seminar on generalised choroidal dystrophies and hereditary vitreoretinal degenerations including albinism

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Seminar: Generalised Choroidal Dystrophies, Hereditary Vitreoretinal Degenerations, and Albinism

Source: Kanski's Clinical Ophthalmology, 10th Edition - Chapter 15

Part 1: Introduction and Basic Science

General Framework

The inherited retinal degenerations ('retinal dystrophies') are a group of disorders exerting their major effect on the RPE-photoreceptor complex and choriocapillaris, causing a range of visual impairment. Hereditary retinal diseases are now the leading cause of blindness certification in the working-age population (age 16-64) in the UK.

Key genetic principles:

Mutations in more than 250 genes have been linked to inherited retinal degenerations (full gene table: RetNet database)
Genetic heterogeneity: mutations in different genes can cause the same clinical phenotype
Phenotypic heterogeneity: the same gene can cause different phenotypes
Genetic sequencing is mandatory in every patient with a suspected IRD

Photoreceptor Anatomy

Feature	Rods	Cones
Number	120 million	6 million
Distribution	Dense outside macula	Concentrated at fovea
Function	Night/peripheral/motion vision	Day, colour, central vision
Types	One type	L (red), M (green), S (blue, ~2%)
Dysfunction symptoms	Nyctalopia, field loss	Poor central VA, dyschromatopsia

Each photoreceptor has an outer segment (light-sensitive, contains visual pigment discs) and an inner segment (metabolic, contains mitochondria). Disc renewal - disc shedding from the outer segment tip and phagocytosis by RPE - is continuous and critical; failure underpins many dystrophies.

Part 2: Generalised Choroidal Dystrophies

2.1 Choroideremia

Inheritance: X-linked (gene: CHM)

Males predominantly affected; clinically significant disease is almost exclusively in males
Female carriers: mild patchy peripheral RPE mottling; VA, fields and ERG usually normal
A contiguous extended gene deletion can also cause deafness and mental handicap

Pathology: Progressive, diffuse degeneration of the choroid, RPE and photoreceptors

Symptoms: Nyctalopia from adolescence → reduced peripheral vision → central vision loss (late)

Fundus signs - staged progression:

Fig. 15.35 Choroideremia: (A) Female carrier showing mild peripheral RPE changes; (B) Advanced male disease; (C) FAF - characteristic scalloped hypo-AF border; (D) FA; (E) ICGA

Fig. 15.35 Choroideremia: (A) Female carrier with subtle peripheral mottling; (B) advanced male disease with chorioretinal atrophy spreading centrally but fovea relatively spared until late; (C) FAF; (D) FA; (E) ICGA

Carriers: patchy peripheral RPE atrophy and mottling (Fig. 15.35A)
Males (early): mid-peripheral RPE abnormalities resembling RP
Males (progress): chorioretinal atrophy spreading peripherally AND centrally
End-stage: isolated choroidal vessels coursing over bare sclera

Key differentiator from primary retinal dystrophies: the fovea is relatively spared until late, allowing reasonable central vision well into middle age.

Investigations:

FAF: characteristic scalloped border with hypoAF centrally and hyperAF at border
ERG: progressively subnormal

Prognosis: Very poor. Most retain some vision until the sixth decade, then severe visual loss.

Genetics/Therapy: CHM gene therapy trials are ongoing. Gene identification is important for trial enrolment.

2.2 Gyrate Atrophy

Inheritance: AR (gene: OAT, chromosome 10q)

Pathophysiology: Deficiency of ornithine aminotransferase → elevated ornithine in plasma, urine, CSF and aqueous humour. This accumulation is toxic to the RPE and photoreceptors.

Symptoms: Myopia and nyctalopia in adolescence → gradual worsening

Fundus signs:

Fig. 15.36 Gyrate atrophy: (A) early disease - sharply demarcated circular/oval chorioretinal atrophic areas; (B) advanced disease - coalescent atrophy

Fig. 15.36 Gyrate atrophy: (A) early disease - sharply demarcated circular/oval areas of chorioretinal atrophy; (B) advanced disease with peripheral and central coalescence

Mid-peripheral depigmented spots + diffuse pigmentary mottling (asymptomatic phase)
Sharply demarcated circular/oval chorioretinal atrophic areas - highly characteristic
Glistening crystals at the posterior pole
Coalescence with progressive peripheral and central spread; fovea spared until late
Posterior subcapsular and posterior sutural cataracts by the second decade
Vitreous degeneration, CMO and ERM may also occur

Investigation:

Serum ornithine levels (confirms diagnosis)
FA: sharp demarcation between areas of choroidal atrophy and normal choriocapillaris
ERG: subnormal early → extinguished late

Treatment:

No cure
Arginine-restricted diet can slow progression (difficult adherence)
Vitamin B6 (pyridoxine) supplementation reduces plasma ornithine in some patients
Cataract surgery may provide transient visual improvement

Prognosis: Legal blindness around age 50

2.3 Central Areolar Choroidal Dystrophy (CACD)

Inheritance: Genetically heterogeneous, typically AD

Presentation: Third to fourth decades, gradual central visual impairment

Progression:

Non-specific foveal granularity
Well-circumscribed RPE atrophy + loss of choriocapillaris
Slowly expanding geographic atrophy with prominence of large choroidal vessels

Investigation: OCT, FAF

Treatment: None available. Prognosis for central vision is poor.

2.4 Progressive Bifocal Chorioretinal Atrophy

A rare AD condition with progressive chorioretinal atrophy beginning in the first months of life as a temporal and nasal focus, which gradually extends to involve the entire fundus. Nystagmus and poor vision are early features.

Part 3: Retinitis Pigmentosa and Atypical Forms

3.1 Retinitis Pigmentosa (RP) - Classic

Definition: Clinically and genetically diverse group of inherited diffuse retinal degenerative diseases initially predominantly affecting rod photoreceptors, with subsequent degeneration of cones and RPE.

Prevalence: Most common hereditary retinal degeneration - 1:3000 to 1:5000

Inheritance patterns:

Pattern	Severity	Notes
AD	Best prognosis	Most due to rhodopsin gene mutations
AR	Intermediate	Genetically most heterogeneous
X-linked	Most severe (6/60 by 5th decade)	90% due to RPGR gene mutations
Sporadic	Variable	May be any of the above

Genetic defect: Mutations in >100 gene loci for non-syndromic RP. About half of affected individuals have no identified molecular genetic abnormality. Gene defects affect: (a) phototransduction cascade, (b) retinoid cycle, (c) photoreceptor structure, (d) other biological functions of photoreceptor/RPE.

Classic diagnostic triad:

Bone-spicule retinal pigmentation (perivascular, mid-peripheral)
Arteriolar attenuation
'Waxy' disc pallor

Symptoms (in order of onset):

Nyctalopia and dark adaptation difficulties (early, often presenting symptom)
Peripheral visual field loss
Photopsia (not uncommon)
Reduced central vision (late, or earlier if cataract develops)
Colour vision affected as cones involved

Additional fundus signs:

Fig. 15.38 - juvenile retinoschisis with classic spoke-like maculopathy (foveal schisis), inner leaf defects, vitreous veils, and peripheral silvery dendritic figures

(This image is actually from juvenile retinoschisis - see section below)

Bilateral mid-peripheral intraretinal perivascular bone-spicule pigmentary changes
RPE atrophy
Macula: atrophy, ERM, CMO (detected in ~15% on OCT)
Optic disc drusen occur more commonly in RP patients
Myopia is common

X-linked carrier females:

Normal fundi OR golden-metallic ('tapetal') reflex at macula
Centrifugal hyperautofluorescent lines on FAF (most striking feature)
Small peripheral bone-spicule patches

RP sine pigmento: Absence/paucity of pigment - not a separate disease; every RP patient is initially sine pigmento as bone spicules develop secondary to degeneration.

Complications: Posterior subcapsular cataract (common), open-angle glaucoma (3%), PVD

Investigations:

FAF: abnormal perimacular ring of hyperAF (increased lipofuscin from RPE dysfunction) + patchy hypoAF in mid-periphery. Distinguishes RP from normal in 95% of cases as a stand-alone test
OCT: macular oedema in ~15%, macular atrophy in ~40%
Visual fields: mid-peripheral scotomas → ring scotoma → tunnel vision → extinguished
Full-field ERG: reduced scotopic rod response in early disease; eventually extinguished (sensitive but rarely needed clinically once diagnosis established)
Dark adaptation test: prolonged (useful in equivocal early cases)
Genetic analysis: identifies specific mutation; enables genetic counselling and trial enrolment

Management:

Luxturna (voretigene neparvovec): approved gene therapy for RPE65 mutations
No other specific commercial treatment available; gene therapy trials ongoing
Annual follow-up for treatable complications (cataract, CMO)
CMO: carbonic anhydrase inhibitors (topical or systemic)
Cataract surgery is safe and appropriate

3.2 Atypical RP - Syndromic Forms (20-30% of cases)

Usher Syndrome (AR, genetically heterogeneous)

Accounts for ~5% of all profound deafness in children; ~50% of all combined deafness and blindness
Type I (MYO7A-associated, 75%): profound congenital sensorineural deafness + severe RP with extinguished ERG in first decade; vestibular dysfunction
Type II (most common in ophthalmic practice): moderate hearing loss, later onset RP
Type III (2%): progressive hearing loss + late-onset RP
Cochlear implants can treat Type I deafness; gene therapy trials (MYO7A) underway

Bassen-Kornzweig Syndrome (Abetalipoproteinemia, AR)

Dysfunctional fat and fat-soluble vitamin (A, D, E, K) absorption
Failure to thrive → severe spinocerebellar ataxia
Blood film: acanthocytosis ('thorny' red cells)
Fundus: scattered white dots → RP-like changes by end of first decade
Other: ptosis, ophthalmoplegia, strabismus, nystagmus
Treatment: vitamin supplementation + low-fat diet

Refsum Disease (AR) - Adult/Infantile Forms

Phytanic acid accumulation throughout body
Skin changes (ichthyosis), neurological and visceral features
Retinal changes: RP-like or 'salt and pepper'
Cataract, optic atrophy may occur
Treatment: low phytanic acid diet retards progression

Bardet-Biedl Syndrome (AR, genetically heterogeneous)

Mutations in genes for proteins involved in non-motor cilia function (ciliopathy)
Systemic features: learning disability, polydactyly, obesity, renal abnormalities, hypogonadism
Retinal: rod-cone dystrophy with bull's eye maculopathy pattern
Management: multidisciplinary; gene-specific therapy under investigation

Neuronal Ceroid Lipofuscinoses (NCL)

Group of lysosomal storage diseases with accumulation of ceroid lipofuscin
Features: progressive neurodegeneration, dementia, seizures, retinal degeneration

3.3 Enhanced S-cone Syndrome and Goldmann-Favre Syndrome

Gene: NR2E3 (encodes ligand-dependent transcription factor) - AR, variable expressivity

Pathophysiology: Hyperfuction of S-cones + severe impairment of M- and L-cones; non-recordable rod function. Goldmann-Favre is the severe variant of the same gene mutation.

Symptoms: Nyctalopia in childhood ± hemeralopia; decreased colour vision (tritan axis preserved)

Signs:

Pigmentary changes along vascular arcades or mid-periphery, with round pigment clumps
Cystoid maculopathy (without fluorescein leakage)
Vitreous degeneration and peripheral retinoschisis

OCT: Disrupted foveal lamination with thickened subfoveal ellipsoid zone

ERG: No rod response; scotopic maximum = photopic (both show S-cone waveform)

Prognosis: Variable; ~30% have VA 6/36 or worse by late middle age

Part 4: Hereditary Vitreoretinal Degenerations

4.1 Juvenile X-linked Retinoschisis

Inheritance: X-linked (gene: RS1, Xp22.13 - encodes retinoschisin)

Pathophysiology: Retinoschisin is secreted by photoreceptors; involved in intercellular adhesion. The basic defect involves splitting of the retinal nerve fibre layer from the rest of the sensory retina (contrast with acquired retinoschisis which splits at outer plexiform layer).

Epidemiology: Rare congenital disease; presents in boys age 5-10 years with difficulty reading; less commonly squint/nystagmus in infancy.

Carrier females: Asymptomatic, no retinal changes

Signs:

Fig. 15.38 - Juvenile retinoschisis with spoke-like 'bicycle wheel' maculopathy, inner leaf defects, vitreous veils, and dendritiform peripheral silvery figures; OCT showing inner nuclear/outer plexiform layer cysts

Fig. 15.38 Juvenile retinoschisis: (A) 'Bicycle wheel' spoke-like foveal schisis; (B) large oval inner leaf defects; (C) 'vitreous veils'; (D) peripheral silvery dendritic figures; (E) OCT with cysts in inner nuclear/outer plexiform layers; (F) ERG with negative a-wave and reduced b-wave

Foveal schisis (most common): spoke-like striae radiating from foveola with cystoid changes - the "bicycle wheel" appearance
White drusen-like dots and pigment variation
Peripheral schisis: infero-temporal quadrant predominantly; inner layer (ILM + nerve fibre layer) develops oval defects → coalesce → 'vitreous veils' (retinal blood vessels floating in vitreous)
Silvery peripheral dendritic figures, vascular sheathing, retinal flecks

Complications: Vitreous/intra-schisis haemorrhage, neovascularisation, subretinal exudation, rarely RD (rhegmatogenous or tractional)

Investigations:

FAF: spoke-like patterns, central hypoAF with surrounding hyperAF
OCT: cystic spaces in inner nuclear and outer plexiform layers
ERG: characteristic negative ERG - reduced b-wave amplitude with preserved a-wave (reflects inner retinal dysfunction); scotopic more affected than photopic
Genetic testing: RS1 mutations

Prognosis: VA deteriorates in first two decades then may stabilise until fifth/sixth decade. Vitreous haemorrhage and RD are the main causes of significant visual loss.

Treatment:

Carbonic anhydrase inhibitors (topical dorzolamide or oral acetazolamide) may reduce foveal schisis
Vitreoretinal surgery for RD or non-clearing vitreous haemorrhage
RS1 gene therapy trials are underway

4.2 Stickler Syndrome (Hereditary Arthro-ophthalmopathy)

Genetics: Genetically heterogeneous collagen connective tissue disorder; 8 sub-groups; mutation identified in 95% of cases

STL1 (AD, most common): COL2A1 mutations; membranous vitreous type
STL2 (AD): COL11A1 mutations; beaded vitreous type
STL3 (AD): COL11A2; no ocular features (non-ocular type)
STL4-8 (AR): extremely rare

Epidemiology: ~1 in 7500-9000. Most common inherited cause of retinal detachment in children

Systemic features:

Mid-facial hypoplasia
Pierre-Robin sequence: micrognathia, cleft palate, glossoptosis
Bifid uvula
Joint hypermobility, spondyloepiphyseal dysplasia, early-onset osteoarthritis
Sensorineural or conductive deafness (recurrent otitis media)

TIP: Consider Stickler syndrome in any infant with cleft palate + deafness + joint hypermobility + myopia

Ocular features (three characteristic):

High myopia (congenital, non-progressive)
Vitreoretinal degeneration with extremely high rate of retinal detachment
Cataract

Vitreous signs:

STL1: optically empty vitreous + retrolenticular membrane + circumferential equatorial vitreous membranes
STL2: fibrillary and beaded vitreous appearance

Retinal signs:

Radial lattice-like degeneration with RPE hyperplasia
Risk of giant retinal tear and RD - leading cause of childhood blindness in this syndrome

Management:

Prophylactic laser/cryotherapy to lattice degeneration and tears
Prompt vitreoretinal surgery for RD
Multidisciplinary: hearing aids, orthodontics, orthopaedics, genetics
Annual retinal surveillance from diagnosis

4.3 Wagner Syndrome (VCAN-related Vitreoretinopathy)

Inheritance: AD (gene: VCAN - versican)

Note: Erosive vitreoretinopathy is now known to be the same disorder

Key distinction from Stickler: No systemic abnormalities

Signs:

Low to moderate myopia
Optically empty vitreous cavity (lacking structural elements - reduced 'scaffolding')
Greyish-white avascular strands/membranes extending into vitreous
Circumferential ridge-like condensation at or anterior to retinal periphery
Progressive peripheral chorioretinal atrophy
Deficient peripheral retinal vasculature
Nyctalopia (commonly troublesome); progressive field constriction
Cataract (common in younger adults); glaucoma

Investigations:

FA: non-perfusion due to choriocapillaris loss
ERG: initially normal → reduction of scotopic b-wave → diffuse abnormality

Complications: Retinal detachment in up to 50%, often before age 15

4.4 Snowflake Vitreoretinal Degeneration

Inheritance: AD (gene: KCNJ13) - rare; some similarities to Wagner syndrome

Stages (I-IV) - characteristic snowflake deposits:

Stage I: Early; fibrillar vitreous condensation
Stage II: Snowflake deposits developing (minute crystalline yellow-white dots)
Stage III: Retinal vessel sheathing
Stage IV: Advanced with RPE changes

Prognosis: Retinal detachment less common than Wagner; prognosis usually very good

Part 5: Albinism

5.1 Introduction

Albinism is a genetically determined heterogeneous group of disorders of melanin synthesis affecting either:

Eyes alone = Ocular albinism (OA)
Eyes + skin + hair = Oculocutaneous albinism (OCA)

OCA is subdivided into:

Tyrosinase-negative (complete; no melanin at all)
Tyrosinase-positive (incomplete; variable melanin)

Molecular genetics: 7 subtypes of non-syndromic OCA (OCA 1-7)

Key unifying mechanism: Different mutations act through a common pathway involving reduced melanin synthesis in the eye during development, leading to:

Foveal hypoplasia
Iris transillumination
Nystagmus
Misrouting of optic nerve fibres at the chiasm (excess crossing)

Important: Patients with oculocutaneous albinism have increased risk of cutaneous basal cell and squamous cell carcinoma - sun protection is mandatory.

5.2 Tyrosinase-negative OCA (OCA Type 1)

Fig. 15.44 Tyrosinase-negative OCA: (A) white hair, pale skin; (B) diaphanous iris translucency on retroillumination; (C) 'pink-eyed' appearance; (D) severe fundus hypopigmentation with foveal aplasia

Fig. 15.44A - OCA type 1: white hair, pale skin in tyrosinase-negative OCA patient

Gene: TYR (chromosome 11q14) - encodes tyrosinase; AR inheritance

Phenotype: Incapable of synthesising ANY melanin - white hair, very pale skin throughout life

Ocular signs:

VA usually <6/60 due to foveal hypoplasia
Pendular horizontal nystagmus - typically increases in bright illumination; lessens with age
Diaphanous, translucent iris - 'pink-eyed' appearance (entire iris diaphanous on retroillumination)
Fundus: totally lacks pigment; conspicuously large choroidal vessels; foveal hypoplasia with absence of foveal pit and poorly formed perimacular vascular arcades
Chiasmal misrouting: majority of fibres from each eye cross to the contralateral hemisphere (more than normal) - demonstrable with visual evoked potentials (asymmetric VEPs are the electrophysiological signature)
High refractive errors, positive angle kappa, squint, absent stereopsis

5.3 Tyrosinase-positive OCA (OCA Type 2)

Gene: OCA2 (chromosome 15q12) - plays role in tyrosine transport in melanosomes; AR; hundreds of mutations

Epidemiology: Most common form in Africa; accounts for one-third of cases worldwide

Phenotype: Synthesise variable amounts of melanin; hair may be white/yellow/red, darkens with age; skin pale at birth but usually darkens by age 2

Ocular signs:

VA usually impaired due to foveal hypoplasia
Iris may be blue or dark brown with variable translucency
Fundus: variable hypopigmentation
Nystagmus and refractive errors common

5.4 OCA Types 3-7

OCA type 3 (TYRP1 gene): seen especially in Black Africans
Types 4-7: extremely rare, reported in single families

5.5 Systemic Associations of Albinism

Chediak-Higashi syndrome: Rare AR disorder - mutation of a lysosomal regulator protein → failure of phagolysosome formation → recurrent pyogenic infections (especially Staphylococcus); partial albinism, neurological features, lymphoma-like accelerated phase

Hermansky-Pudlak syndrome: AR lysosomal storage disease with platelet dysfunction (easy bruising, excessive bleeding); in some cases pulmonary fibrosis and granulomatous colitis with bleeding - potentially life-threatening

Waardenburg syndrome: AD condition with:

White forelock, poliosis
Synophrys ('monobrow')
Sensorineural deafness
Sometimes limb abnormalities
Iris heterochromia

5.6 Ocular Albinism (OA)

Inheritance: X-linked (OA1; GPR143 gene)

Key distinction: Skin and hair pigmentation is normal (or near-normal); ocular features predominate

Carrier females: Normal vision but show characteristic iris translucency and a mottled/mud-splattered fundal appearance (due to X-inactivation mosaic)

Males: Full ocular phenotype - nystagmus, foveal hypoplasia, reduced VA, iris transillumination, fundus hypopigmentation, chiasmal misrouting

Part 6: Investigations Summary

Electrophysiology

Condition	ERG pattern
RP (early)	Reduced scotopic rod response, combined response
RP (advanced)	Extinguished all responses
XLRS (juvenile retinoschisis)	Negative ERG (reduced b-wave, preserved a-wave)
Enhanced S-cone syndrome	No rod response; scotopic max = photopic (both S-cone shaped)
Gyrate atrophy (early)	Subnormal
Choroideremia (advanced)	Subnormal to extinguished
Albinism	Asymmetric VEPs (chiasmal misrouting)

Multimodal Imaging

Modality	Key use
FAF	RP (perimacular ring), choroideremia (scalloped borders), XLRS
OCT	Macular oedema/atrophy in RP; cystic spaces in XLRS; foveal schisis
FA	Choroidal atrophy in gyrate, Wagner, choroideremia
Full-field ERG	Sensitive for early/equivocal RP; diagnostic for XLRS
Dark adaptation test	Early RP, equivocal cases
VEP	Albinism (misrouting)

Part 7: Management Principles

Gene Therapy - Current Status

Condition	Gene	Therapy Status
RP with RPE65 mutations	RPE65	Luxturna - FDA/EMA approved, commercially available
Choroideremia	CHM	Phase II/III trials ongoing
XLRS	RS1	Phase I/II trials
Usher Syndrome Type I	MYO7A	Trials ongoing

Medical/Supportive Management

RP: Vitamin A palmitate (historically used, evidence debated); annual review; low vision aids; genetic counselling
Gyrate atrophy: Arginine-restricted diet; Vitamin B6; cataract surgery
RP macular oedema: Topical/oral carbonic anhydrase inhibitors (acetazolamide)
XLRS macular schisis: Topical CAIs (dorzolamide) to reduce cystic spaces
Albinism: Tinted lenses/photochromic lenses for photophobia; refraction correction; low vision rehabilitation; mandatory sun protection (photocarcinogenesis risk); strabismus surgery

Genetic Counselling

All inherited retinal degenerations require:

Pedigree construction
Molecular genetic testing to identify causative mutation
Counselling regarding transmission risks
Identification of potential trial eligibility
Cascade testing of family members

Quick Reference: Key Differentials

Feature	Choroideremia	Gyrate Atrophy	RP
Inheritance	X-linked	AR	AD/AR/X-linked
Gene	CHM	OAT	>100 genes
Biochemical marker	None	Elevated ornithine	None
Atrophy pattern	From periphery, scalloped	Discrete oval areas coalesce	Mid-peripheral pigment
Foveal sparing	Until late	Until late	May be involved earlier
ERG	Subnormal → extinguished	Subnormal → extinguished	Rod reduced → extinguished
Treatment	Gene therapy (trial)	Low-arg diet, Vit B6	Luxturna (RPE65 only)

Source: Kanski's Clinical Ophthalmology: A Systematic Approach, 10th Edition, Chapter 15 - Inherited Retinal Degenerations. RetNet gene database lists all currently known IRD genes.

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