degeneration begins in the mid-periphery where rod density is physiologically highest:

$$\text{Primary Rod Degeneration} \implies \text{Loss of RdCVF} + \text{Hyperoxia \& ROS} \implies \text{Secondary Cone Apoptosis} \implies \text{Central Blindness}$$

Secondary cone loss is mediated by two non-cell-autonomous mechanisms:

• Loss of Rod-Derived Cone Viability Factor (RdCVF): Healthy rods continuously secrete RdCVF (encoded by the NXNL1 gene), a thioredoxin-like trophic factor that binds to basigin-1 on cone photoreceptors, accelerating glucose uptake and aerobic glycolysis. When rods degenerate, the deprivation of RdCVF causes cone starvation and metabolic collapse.
• Hyperoxia and Oxidative Stress: As rods die, consumption of oxygen delivered by the unyielding choriocapillaris plummets. The resulting hyperoxic microenvironment generates toxic reactive oxygen species (ROS), driving oxidative apoptosis of residual cones.

Classical Clinical Triad & Chronological Symptoms

• Presenting Symptom: Nyctalopia (night blindness) is the universal earliest manifestation, typically recognized during childhood or early adolescence.
• Visual Field Progression: Loss of mid-peripheral rods produces an initial patchy ring scotoma that coalesces into a dense mid-peripheral annular scotoma. The scotoma gradually expands centripetally and centrifugally, leaving a constricted central tunnel of vision ("tunnel vision").
• The Classical Diagnostic Triad on Funduscopy:
  1. Bone-Spicule Intraretinal Pigmentation: Dark, stellate, branching hyperpigmented deposits situated in the mid-periphery, predominantly along the adventitia of retinal vessels. As rods degenerate, RPE cells detach from Bruch's membrane, migrate into the inner sensory retina, and cluster around retinal venules, releasing melanin granules.
  2. Marked Arteriolar Attenuation: Severe narrowing and "thread-like" thinning of retinal arterioles, resulting from reduced metabolic demand of the atrophied retina and local endothelin-mediated vasoconstriction.
  3. Waxy Optic Disc Pallor: The optic nerve head exhibits a yellowish-waxy, pale appearance caused by diffuse astrocytic glial proliferation (gliosis) covering the disc surface, rather than true primary descending axonal atrophy.

Associated Ocular Complications

• Posterior Subcapsular Cataract (PSC): Develops in 40% to 50% of RP patients at a relatively young age (3rd–5th decades). Surgical phacoemulsification yields substantial subjective visual improvement, provided the fovea is functional.
• Cystoid Macular Oedema (CMO): Occurs in 10% to 20% of RP eyes, driven by blood-retinal barrier breakdown and chronic low-grade inflammation. First-line therapy is oral carbonic anhydrase inhibitors (acetazolamide $250-500\,\text{mg/day}$) or topical dorzolamide 2% TDS. Notably, RP-associated CMO responds poorly to anti-VEGF therapy.
• Other Associations: Keratoconus, high myopia, optic disc drusen, and vitreous condensation (pigmented vitreous cells and posterior vitreous detachment).

Systemic Syndromes Associated with Retinitis Pigmentosa