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):

1. Night blindness (nyctalopia) — earliest, due to rod loss.
2. Tubular / tunnel vision — progressive concentric peripheral field constriction (ring scotoma enlarges centripetally).
3. 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:

1. Counselling & genetic counselling — explain inheritance, prognosis, recurrence risk; register for low-vision aids.
2. 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.
3. 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.
4. Low-vision aids, mobility training, sunglasses (UV/blue-light protection).
5. Gene therapy — voretigene neparvovec (Luxturna) for biallelic RPE65 mutation–associated retinal dystrophy/LCA: the first approved ocular gene therapy, delivered subretinally.
6. 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

1. RP = bilateral, progressive rod-cone dystrophy; earliest symptom night blindness.
2. Classic triad: bone-spicule pigment + attenuated arterioles + waxy disc pallor.
3. ERG is the diagnostic test — scotopic (rod) response extinguished first; abnormal even in RP sine pigmento.
4. EOG Arden index < 1.85; field shows ring scotoma → tunnel vision with preserved central island.
5. Inheritance: AR most common, AD best prognosis, X-linked earliest/most severe.
6. Commonest gene: rhodopsin (RHO) in AD; RPGR in X-linked; RPE65 → LCA & Luxturna target.
7. Commonest cataract in RP = posterior subcapsular; CMO treated with acetazolamide/dorzolamide.
8. Usher = RP + sensorineural deafness; commonest deaf-blindness cause.
9. Bardet-Biedl = RP + obesity + polydactyly + hypogonadism + renal + low IQ; Laurence-Moon = RP + paraplegia, no polydactyly.
10. Kearns-Sayre (mitochondrial) = RP + CPEO + heart block, onset < 20; Refsum = RP + ↑ phytanic acid (treat with diet).
11. Best disease: egg-yolk macula, EOG abnormal but ERG normal; Stargardt: ABCA4, dark/silent choroid, vitamin A contraindicated.
12. Pseudo-RP (unilateral, normal ERG): drugs (thioridazine, chloroquine), trauma, congenital rubella = salt-and-pepper retinopathy.