A 25-year-old man reports difficulty seeing at night since his teens, worsening to "tunnel vision" over the past 5 years; he is now bumping into objects in his peripheral field. Fundoscopy shows the classic triad of bone-spicule pigmentation in the mid-periphery, attenuated retinal vessels, and a waxy-pale optic disc. Full-field ERG shows severely reduced rod responses with relatively preserved cone responses, confirming a rod-cone dystrophy pattern.
Retinitis pigmentosa (RP) is the prototypical inherited rod-cone dystrophy: primary degeneration of rod photoreceptors, with cones following later. "RP" by convention refers to non-syndromic disease; syndromic RP (RP as part of a multi-system genetic disorder) is a separate clinical category.
| Category | Key examples |
|---|---|
| Non-syndromic RP | This entry |
| Syndromic RP | Usher syndrome (RP + sensorineural hearing loss), Bardet-Biedl syndrome (RP + obesity + polydactyly + ID + renal anomalies), Refsum disease (RP + anosmia + ataxia + elevated phytanic acid), Alström syndrome, Cohen syndrome, neuronal ceroid lipofuscinoses |
Extremely heterogeneous: >80 genes; all Mendelian inheritance patterns plus mitochondrial.
| Inheritance | Approximate frequency | Common genes |
|---|---|---|
| AD | ~30-40% | RHO (rhodopsin, most common AD gene), PRPH2, RP1, PRPF31, IMPDH1, NR2E3 |
| AR | ~50-60% | USH2A (also Usher type 2, same gene different phenotype), RPE65 (also Leber congenital amaurosis), EYS, CRB1, CNGA1, PDE6A/B, ABCA4 |
| X-linked | ~10-15% | RPGR (most common XL form, especially the ORF15 mutation hotspot), RP2 |
| Mitochondrial | rare | Consider in maternal-pattern pedigrees; usually with broader mitochondrial features |
| Digenic | rare | PRPH2 + ROM1 classic example |
Key counseling pearls:
- USH2A pleiotropy: the same USH2A variants can cause non-syndromic RP or Usher type 2 (RP + congenital hearing loss). Audiologic evaluation is mandatory at diagnosis of USH2A RP.
- RPGR XL pattern: affected males have severe early-onset RP; carrier females show variable findings on exam (tapetal-like reflex, sectoral retinopathy) due to X-inactivation and may have meaningful visual symptoms.
- RPE65 biallelic disease is now treatable. See Management.
Diverse molecular pathways converge on rod photoreceptor death:
- Phototransduction defects (RHO, PDE6A/B, CNGA1)
- Visual cycle / RPE function (RPE65, LRAT)
- Outer segment structure (PRPH2, ROM1, RP1)
- Cilium / connecting cilium (RPGR, USH2A, CEP290)
- Splicing factors (PRPF31, PRPF8, PRPF3), surprisingly retina-specific despite ubiquitous expression
Once rod death is established, secondary cone death occurs partly via loss of rod-derived cone viability factor (RdCVF).
Symptoms (in order of typical progression):
- Nyctalopia (night blindness): usually the first symptom, often in childhood/adolescence
- Mid-peripheral visual field loss → "tunnel vision" over years
- Eventual loss of central vision
- Photopsias, slow dark adaptation
Fundus (classic triad):
- Bone-spicule pigmentation: black perivascular pigment clumping in the mid-periphery (RPE migration)
- Attenuated retinal vessels ("threadlike" arterioles)
- Waxy-pale optic disc (reflects long-standing RGC stress)
Other findings:
- Posterior subcapsular cataract (common in adults; often a treatable cause of acute visual decline)
- Cystoid macular edema (CME): treatable; topical/oral CAIs help
- Refractive error (myopia common)
- Vitreous cells/pigment
Functional testing:
- Full-field ERG: reduced/extinguished rod responses early, cone responses follow
- Visual field testing: mid-peripheral ring scotoma → progressive constriction
- OCT: thinning of the outer nuclear layer with preservation of central ellipsoid zone until later
- Fundus autofluorescence (FAF): hyperautofluorescent ring around the macula at the boundary of preserved photoreceptors
- Clinical recognition + ERG → multigene panel sequencing (best yield) covering all RP genes plus syndromic mimics
- Audiology evaluation (mandatory; Usher syndrome considerations)
- Renal/metabolic workup if syndromic features suggest BBS, Senior-Løken, etc.
- For females with isolated RP, consider RPGR carrier testing (cascade implications)
Disease-modifying:
- Voretigene neparvovec (Luxturna): FDA-approved subretinal AAV2 gene therapy for biallelic RPE65-related retinal dystrophy (RP/LCA spectrum). The first FDA-approved gene therapy for an inherited disease and a major reason molecular diagnosis matters in RP.
- Multiple AAV-based and antisense oligonucleotide therapies in trials for other genotypes (RHO, USH2A, RPGR, CEP290)
- Retinal prostheses (Argus II historically, newer optogenetic approaches in trials)
Symptomatic / supportive:
- Vitamin A palmitate: modestly slows ERG decline in some adult RP (NOT in Stargardt disease / ABCA4, and avoid in pregnancy)
- DHA supplementation, low-glycemic diet (modest evidence)
- UV protection
- Cataract extraction when visually significant
- CME treatment (topical brinzolamide, oral acetazolamide, intravitreal steroids)
- Low-vision rehabilitation, orientation/mobility, vocational support
- Genetic counseling and cascade testing based on identified inheritance pattern
- Cone-rod dystrophy: central vision loss precedes peripheral; cones affected first
- Choroideremia: XL, CHM; scalloped chorioretinal atrophy
- Gyrate atrophy: AR, OAT; ornithine elevated; arginine-restricted diet
- Vitamin A deficiency: acquired phenocopy with night blindness; reversible
- Drug-induced retinopathy: chloroquine, thioridazine; medication history