# 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.

![Fundus photograph showing classic retinitis pigmentosa with bone-spicule pigmentation, arteriolar attenuation, and disc pallor](images/retinitis-pigmentosa-fundus.jpg)

## 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.

![Fundus autofluorescence showing the hyperautofluorescent ring in retinitis pigmentosa](images/rp-faf-ring.jpg)

## 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.

![OCT showing outer retinal layer loss and preserved central ellipsoid zone in retinitis pigmentosa](images/rp-oct-ellipsoid-zone.jpg)

## 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

1. Hartong DT, Berson EL, Dryja TP. Retinitis pigmentosa. *Lancet*. 2006;368(9549):1795-1809.
2. 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.
3. 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.
4. 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.