Retinitis Pigmentosa & Hereditary Dystrophies
Ophthalmology · Retina · lean revision notes
Retinitis Pigmentosa & Hereditary Dystrophies
Retinitis pigmentosa (RP) is the prototype of the hereditary retinal dystrophies — a genetically heterogeneous group of disorders causing progressive degeneration of photoreceptors and the retinal pigment epithelium (RPE). For NEET PG, the clinical triad, the classic fundus picture, the inheritance patterns and the systemic associations (Usher, Bardet-Biedl, Kearns-Sayre, Refsum) are repeatedly tested, often in integrated paediatric/medicine cross-over questions.
Definition & classification
Retinitis pigmentosa is a group of inherited, bilateral, progressive rod-cone dystrophies characterised by primary degeneration of rod photoreceptors followed by cones, with secondary RPE migration into the neurosensory retina. It is the commonest hereditary fundus dystrophy (prevalence ≈ 1 in 4000).
Classification axes you must know:
| Basis | Types |
|---|---|
| Cell affected first | Rod-cone dystrophy (typical RP — night blindness first) vs Cone-rod dystrophy (day/colour vision first) |
| Inheritance | Autosomal dominant (AD), Autosomal recessive (AR), X-linked recessive (XLR), mitochondrial, sporadic |
| Extent | Typical (diffuse), Sectoral (one quadrant), Pericentric, Unilateral, RP sine pigmento (no pigment yet) |
| Syndromic vs non-syndromic | Non-syndromic (isolated eye) vs Syndromic (Usher, Bardet-Biedl, Refsum, Kearns-Sayre, Bassen-Kornzweig) |
High-yield: Typical RP is a rod-cone dystrophy — rods die first, hence the earliest symptom is night blindness (nyctalopia), classically beginning in adolescence.
The inheritance pattern carries prognostic weight:
| Inheritance | Frequency | Onset / severity |
|---|---|---|
| Autosomal recessive | Most common overall | Intermediate severity |
| Autosomal dominant | ~Best prognosis | Latest onset, mildest, slowest progression |
| X-linked recessive | Least common | Earliest onset & most severe; carrier females show tapetal reflex |
| Sporadic / simplex | Single affected member | Variable |
High-yield: X-linked RP is the most severe with the earliest onset; autosomal dominant carries the best prognosis. AR is the most common inheritance type.
Etiology & pathophysiology
RP is enormously genetically heterogeneous — over 80 causative genes are known. The unifying defect is disruption of the phototransduction cascade or photoreceptor structural integrity, leading to apoptotic photoreceptor death.
Key genes/mechanisms (NEET-worthy):
- RHO (rhodopsin) — commonest AD RP gene (the Pro23His mutation is classic). Rhodopsin misfolding.
- RPGR — commonest X-linked RP gene.
- USH2A — Usher syndrome and non-syndromic AR RP.
- RPE65 — Leber congenital amaurosis; target of the first FDA-approved ocular gene therapy, voretigene neparvovec (Luxturna).
- PDE6 (phosphodiesterase), peripherin/RDS, CRB1 — other recognised loci.
Pathophysiology in sequence:
Genetic defect in phototransduction/structural protein → rod outer-segment dysfunction & oxidative stress → rod apoptosis (night blindness, ring scotoma) → secondary cone death (loss of central/colour vision) → RPE degenerates, liberated pigment migrates around retinal vessels forming bone-spicule pigmentation → retinal vascular attenuation and optic atrophy (waxy disc pallor).
High-yield: The pigment in RP is RPE-derived melanin that migrates into the neurosensory retina and clusters perivascularly — producing the pathognomonic bone-corpuscle / bone-spicule pattern, classically in the mid-periphery first.
Clinical features
The classic RP triad (must memorise):
- Night blindness (nyctalopia) — earliest, due to rod loss.
- Tubular / tunnel vision — progressive concentric peripheral field constriction (ring scotoma enlarges centripetally).
- Bone-spicule retinal pigmentation with arteriolar attenuation and waxy pallor of the disc.
Symptom evolution:
- Nyctalopia in childhood/adolescence (rods).
- Progressive peripheral field loss → ring scotoma → tunnel vision; central vision (and hence acuity) preserved until late.
- Photopsia (flashing lights) common.
- Late central involvement → loss of acuity and colour vision when cones finally fail.
- Slow, relentless course; most become legally blind by 40–60 years.
Classic fundus triad (the “sine qua non”):
| Sign | Description |
|---|---|
| Bone-spicule pigmentation | Mid-peripheral perivascular pigment clumps; spares macula early |
| Attenuated (thread-like) retinal arterioles | Reduced metabolic demand of dying retina |
| Waxy pallor of the optic disc | Optic atrophy + gliosis |
Additional ocular associations frequently asked:
- Posterior subcapsular cataract (PSC) — the commonest cataract type in RP and a common cause of further visual drop.
- Open-angle glaucoma (increased incidence).
- Cystoid macular oedema (CMO) — a treatable cause of central vision loss in RP.
- Myopia and keratoconus associations.
- Vitreous cells / posterior vitreous detachment, fine “dust-like” vitreous opacities.
High-yield: In an RP patient with sudden drop in central acuity, think posterior subcapsular cataract or cystoid macular oedema — both potentially treatable, unlike the dystrophy itself.
Investigation of choice
Electroretinogram (ERG) is the single most important & diagnostic investigation.
- ERG shows a markedly reduced or extinguished (flat) scotopic (rod) response early, with later involvement of the photopic (cone) response.
- ERG becomes abnormal before symptoms or visible fundus changes — so it detects subclinical/RP sine pigmento and identifies carriers.
High-yield: ERG is the investigation of choice in RP — the rod (scotopic) b-wave is reduced/extinguished first. In RP sine pigmento, ERG is abnormal despite a near-normal fundus.
Other investigations:
| Test | Finding |
|---|---|
| ERG | Subnormal/extinguished scotopic response (diagnostic) |
| EOG (electro-oculogram) | Subnormal; Arden index < 1.85 (reflects RPE dysfunction) |
| Perimetry (visual fields) | Mid-peripheral ring scotoma → progressive constriction → tubular field |
| Dark adaptometry | Raised final rod threshold (objective night blindness) |
| Fundus autofluorescence | Hyperautofluorescent ring at the border of surviving retina |
| OCT | Loss of outer retinal layers / ellipsoid zone; detects CMO |
| Fluorescein angiography | Window defects, helps confirm CMO |
| Genetic testing | Confirms mutation, guides gene therapy & counselling |
| Colour vision | Blue-yellow (tritan) defect characteristic |
Management & drug of choice
There is no definitive cure for typical RP; management is supportive, with emerging gene therapy for specific subtypes.
Stepwise approach:
- Counselling & genetic counselling — explain inheritance, prognosis, recurrence risk; register for low-vision aids.
- Vitamin A palmitate — high-dose (15,000 IU/day) may modestly slow ERG decline in adults (controversial; avoid in pregnancy and in ABCA4/Stargardt disease). DHA and lutein adjuncts.
- Treat treatable complications:
- Cystoid macular oedema → oral/topical carbonic anhydrase inhibitors (acetazolamide / dorzolamide) are first line.
- Cataract → posterior subcapsular cataract extraction with IOL improves vision.
- Low-vision aids, mobility training, sunglasses (UV/blue-light protection).
- Gene therapy — voretigene neparvovec (Luxturna) for biallelic RPE65 mutation–associated retinal dystrophy/LCA: the first approved ocular gene therapy, delivered subretinally.
- Retinal prosthesis / “bionic eye” (Argus II) historically for end-stage RP; investigational stem-cell and optogenetic therapies ongoing.
High-yield: Acetazolamide / topical dorzolamide is first-line for RP-associated cystoid macular oedema. Voretigene neparvovec (Luxturna) is the gene therapy for RPE65 mutations.
High-yield: High-dose vitamin A palmitate is contraindicated in Stargardt disease (ABCA4) because it accelerates lipofuscin (A2E) accumulation.
Syndromic associations (very high-yield for integrated questions)
| Syndrome | Inheritance | RP + key extra-ocular features | Buzzword |
|---|---|---|---|
| Usher syndrome | AR | RP + sensorineural deafness (± vestibular) | Commonest cause of combined deaf-blindness |
| Bardet-Biedl | AR | RP (cone-rod) + obesity + polydactyly + hypogonadism + renal anomalies + intellectual disability | Cardinal pentad |
| Laurence-Moon | AR | RP + obesity + hypogonadism + spastic paraplegia (NO polydactyly) | Spasticity, not polydactyly |
| Kearns-Sayre | Mitochondrial | RP + chronic progressive external ophthalmoplegia (CPEO) + heart block (onset < 20 yr) | Ptosis + ophthalmoplegia + cardiac conduction block |
| Refsum disease | AR | RP + phytanic acid ↑ + peripheral neuropathy + cerebellar ataxia + anosmia + ichthyosis | Treat with phytanic-acid–free diet |
| Bassen-Kornzweig (abetalipoproteinaemia) | AR | RP + acanthocytosis + steatorrhoea + ataxia; low vitamin A/E | Treat with vitamin A & E |
| Cockayne, Friedreich ataxia, NARP, Senior-Løken | varied | RP-like retinopathy with systemic features | — |
Mnemonics:
- Bardet-Biedl pentad — “PROOM/POOR-I”: Polydactyly, Obesity, Retinitis pigmentosa, Renal anomalies, hypogonadism (genital), Intellectual disability.
- Kearns-Sayre triad — “Ptosis, Pigment, Pump-block”: external ophthalmoplegia (ptosis), RP, cardiac (heart block) — onset before 20.
- Differentiate Laurence-Moon vs Bardet-Biedl: Laurence-Moon has Limb spasticity (paraplegia) but no polydactyly; Bardet-Biedl has polydactyly but no paraplegia.
High-yield: Usher syndrome = RP + congenital sensorineural deafness and is the commonest cause of combined deaf-blindness. Kearns-Sayre = RP + CPEO + heart block (needs a pacemaker watch — cardiology referral mandatory).
Other hereditary fundus dystrophies (compare & contrast)
NEET frequently pairs RP with these dystrophies:
| Dystrophy | Defect / gene | Hallmark | Test/finding |
|---|---|---|---|
| Leber congenital amaurosis (LCA) | AR; RPE65, GUCY2D etc. | Severe blindness from infancy, roving nystagmus, oculodigital sign (Franceschetti), sluggish pupils | Flat ERG at birth; Luxturna for RPE65 |
| Stargardt disease / fundus flavimaculatus | AR; ABCA4 | Commonest juvenile macular dystrophy; central vision loss in childhood; “beaten-bronze” macula, yellow-white flecks | “Dark/silent choroid” on FFA (pathognomonic) |
| Best vitelliform dystrophy | AD; BEST1 (bestrophin) | “Egg-yolk” macular lesion, later pseudohypopyon/scrambled egg | EOG markedly abnormal (low Arden index) with normal ERG |
| Choroideremia | X-linked; CHM | Progressive diffuse choroid + RPE atrophy in males | Scalloped chorioretinal atrophy |
| Gyrate atrophy | AR; ornithine aminotransferase deficiency | Scalloped atrophy + hyperornithinaemia | Treat: arginine-restricted diet, vitamin B6 |
| Cone / cone-rod dystrophy | varied | Day blindness (hemeralopia), early colour & central vision loss, photophobia | “Bull’s-eye” maculopathy |
| Fundus albipunctatus | AR; RDH5 | Stationary night blindness, white dots, delayed dark adaptation but normal final threshold | Non-progressive |
High-yield: Best disease — ERG normal, EOG grossly abnormal (defect is at the RPE level). This is a classic single-best-answer distinguishing point from RP (where ERG is abnormal).
High-yield: Stargardt disease shows a “dark/silent choroid” on fluorescein angiography due to lipofuscin (A2E) at the RPE blocking choroidal fluorescence.
Key differentials of a “pigmentary retinopathy”
Not all bone-spicule fundi are inherited RP. Pseudoretinitis pigmentosa / phenocopies (acquired, often unilateral, ERG may be near-normal):
- Drug toxicity — thioridazine, chlorpromazine, chloroquine/hydroxychloroquine (bull’s-eye maculopathy), clofazimine.
- Inflammatory/infective — old chorioretinitis, congenital rubella (“salt-and-pepper” retinopathy), congenital syphilis, measles.
- Trauma — blunt ocular trauma with traumatic chorioretinopathy.
- Resolved exudative retinal detachment.
High-yield: Unilateral, non-progressive, normal-ERG pigmentary fundus = think pseudo-RP (inflammatory/traumatic/rubella), NOT true hereditary RP. Congenital rubella = salt-and-pepper retinopathy.
Complications
- Posterior subcapsular cataract (commonest).
- Cystoid macular oedema (treatable central vision loss).
- Open-angle glaucoma.
- Optic disc drusen / posterior vitreous detachment.
- Refractive errors (myopia), keratoconus.
- Progressive irreversible blindness — legal blindness usually by 4th–6th decade.
- In syndromic forms: deafness (Usher), cardiac block (Kearns-Sayre), renal failure (Bardet-Biedl) — systemic morbidity.
Recently asked / exam angle
- Most common symptom / earliest feature of RP → Night blindness (rod-cone dystrophy).
- Investigation of choice in RP → ERG (scotopic/rod response reduced first).
- Pigment pattern → bone-spicule / bone-corpuscle, perivascular, mid-peripheral.
- Inheritance correlations → AR commonest; AD best prognosis; X-linked earliest & worst.
- Triad of fundus signs → bone-spicules + arteriolar attenuation + waxy disc pallor.
- RP + deafness → Usher; RP + polydactyly/obesity → Bardet-Biedl; RP + ophthalmoplegia + heart block → Kearns-Sayre; RP + raised phytanic acid → Refsum.
- Best disease → EOG abnormal, ERG normal; Stargardt → silent/dark choroid + ABCA4; LCA → infantile blindness + oculodigital sign + RPE65 + Luxturna.
- Gene therapy in eye (first FDA-approved) → voretigene neparvovec (Luxturna) for RPE65.
- Treatment of CMO in RP → acetazolamide/dorzolamide.
- Vitamin A contraindicated in → Stargardt (ABCA4) disease.
- Type of field defect → ring scotoma → tubular field with preserved central island.
Rapid revision
- RP = bilateral, progressive rod-cone dystrophy; earliest symptom night blindness.
- Classic triad: bone-spicule pigment + attenuated arterioles + waxy disc pallor.
- ERG is the diagnostic test — scotopic (rod) response extinguished first; abnormal even in RP sine pigmento.
- EOG Arden index < 1.85; field shows ring scotoma → tunnel vision with preserved central island.
- Inheritance: AR most common, AD best prognosis, X-linked earliest/most severe.
- Commonest gene: rhodopsin (RHO) in AD; RPGR in X-linked; RPE65 → LCA & Luxturna target.
- Commonest cataract in RP = posterior subcapsular; CMO treated with acetazolamide/dorzolamide.
- Usher = RP + sensorineural deafness; commonest deaf-blindness cause.
- Bardet-Biedl = RP + obesity + polydactyly + hypogonadism + renal + low IQ; Laurence-Moon = RP + paraplegia, no polydactyly.
- Kearns-Sayre (mitochondrial) = RP + CPEO + heart block, onset < 20; Refsum = RP + ↑ phytanic acid (treat with diet).
- Best disease: egg-yolk macula, EOG abnormal but ERG normal; Stargardt: ABCA4, dark/silent choroid, vitamin A contraindicated.
- Pseudo-RP (unilateral, normal ERG): drugs (thioridazine, chloroquine), trauma, congenital rubella = salt-and-pepper retinopathy.