Retinitis Pigmentosa (RP)

Overview

Retinitis pigmentosa is a collective term for a heterogeneous group of inherited rod-cone dystrophies causing progressive photoreceptor degeneration. Despite its name, it is not an inflammatory condition — the "pigmentosa" refers to characteristic pigmentary deposits seen on fundoscopy. (Harrison's, p. 974)

Genetics & Pathophysiology

RP is genetically diverse, with >90 causative genes identified. Inheritance patterns include:

Pattern	Proportion	Key Genes
Autosomal recessive	~50–60%	ABCA4, USH2A, CNGB1
Autosomal dominant	~30–40%	RHO (rhodopsin), PRPF31, PRPH2 (peripherin)
X-linked	~5–15%	RPGR, RP2 (most severe phenotype)
Sporadic/mitochondrial	Variable	Multiple

Mutations in rhodopsin (the rod photopigment) and peripherin (a glycoprotein in photoreceptor outer segments) are among the most commonly identified. (Harrison's, p. 974)

Pathophysiologic sequence:

Mutant gene → dysfunctional/misfolded protein in rod outer segments
Rod photoreceptor apoptosis → peripheral visual loss
Secondary cone photoreceptor degeneration (mechanism debated — oxidative stress, loss of trophic support)
Retinal pigment epithelium (RPE) dysfunction → pigment migration into retina

Clinical Features

Symptoms (typically appear in adolescence to early adulthood):

Nyctalopia (night blindness) — earliest and cardinal symptom; due to rod loss
Progressive peripheral visual field loss → tunnel vision
Photopsia (flickering lights)
Loss of visual acuity — later finding, when foveal cones are affected

Signs on fundoscopy (classic triad):

Bone-spicule pigmentation — irregular black deposits in mid-peripheral retina
Arteriolar attenuation — narrowed retinal vessels
Waxy disc pallor — optic disc appears pale/waxy

Multimodal Imaging

Top row: Fundus photographs showing bone-spicule pigmentary changes and arteriolar attenuation. Middle row: OCT showing marked thinning of the outer nuclear layer (ONL) with disruption/loss of the IS/OS junction, sparing only the fovea. Bottom: Goldmann perimetry demonstrating ring scotomas and peripheral constriction. Right: Fundus autofluorescence (FAF) showing a characteristic perifoveal hyperautofluorescent ring.

Diagnosis

Test	Finding
Electroretinogram (ERG)	Severely reduced or absent rod (scotopic) responses; gold standard for diagnosis and monitoring
Visual field testing (Goldmann/Humphrey)	Ring scotoma progressing to tunnel vision
OCT	ONL thinning, IS/OS junction loss; foveal sparing until late
Fundus autofluorescence	Perifoveal hyperautofluorescent ring (marks zone of active degeneration)
Genetic testing	Identifies specific mutation; guides prognosis and eligibility for gene therapy

Associated Syndromes

RP can be an isolated finding or part of a syndrome:

Usher syndrome — RP + sensorineural hearing loss (most common syndromic RP; USH2A)
Bardet-Biedl syndrome — RP + obesity + polydactyly + renal anomalies + cognitive impairment
Kearns-Sayre syndrome — RP + external ophthalmoplegia + cardiac conduction defects (mitochondrial)
Refsum disease — RP + peripheral neuropathy + cerebellar ataxia (phytanic acid metabolism defect)

Management

Supportive & Pharmacologic

Vitamin A palmitate (15,000 IU/day): Modestly slows ERG deterioration; no proven benefit on visual acuity or visual fields. Use with caution (hepatotoxicity, teratogenicity). (Harrison's, p. 974)
DHA (docosahexaenoic acid) supplementation: adjunctive, evidence limited
UV-blocking sunglasses: Reduce phototoxic stress
Low vision aids: Magnifiers, contrast enhancement, mobility training
Carbonic anhydrase inhibitors (e.g., acetazolamide): For associated cystoid macular edema

Gene Therapy

Voretigene neparvovec (Luxturna): FDA-approved (2017) for biallelic RPE65-mutation–associated retinal dystrophy. Subretinal AAV2 delivery. Represents a landmark proof-of-concept for retinal gene therapy, though RPE65 mutations account for only ~1–2% of RP cases.
Numerous other gene therapy trials ongoing for RPGR, CNGB3, CNGA3, and other targets.

Emerging Therapies

Retinal prostheses (e.g., Argus II / Second Sight): Epiretinal electrode array for end-stage RP; provides rudimentary light perception
Optogenetic therapy: Introducing light-sensing proteins (channelrhodopsins) into surviving retinal cells; early clinical trials show promise
Stem cell / RPE transplantation: Under investigation
CRISPR gene editing: Preclinical research stage

Prognosis

Highly variable, depending on mutation type and inheritance pattern
X-linked RP tends to be most severe (earlier onset, faster progression)
Most patients retain some useful central vision until the 5th–7th decade
Legal blindness (visual acuity <20/200 or field <20°) eventually develops in the majority
Associated cystoid macular edema and posterior subcapsular cataracts can cause additional, treatable vision loss

Key Pearls

ERG is the gold standard — can be diagnostic even before symptoms appear
Always screen for syndromic associations (hearing test, renal function, cardiac evaluation)
Genetic testing is increasingly important for prognosis and treatment eligibility
Avoid vitamin A in pregnancy; monitor liver function with supplementation

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