Retinitis Pigmentosa

Slide 1 · Retinitis Pigmentosa

Inherited photoreceptor degeneration

Pathogenesis | Morphology | Clinical diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why rod degeneration produces nyctalopia and field constriction.

Distinguish nonsyndromic from syndromic RP and recognize inheritance patterns.

Relate photoreceptor and RPE injury to the characteristic fundus signs.

Select investigations that establish phenotype and enable molecular diagnosis.

Slide 3 · Retinitis pigmentosa: An inherited retinal dystrophy

A heterogeneous group of progressive disorders affecting retinal photoreceptors.

Pathogenic variants can impair rods, cones, or the retinal pigment epithelium (RPE).

Functional decline can range from mild impairment to profound visual loss.

Slide 4 · Why the name “retinitis” is misleading

Historical label

“Retinitis” implied inflammation

“Pigmentosa” described the fundus

Current concept

Inherited photoreceptor dystrophy

Secondary pigment redistribution

The historical name predates recognition of its genetic, degenerative basis.

Slide 5 · RP is a phenotype, not a single genotype

Different pathogenic variants

Photoreceptor dysfunction

Progressive retinal degeneration

RP clinical phenotype

Different genetic defects may converge on progressive retinal dysfunction.

The age at onset, severity, and clinical course vary.

A similar retinal phenotype does not establish the same molecular diagnosis.

Slide 6 · Retinal architecture: Where RP begins

Neural retina / interneurons

Photoreceptor cell bodies

Rod / cone outer segments

Retinal pigment epithelium

Bruch membrane / choriocapillaris

Conceptual retinal-layer schematic — not a histologic section

Photoreceptor outer segments contact the apical RPE.

The RPE supports photoreceptor homeostasis and visual-cycle function.

Slide 7 · Rod and cone functions

Rod pathway

Dim-light sensitivity

Peripheral field function

Night-vision symptoms

Cone pathway

Fine central acuity

Color and daylight vision

Later central impairment

Rods support dim-light vision and contribute strongly to peripheral vision.

Slide 8 · Spatial distribution matters

Central field

More vulnerable peripheral function

Conceptual field schematic — not a patient perimetry plot

Rods are abundant in the extrafoveal retina.

The central fovea is cone-rich.

Early rod-predominant injury can reduce peripheral function despite useful central acuity.

Slide 9 · A common endpoint of genetically diverse insults

Inherited defect

Cellular dysfunction

Photoreceptor loss

Visual impairment

Pathogenic variants disturb essential photoreceptor or RPE functions.

Cellular dysfunction is followed by photoreceptor loss.

Clinical dysfunction may precede conspicuous pigmentary signs.

Slide 10 · Isolated and syndromic disease

Nonsyndromic RP

Retinal phenotype predominates

Gene-specific inheritance

Eye-focused assessment

Syndromic RP

Retinal plus systemic findings

Examples: Hearing, metabolic, renal

Multidisciplinary assessment

Nonsyndromic RP predominantly affects the retina.

Slide 11 · Three major Mendelian patterns

Autosomal patterns

Dominant: One disease allele may suffice

Recessive: Biallelic disease variants

Family history may be negative

X-linked pattern

Variant on the X chromosome

Often more severe in hemizygous males

Female carrier expression varies

Autosomal dominant RP is transmitted vertically in some pedigrees.

Slide 12 · Autosomal dominant RP: Pedigree implications

Single pathogenic allele

Autosomal dominant transmission

Variable severity / age

Family counseling

A pathogenic variant in one allele may cause disease.

Affected individuals may appear in successive generations.

Variable expressivity and incomplete penetrance can complicate pedigree interpretation.

Slide 13 · Autosomal recessive RP: Pedigree implications

Two disease alleles

Photoreceptor dysfunction

Affected proband

Carrier evaluation

Biallelic pathogenic variants are generally required.

Parents can be clinically unaffected carriers.

Apparently sporadic disease does not exclude a monogenic recessive disorder.

Slide 14 · X-linked RP: A distinct clinical pattern

RPGR pathogenic variant

X-linked inheritance

Rod–cone dysfunction

Variable expression

RPGR is an important gene in X-linked RP.

Hemizygous males may present with early, severe rod–cone dysfunction.

Heterozygous females can have widely variable phenotypes.

Slide 15 · Onset and severity are not fixed by inheritance alone

A tendency toward later onset in autosomal dominant RP.

Genotype, specific variant, and individual context influence expression.

Avoid assuming inheritance pattern from age at presentation alone.

Slide 16 · Genetic heterogeneity has two dimensions

Locus heterogeneity

Many genes

Convergent retinal phenotype

Panel-based testing helps

Allelic heterogeneity

Different variants in one gene

Variable severity or phenotype

Variant-level interpretation matters

Locus heterogeneity: Disease variants in different genes produce RP.

Slide 17 · Core genes emphasized

Gene

High-yield association

RHO

Rhodopsin / rod function

USH2A

RP ± hearing phenotype

RPGR

X-linked RP

EYS

Autosomal recessive RP

RHO — encodes rhodopsin, a major rod photopigment.

Slide 18 · RHO: Linking phototransduction to degeneration

RHO variant

Abnormal rod photopigment biology

Rod dysfunction

Nyctalopia / field loss

Rhodopsin mediates light detection in rods.

Disease-causing RHO variants perturb normal rod biology by variant-dependent mechanisms.

Rod dysfunction can therefore be an early clinical feature.

Slide 19 · USH2A: Retinal disease with or without hearing loss

Isolated retinal phenotype

Typical RP features

No recognized hearing phenotype

Ongoing phenotype assessment

Usher-associated phenotype

RP plus sensorineural hearing loss

Additional evaluation indicated

Genotype–phenotype nuance

USH2A variants can cause nonsyndromic RP or Usher syndrome.

Slide 20 · RPGR: An important X-linked locus

RPGR is a recognized cause of X-linked RP.

Some RPGR regions are technically challenging for sequencing.

Molecular assay limitations should be considered if suspicion remains high.

Slide 21 · EYS: Structural maintenance and recessive RP

Biallelic EYS pathogenic variants are associated with retinal degeneration.

The clinical presentation overlaps other forms of rod–cone dystrophy.

Phenotype alone generally cannot assign EYS as the cause.

Slide 22 · Source-text quality control: RPGR versus RGPR

Extracted wording

“RGPR” in supplied conversion

Not the standard disease gene symbol

Verified nomenclature

RPGR

Retinitis pigmentosa GTPase regulator

The extracted Robbins paragraph spells the gene “RGPR”.

Slide 23 · Functional categories of RP-associated genes

Functional domain

What can fail

Phototransduction

Normal conversion of light into signal

Visual cycle / RPE support

Photopigment regeneration and homeostasis

Structure / transport

Outer-segment maintenance

Gene expression

Photoreceptor protein regulation

Phototransduction: Processing the light signal.

Slide 24 · Phototransduction failure can precede cell loss

Molecular defect

Altered signaling

ERG abnormality

Later visible atrophy

Mutated pathway components can impair retinal response before overt structural atrophy.

Functional testing is therefore complementary to structural examination.

A normal-looking early fundus does not exclude inherited retinal dysfunction.

Slide 25 · The photoreceptor–RPE relationship

Neural retina / interneurons

Photoreceptor cell bodies

Rod / cone outer segments

Retinal pigment epithelium

Bruch membrane / choriocapillaris

Conceptual retinal-layer schematic — not a histologic section

Photoreceptors depend on an intact supporting RPE.

Variants may primarily affect photoreceptor cells or RPE-associated pathways.

Slide 26 · Programmed cell death in retinal degeneration

Cellular stress

Degenerative injury

Photoreceptor apoptosis

Retinal atrophy

The Robbins account identifies apoptosis as a mechanism of rod and cone death.

Progressive cell depletion explains irreversible loss of light-sensing capacity.

Different causal mutations may converge on this tissue-level outcome.

Slide 27 · RIP kinase and cone cell death

RIP kinase activation as a partial mediator of cone death.

This is a mechanistic observation, not a clinical diagnostic criterion.

It does not establish a routinely available RP treatment target.

Slide 28 · Typical rod–cone progression

Rod dysfunction

Night blindness

Peripheral field loss

Later cone / central loss

Rod dysfunction often dominates early manifestations.

Peripheral field reduction develops as rod-mediated function deteriorates.

Progression to cone involvement may reduce central acuity.

Slide 29 · Why night blindness appears early

Rod loss

Reduced scotopic response

Poor dim-light vision

Nyctalopia

Rods are specialized for low-light vision.

Loss of rod-mediated sensitivity impairs dark adaptation and navigation in dim environments.

Nyctalopia is a functional manifestation, not an inflammation-related symptom.

Slide 30 · Why visual fields constrict

Central field

More vulnerable peripheral function

Conceptual field schematic — not a patient perimetry plot

Photoreceptor dysfunction may be pronounced outside the central macula.

Peripheral or ring scotomas can expand with disease progression.

Preserved central acuity can coexist with disabling field loss.

Slide 31 · Why central acuity may decline later

Earlier phase

Night-vision complaints

Constriction of side vision

Central acuity may remain good

Advanced phase

More extensive cone dysfunction

Central visual impairment

Major daily-living consequences

The cone-rich central retina may initially remain relatively functional.

Slide 32 · Clinical trajectories vary substantially

Age of onset and rate of progression differ between genotypes and individuals.

Symptoms, function, and retinal appearance are not always synchronous.

Prognosis requires longitudinal measurements rather than a single snapshot.

Slide 33 · Funduscopic morphology: Classic triad

Finding

Pathologic interpretation

Bone-spicule pigmentation

Pigment redistribution around retinal vessels

Vessel attenuation

Reduced caliber with retinal atrophy

Waxy disc pallor

Optic nerve head pallor in advanced disease

Bone-spicule–like intraretinal pigment clumping.

Slide 34 · Bone-spicule pigmentation: Why the pattern forms

Outer retinal injury

RPE disruption / migration

Perivascular pigment deposits

Pigmentary fundus pattern

Degeneration accompanies migration or redistribution of RPE pigment.

Dark pigment clumps become conspicuous along retinal vessels.

Pigment location is a consequence of chronic injury, not evidence of active retinitis.

Slide 35 · Retinal vessel attenuation

Narrowed retinal vessels accompany chronic retinal atrophy.

Attenuation should be interpreted together with functional and other fundus findings.

Vessel narrowing is not specific enough to establish RP by itself.

Slide 36 · Waxy optic-disc pallor

A pale optic nerve head can develop in longstanding RP.

It belongs to the classic phenotypic triad with pigmentation and vessel attenuation.

It should not be confused with proof of primary optic neuropathy.

Slide 37 · Tissue-level consequence: Outer retinal atrophy

Neural retina / interneurons

Photoreceptor cell bodies

Rod / cone outer segments

Retinal pigment epithelium

Bruch membrane / choriocapillaris

Conceptual retinal-layer schematic — not a histologic section

Photoreceptor loss primarily affects the outer neural retina.

Associated RPE changes alter the overlying retinal appearance.

Slide 38 · Early RP may lack the classic appearance

Symptoms / family history

Subtle retinal examination

Functional + imaging tests

Molecular assessment

Photoreceptor dysfunction can be detectable before extensive pigmentation develops.

Normal or subtle fundus appearance does not rule out early RP.

ERG, visual fields, multimodal imaging, and genetics may clarify the diagnosis.

Slide 39 · Systemic clues can redefine the diagnosis

Clinical clue

Consider

Hearing impairment

Usher syndrome

Obesity, polydactyly, renal issues

Bardet–Biedl syndrome

Neuropathy / ataxia / hearing symptoms

Refsum disease

Ask about hearing loss, vestibular symptoms, developmental findings, and multisystem disease.

Slide 40 · Usher syndrome: Retina and hearing

Ophthalmic phenotype

Progressive rod–cone dysfunction

Night blindness / field loss

Pigmentary degeneration

Systemic phenotype

Sensorineural hearing impairment

Vestibular findings vary by type

Multidisciplinary counseling

RP is associated with sensorineural hearing loss in Usher syndrome.

Slide 41 · Bardet–Biedl syndrome: A multisystem disorder

Retinal dystrophy may occur with obesity, polydactyly, and renal or developmental features.

A syndromic diagnosis has implications beyond visual prognosis.

Recognition prompts comprehensive systemic assessment.

Slide 42 · Refsum disease: A relevant syndromic differential

RP-like retinal degeneration can occur in Refsum disease.

Neurologic, hearing, and other systemic clues should prompt targeted evaluation.

Unlike many inherited retinal dystrophies, identifying its metabolic cause can influence management.

Slide 43 · Diagnostic approach: Phenotype first

History + pedigree

Ophthalmic examination

Functional / imaging tests

Molecular diagnosis

Document symptoms, visual acuity, and family history.

Evaluate retinal appearance and distribution of dysfunction.

Combine fields, ERG, retinal imaging, and genetic analysis as indicated.

Slide 44 · History: Questions that discriminate

When did night blindness or dark-adaptation difficulty begin?

Is field loss progressive and bilateral?

Are relatives affected or are there consanguineous relationships?

Are hearing, neurologic, renal, or metabolic manifestations present?

Slide 45 · Pedigree analysis guides—not replaces—testing

Pedigree information

Affected relatives

Sex distribution

Age at symptom onset

Limitations

Small pedigrees

Reduced penetrance

Variable expressivity / de novo variants

Vertical transmission raises suspicion for autosomal dominant disease.

Slide 46 · Visual fields document peripheral impairment

Central field

More vulnerable peripheral function

Conceptual field schematic — not a patient perimetry plot

Perimetry detects constriction and scotomas that acuity tests can miss.

Field mapping can establish functional impairment at baseline.

Serial assessments support evaluation of progression.

Slide 47 · Full-field ERG: Evidence of generalized dysfunction

Scotopic / dark adapted

Rod-mediated response

Often reduced early

Useful for rod–cone distinction

Photopic / light adapted

Cone-mediated response

May be relatively preserved early

Can decline with progression

Dark-adapted responses assess rod-mediated function.

Slide 48 · Optical coherence tomography

Neural retina / interneurons

Photoreceptor cell bodies

Rod / cone outer segments

Retinal pigment epithelium

Bruch membrane / choriocapillaris

Conceptual retinal-layer schematic — not a histologic section

OCT delineates retinal layers and outer-retinal structural loss.

It can document macular integrity and associated complications such as cystoid macular edema.

Slide 49 · Fundus autofluorescence

Fundus autofluorescence provides an indirect view of RPE-associated signal patterns.

It can map retinal changes beyond what color photography shows.

Findings need interpretation alongside fundus examination, OCT, and function.

Slide 50 · Genetic testing: Why broad panels are useful

Clinical RP phenotype

Gene panel / genomic test

Variant classification

Genotype–phenotype review

Many genes can produce similar clinical RP phenotypes.

A well-designed inherited retinal dystrophy gene panel is often appropriate.

Assay coverage and copy-number / difficult-region limitations matter.

Slide 51 · Interpreting a molecular result

Result category

Clinical use

Causal variant(s)

Supports gene-specific diagnosis

VUS

Not proof of causality

Negative / inconclusive

Revisit assay coverage and phenotype

“Pathogenic” and “likely pathogenic” differ from a variant of uncertain significance.

Slide 52 · Differential: Rod–cone versus cone–rod dystrophy

Feature

Typical RP

Cone–rod dystrophy

Early problem

Night / side vision

Central / color vision

Early function

Rod-predominant

Cone-predominant

Testing

ERG rod deficit

ERG cone deficit

RP usually has a rod-predominant initial dysfunction.

Slide 53 · Differential: Choroideremia

Choroideremia can also cause night blindness and progressive peripheral field loss.

Its characteristic RPE and choroidal atrophy differs from typical RP patterns.

Fundus structure, inheritance, and genetics support distinction.

Slide 54 · Differential: Inherited retinal dystrophy is broader than RP

RP pattern

Rod–cone dysfunction

Classic triad may appear

Progressive bilateral phenotype

Alternatives

Cone–rod dystrophy

Choroideremia

Other retinal dystrophies / mimics

Other inherited retinal disorders may share night blindness or pigmentary changes.

Slide 55 · Differential: RP versus age-related macular degeneration

Feature

Retinitis pigmentosa

AMD

Main early phenotype

Night / peripheral dysfunction

Central macular dysfunction

Distribution

Generalized rod–cone retina

Macula-centered

Hallmark morphology

Spicules / vessel attenuation

Drusen / atrophy or neovascularity

RP: Inherited, typically rod–cone retinal degeneration with peripheral symptoms.

Slide 56 · Management: Preserving function and independence

No general cure exists for the heterogeneous group of RP disorders.

Visual rehabilitation, appropriate aids, and support services can mitigate disability.

Management should address treatable complications and systemic syndromic disease.

Slide 57 · Gene-specific therapy is not a universal RP treatment

Inherited retinal dystrophy

Confirm biallelic RPE65

Specialist eligibility review

Approved indication

The FDA-approved voretigene neparvovec indication is specific to confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Eligibility is molecularly defined and requires specialist assessment.

This approval must not be extrapolated to RHO-, RPGR-, USH2A-, or EYS-related RP.

Slide 58 · Separating approved care from investigational approaches

Available care

Diagnostic assessment

Low-vision rehabilitation

RPE65-specific treatment in eligible patients

Research directions

Additional gene-based interventions

Cell therapies

Other experimental approaches

Gene-based, cellular, and neuroprotective strategies remain under study for many genotypes.

Slide 59 · Integrated clinicopathologic reasoning

Symptoms

Retinal pattern

Functional phenotype

Genetic cause

Night blindness suggests rod dysfunction.

Progressive constricted fields support diffuse photoreceptor involvement.

Pigmentary migration, arteriolar attenuation, and disc pallor reflect chronic retinal degeneration.

Slide 60 · Teaching case: Progressive night blindness

Hypothetical teaching case

Hypothetical case: Adolescent with difficulty walking in dim light and slowly narrowing side vision.

Central acuity remains useful; Family history is initially unrevealing.

Question: Which photoreceptor population is most likely to be impaired first?

Slide 61 · Teaching case: Retinal dystrophy plus hearing loss

Hypothetical teaching case

Hypothetical case: Young adult with night blindness and sensorineural hearing impairment.

Retinal examination suggests generalized pigmentary degeneration.

Question: Which category of inherited disease must be evaluated?

Slide 62 · Teaching case: Central impairment precedes nyctalopia

Hypothetical teaching case

Hypothetical case: Early color difficulty and photophobia, followed later by peripheral symptoms.

Full-field ERG shows disproportionately impaired cone responses.

Question: Does this sequence favor classic rod–cone RP or cone–rod dystrophy?

Slide 63 · Pathogenesis: The core causal chain

Genetic defect

Photoreceptor / RPE dysfunction

Cell death

Morphologic + visual loss

Inherited defects can impair rod/cone and RPE function.

Photoreceptor loss drives progressive loss of visual sensitivity.

Secondary retinal atrophy and pigment migration produce classic morphology.

Slide 64 · Diagnosis: The core evidence chain

History / pedigree

Structure / function

Genetic testing

Integrated diagnosis

Clinical history and pedigree establish the suspected phenotype.

Fundus examination, fields, OCT/FAF, and ERG provide complementary evidence.

Molecular testing identifies genotype when an interpretable causal variant is found.

Slide 65 · Key discriminators to retain

Night blindness with field constriction indicates rod-predominant dysfunction.

Bone-spicule pigmentation is secondary and may be absent early.

Syndromic clues—especially hearing or multisystem findings—must not be overlooked.

A molecularly defined treatment for one genotype is not treatment for all RP.

Slide 66 · Selected sources and scientific provenance

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 29, p 1206.

GeneReviews: Nonsyndromic Retinitis Pigmentosa Overview (NCBI Bookshelf NBK1417).

National Eye Institute: Retinitis Pigmentosa (2025).

U.S. Food and Drug Administration: LUXTURNA prescribing/indication information.