Residency · Residency · Ophthalmology
Inherited Retinal Dystrophies: Retinitis Pigmentosa and Allied Disorders
Introduction
Inherited retinal dystrophies (IRDs) are a genetically and clinically heterogeneous group of disorders characterized by progressive photoreceptor and/or RPE degeneration leading to vision loss. Retinitis pigmentosa (RP) is the most common IRD, affecting approximately 1 in 3,000-4,000 individuals worldwide. Advances in genetic testing and gene therapy have transformed the approach to diagnosis and management of these previously untreatable conditions.
Classification of Inherited Retinal Dystrophies
By Predominantly Affected Photoreceptor
Rod-cone dystrophies: RP and allied disorders; rods affected first (night blindness, peripheral field loss) Cone-rod dystrophies: cones affected first (central vision loss, color vision defects, photophobia) Cone dystrophies: selective cone involvement (achromatopsia, blue cone monochromatism) Macular dystrophies: Stargardt disease, Best disease, pattern dystrophies.
By Inheritance Pattern
Autosomal recessive: most common (50-60% of RP); often more severe. Autosomal dominant: 15-25% of RP; generally milder phenotype. X-linked recessive: 5-15%; severe; early onset; carrier females may show fundus changes. Digenic and mitochondrial: rare.
By Syndromic vs. Non-Syndromic
| Syndrome | Inheritance | Ocular Finding | Systemic Associations |
|---|---|---|---|
| Non-syndromic RP | Variable | RP alone | None |
| Usher syndrome | AR | RP | Sensorineural hearing loss (most common syndromic IRD) |
| Bardet-Biedl syndrome | AR | RP | Obesity, polydactyly, renal anomalies, hypogonadism, intellectual disability |
| Kearns-Sayre syndrome | Mitochondrial | RP + CPEO | Cardiac conduction defects, elevated CSF protein |
| Refsum disease | AR | RP | Peripheral neuropathy, cerebellar ataxia, elevated phytanic acid |
| Cockayne syndrome | AR | RP | Dwarfism, photosensitivity, intellectual disability |
Retinitis Pigmentosa
Genetics
Over 80 genes implicated in non-syndromic RP. Most commonly mutated genes: RHO (rhodopsin): most common cause of autosomal dominant RP. USH2A (usherin): most common cause of autosomal recessive RP. RPGR: most common cause of X-linked RP. RPE65: important as the target of the first FDA-approved gene therapy.
Clinical Features
Night blindness (nyctalopia): earliest symptom; often noted in childhood or adolescence. Progressive peripheral visual field constriction: ring scotoma expanding to tunnel vision. Central vision often preserved until late stages. Photopsia (sparkles, flashes) in some patients.
Fundus Findings
Bone-spicule pigmentation: perivascular pigment clumps in the mid-periphery (pathognomonic) Arteriolar attenuation: narrowing of retinal vessels. Waxy pallor of the optic disc. RPE atrophy in the periphery. Cystoid macular edema: common (up to 50%); treatable cause of vision loss. Epiretinal membrane.
Posterior subcapsular cataract (frequent association)
Variants
Retinitis punctata albescens: white dots at the RPE level; associated with RLBP1 mutations. Sector RP: involvement limited to one quadrant or sector; often autosomal dominant (RHO) Pericentral RP: ring of atrophy around the macula with preserved peripheral retina. Inverse RP (cone-rod pattern): central involvement first; macular atrophy early.
Diagnostic Testing
Electroretinography (ERG)
Full-field ERG (ffERG): gold standard for diagnosis and monitoring. Reduced or absent scotopic (rod) responses; reduced photopic (cone) responses. In early disease, rod responses are more affected than cone responses. Follows ISCEV (International Society for Clinical Electrophysiology of Vision) standards. Multifocal ERG (mfERG): assesses localized macular function; useful in cone and macular dystrophies.
Visual Fields
Goldmann perimetry: preferred for documenting peripheral field loss in RP. Ring scotoma progressing to concentric constriction. Humphrey visual field may miss far peripheral loss.
Optical Coherence Tomography
Outer retinal layer thinning (loss of ellipsoid zone/IS-OS junction line) Preserved ellipsoid zone (EZ) width correlates with residual visual function. CME detection and monitoring. Hyperautofluorescent ring on FAF corresponds to the boundary of functioning retina.
Fundus Autofluorescence
Hyperautofluorescent ring around the macula: ring of increased metabolic stress at the border of functional and dysfunctional retina. Ring constriction over time correlates with visual field loss. Hypoautofluorescence in areas of RPE atrophy.
Genetic Testing
Panel-based next-generation sequencing (NGS) covering known IRD genes (>300 genes) Whole exome or whole genome sequencing for unsolved cases. Diagnostic yield: 60-70% with current panels. Genetic counseling is essential before and after testing.
Allied Disorders
Stargardt Disease
Most common juvenile macular dystrophy (1 in 8,000-10,000) ABCA4 gene mutations (autosomal recessive); impaired transport of retinoid byproducts. Accumulation of lipofuscin (A2E) in RPE. Fundus: yellow-white flecks at the posterior pole; "beaten-bronze" macular atrophy. Dark choroid on fluorescein angiography (lipofuscin blocks choroidal fluorescence) Central vision loss in childhood or adolescence; peripheral vision usually preserved.
No proven treatment; avoid excessive vitamin A supplementation.
Best Disease (Vitelliform Macular Dystrophy)
BEST1 gene mutation (autosomal dominant); dysfunction of bestrophin-1 chloride channel in RPE. Classic "egg-yolk" (vitelliform) macular lesion. Stages: previtelliform, vitelliform, pseudohypopyon, vitelliruptive, atrophic, CNV. Electrooculography (EOG): abnormal Arden ratio (< 1.5); diagnostic. ERG is normal (distinguishes from RP) Variable visual outcome; some patients maintain good vision for decades.
Choroideremia
CHM gene (X-linked recessive); REP-1 protein deficiency. Progressive chorioretinal atrophy from periphery to center. Night blindness and field loss similar to RP. Fundus: scalloped areas of RPE and choroidal atrophy with visible sclera. Gene therapy clinical trials ongoing (AAV-REP1)
Leber Congenital Amaurosis (LCA)
Severe retinal dystrophy presenting in infancy (first year of life) Severe visual impairment, nystagmus, amaurotic pupils, oculodigital sign (eye rubbing) Over 25 genes implicated; RPE65 mutations cause LCA type 2. Voretigene neparvovec (Luxturna): FDA-approved gene therapy for RPE65-associated retinal dystrophy.
Management
Current Treatments
Voretigene neparvovec (Luxturna): subretinal injection of AAV2 vector carrying RPE65 gene. Improves functional vision (navigational ability, light sensitivity) One-time treatment per eye; durability under ongoing study. Requires confirmed biallelic RPE65 mutations and viable retinal cells. Oral acetazolamide or topical dorzolamide: for RP-associated CME. Posterior subcapsular cataract surgery with IOL implantation.
Low vision rehabilitation: magnifiers, adaptive technology, orientation and mobility training. Avoid excessive light exposure (UV-protective sunglasses) Vitamin A palmitate (15,000 IU/day): modest slowing of ERG decline (Berson et al.); controversial; risk of liver toxicity; avoid in Stargardt disease.
Emerging Therapies
Gene therapy for other IRD genes (RPGR, CNGA3, CNGB3, choroideremia) Antisense oligonucleotides: sepofarsen for CEP290-associated LCA (intravitreal) Optogenetics: rendering remaining retinal cells light-sensitive. Retinal prostheses: Argus II (discontinued) and next-generation devices. Stem cell therapy: RPE cell transplantation (clinical trials) CRISPR-based gene editing for dominant-negative mutations.
Key Clinical Pearls
Retinitis pigmentosa is the most common inherited retinal dystrophy; over 80 genes can cause the phenotype, making genetic testing essential for counseling and potential gene therapy eligibility. Voretigene neparvovec (Luxturna) is the first FDA-approved gene therapy for an inherited retinal disease, specifically for biallelic RPE65-associated retinal dystrophy. Fundus autofluorescence showing a hyperautofluorescent ring is a sensitive biomarker for disease progression in RP; ring constriction correlates with visual field loss. Cystoid macular edema occurs in up to 50% of RP patients and is a treatable cause of additional vision loss (oral acetazolamide or topical dorzolamide).
References
- Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. Lancet. 2006;368(9549):1795-1809.
- Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy. Lancet. 2017;390(10097):849-860.
- Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761-772.
- Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2017;101(1):25-30.