Hereditary Dystrophies

8/2/2019 Hereditary Dystrophies

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ELECTRORETINOGRAM

I. ERG RESPONSESA. Definition

Mass response evoked from entire retina by a brief flash of light Measures panretinal response i.e. does not necessarily correlate with VA Occurs secondary to transretinal movement of ions induced by the light stimulus

B. ISCEV Standard ERG (5 different responses allow interpretation)1.Scotopic: Dark adapted (30 mins)

Rod response (scotopic) Maximal combined response Oscillatory potentials

2.Photopic: Light adapted (10 mins) Single flash cone response (photopic) 30-Hz flicker responses

II. ERG CHARACTERISTICSA. Normal ERG is biphasic

a-wave: photoreceptor response (initial, fast, negative waveform) b-wave: Muller and BPC (next, slower, positive waveform)

i. directly dependent on functional photoreceptorsii. magnitude = photoreceptor integrity

Duration usually less than 150 msec


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Duration: usually less than 150 msec

B. Maximal combined rod and cone response Bright flash in dark adapted state Maximally stimulates both cones and rods Waveform: large a- and b-wave with oscillatory potentials superimposed on ascending

b-wave

C. Oscillatory potentials Isolated by filtering out slower ERG components Result of feedback interactions between Amacrine and interplexiform cells Reflects primarily cone function

Reduced in ischaemic states and some forms of CSNB

IV. PHOTOPHIC ERG (LIGHT-ADAPTED)A. Single flash cone response

Obtained by maintaining patient in light-adapted state Stimulus: bright white flash Rods suppressed by light adaptation and do not contribute to waveform Results in an a-wae and b-wave with small oscillations

B. 30-Hz flicker responses Rods can respond to stimulus up to 20 Hz (8Hz clinical situations) Stimulus: 30 Hz measures cone response only Normally shows a b-wave implicit time of less than 32 msec Allows easy assessment of ERG timing Elicited up to 50 Hz after which individual responses not recordable (critical

flicker fusion)


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VI. OTHER ERG TYPESA. Early receptor potentials and c-wave1.ERP

Small response occurring with no detectable latency before the a-wave Evoked by an intense flash Correlated with electrical charge in cell membrane during conversion of

lumirhodopsin to metarhodopsin

60-80% of amplitude generated by cones Used primarily in research to measure visual pigment bleaching and

regeneration

2.C-wave Late response occurring 2-4 seconds after stimulus in dark adapted eye Generated by RPE

B. Focal (Foveal) ERG Stimulate only foveal or parafoveal cones Suppress rods and prevent interference with bright light Rapidly flickering stimulus used so that several hundred small ERG responses

can be summated Used primarily when clinical findings do not correlate with patients VA Provides objective information on the presence/absence of macular disease

C. Multifocal ERG Topographic map of the retina Cone-generated responses that subtend 25o radially from fixation Can determine macular dysfunction in patients with stable and accurate

fixation e g early detection of hydroxychloroquine toxicity


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VII. APPLICATIONSA. Diagnosing and following generalised retinal dystrophies

1.Evaluation of macular disease peripheral involvementa. RPb. Retinitis punctate albescensc. Lebers congenital amaurosisd. Choroideraemiae. Gyrate atrophyf. Achromatopsiag. CSNBh. Cone dystrophiesi. Goldman-Favre syndromej. XL Juvenile Retinoschisisk. Disorders mimicking RP

2.Distinguish diffuse disease vs focal diseasea. Diffuse: hereditary dystrophy, drug toxicity

i.

Reduced amplitude and cause delayed and abnormal waveforms(reflects gross malfunction)

b. Focal: BVO, regional uveitic damagei. Reduced amplitude in proportion to area of damage with normal

waveform and timing

B. Assess family members for known hereditary disease1.X-Linked conditions e.g. choroideremia

a. Female carriers show mosaic patternb ERG shows subtle abnormalities


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F. Cataract or corneal opacity may act as a diffuser of light occasionally resulting in supernormalERG


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Interpreting ERG results

Nonrecordable/Extinguished ERG (Reduced a and b waves)

LCA Retinal aplasia RP TRD OAO TRD Metallosis Diffuse unilateral subacute neuroretinitis (DUSN) Drugs (phenothiazines, chloroquine) Cancer and Metastatic associated retinopathyNegative wave form (normal a wave, reduced b wave)

CSNB XL Retinoschisis CRVO/CRAO Myotonic Dystrophy Duchenne Muscular Dystrophy Oguchis disease Quinine Toxicity Enhanced S-cone (Goldmann-Favre) Some auto-immune retinopathies OA or CRAO (transynaptic degeneration from RGC to

BPC)

Abnormal cone and rod b-wave amplitudes

Cones more affected than rods

Cone rod degenerations/dystrophies (AD AR XR)

Abnormal/Nonrecordable Photopic ERG

Often mild rod ERG abnormality

Cone degenerations Achromatopsia XL blue-cone monochromatism XL cone dystrophy with tapetal-like sheen Abnormal/Nonrecordable Scotopic ERG

Abnormal photopic b-wave ERG

Rod-cone degenerations (RP) LCA Choroideraemia Chorioretinitis (variable) Secondary RP (storage disease) Progressive retinitis punctate albescensNon recordable rod ERG

Abnormal dark-adapted FERG

Normal to near-normal photopic ERG

CSNB Early RP (rare) which is progressiveReduced oscillatory potentials

Increased risk of developing severe PDRNon-specific

Metallic FB Chorioretinitis (acute or old)


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ELECTRO-OCULOGRAM

I. PRINCIPLESA. Standing potential

1.Positive voltage at cornea (6-10mV)2.Generated across RPE cell3.Activation of PR leads to changes in ionic composition of subretinal space4.Exposure of steady light to dark-adapted eye leads to slow increase in standing potential

across RPE

5.Light response reaches peak 5-10 mins after onseta. Affected by movement artefact and electrical drift

B. Electro-oculography1.Indirectly measures the standing potential2.Electrodes placed on skin at canthi3.Voltage between them recoded as patient looks left to right over 30o4.Amplitude

a. Dominated by the rod system (mass response)b. Proportional to the actual voltage across the eye5.International standard technique

a. Placementb. Time of adaptationc. Light intensity (=pupil dilation)

C. Arden (Light-Dark) ratio1.Light peak/Dark trough x 100

N l 1 85 185% ( id bl i ti )


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III. OTHER RPE TESTSA. ERG c-wave1.Cornea-positive wave

2.Appears 1-5 secs after onset of light stimulus3.Represents hyperpolarisation of apical RPE in response to decrease in subretinal K+4.Difficult to record (too fast for EOG, too slow to avoid artefact)5.Correlates clinically with EOG

B. Fast oscillation1.Cornea-negative wave2.Appears 1-2 mins after light stimulus3.Represents delayed effect from K+ changes in subretinal space4.Generated across basal RPE membrane5.Probably involves chloride conductance pathways6.Does not always mirror EOG in disease7.May show changes in cystic fibrosis

C. Non-photic responses1.

Changes in standing potential induced by chemicals2.IV hyperosmolar solution, acetazolamide or sodium bicarbonate

3.Lead to depolarisation of basal RPE membrane4.Provide information independent of photoreceptor activity


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VISUALLY EVOKED POTENTIALS

I. PRINCIPLESA. Visually evoked cortical potential

1.Generated by the occipital visual cortex2.Stimulated by light flashes or patterned stimuli (alternating checkerboard or stripes on

TV monitor)

3.Response to many alternations or flashes is recorded and averaged4.Use of checkerboard stimulus preferable when eye is optically correctable

a. Cortex very sensitive to sharp edges and contrastb. Relatively insensitive to diffuse light

5.Determines macular function6.Minimal peripheral retinal input7.Reflects visual endpoint i.e. any abnormality between retina and cortex

B. Normal pattern-evoked VECP1.Recorded with electroencephalogram electrodes2.Often the inion (back of occiput) is compared to locations to right and left3.Characterised by 2 negative (N75 and N135) and 2 positive (P100) peaks4.Amplitude and implicit times depend on check size, contrast and alternation frequency5.Absolute amplitudes: difficult due to variability among normal individuals6.Implicit times: less variable and more reliable7.P100 latency is most useful clinical indicator

C. Interpretation1.Optic nerve dysfunction: decreased amplitude, increased P100 latency2 D l l i l d f ti i d l d VEP ON di


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PSYCHOPHYSICAL TESTING

I. PRINCIPLESA. Electrophysiological testing

1.Objectively measures cell layers and cell types2.Does not always allow testing of localised responses3.May not be sensitive to small degrees of visual dysfunction

B. Pyschophysical tests1.Types

a. VAb. VFc. Dark adaptationd. Colour visione. Contrast sensitivity

2.Advantagesa. Exceedingly sensitiveb. Always subjectivec. Usually not tissue specific

II. DARK ADAPTATIONA. Principles

1.Measures the absolute thresholds of cone and rod sensitivitya. Human eye sensitive to range of 10-11 log unitsb C l t iti t ERG i f l t t


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a. Tritan: Blue-sensitive (short; 414-424nm)b. Deuteran: Green-sensitive (middle; 522-539nm)c. Protan: Red-sensitive (long; 549-570nm)5.Integrative cells (retina, higher visual centres) organised primarily to recognise contrasts

between light or colours

B. Classification1.Red-green colour deficiency2.Blue-yellow colour deficiency

C. Tests1.Anomaloscope

a. Most accurate instrument for classifying congenital red-green deficiencyb. Not widely usedc. Patient views split screen

i. Match yellow appearance of one half by mixing varying proportions ofred and green light in the other half

ii. Abnormal proportions used to make the match2.

Pseudoisochromatic platesa. Ishihara

i. Coloured numbers or figures standing out from background ofcoloured dots

ii. Defects result in either no pattern or alternative pattern seen based onbrightness rather than hue

iii. Can be done quicklyiv. Sensitive for screening congenital protan and deuteran defectsv. Not effective in classifying the deficiencyi R i bl hit li ht ( i i li ht)


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DIFFUSE PHOTORECEPTOR DYSTROPHIES

I. RETINITIS PIGMENTOSAA. Aetiology

1.Definition Clinically and diverse group of diffuse retinal (RPE and NSR) dystrophies TRIAD: nyctalopia, progressive VF loss and abnormal ERG Rod-cone dystrophy: initially predominantly affects rods then cones Prevalence: 1 in 5,000 (most common hereditary retinal dystrophy) Gene mutation: rhodopsin gene

B. Inheritance1.AR (20%)

Most common, severely reduced VA and night blindness occur early Incidence increased if including families with several affected siblings (multiplex

RP) or parent consanguinity

17 genetic types identified: 12 cloned2.AD (10-20%)

Least severe, gradual onset of RP, typically adult life with variable penetrance Late onset cataract, less severe VA loss 16 genetic types identified: 14 cloned

Rh d i t ti ild f f CSNB i i t d ith d


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CRB1

C. Clinical features1. Symptoms

TRIAD: Bilateral involvement (may be asymmetric), peripheral VF loss andnyctalopia

Night vision: decreased, often night blindness Peripheral vision: decreased Central vision: decreased, early or late Colour vision: intact until late

2. Signs TRIAD: bone-spicule pigmentation, arteriolar attenuation (earliest sign) and

waxy optic disc pallor (least reliable)

Peripheral pigment clumps: perivascular, often bone-spicule (may be absent) RPE: depigmentation, atrophy, unmasking of choroidal vessels Macula: TRIAD of Atrophy, ERM and CMO

DIFFERENTIAL DIAGNOSIS (DISC)

Drug toxicity

Quinine/hydroxychloroquine

Phenothiazine

Infective

Syphillis

C it l b ll

Vascular

OAO

CRAO

Scarring

Chronic CSR

L PRP


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Macular signs peripheral changes

RP sine pigmento

Absence or paucity of pigment accumulation

Retinitis punctate albescens

AR variant; whitish-yellow spots, mostly at equator

Usually sparing macula and associated with arteriolar attenuation

More radial pattern vs. fundus albipunctatus

Sector RP

AD variant; generally symmetric involvement of 1-2 sectors e.g. inferior quadrants

Slow progression; many stationary

Unilateral RP

Rare; usually sporadic; Diagnosis requires normal ERG in fellow eye

E. Management1.Investigations

Fundus photographs ERG: early - reduced scotopic (rod and combined) response; late reduced

photophic response and eventually extinguished ERG (not diagnostic); female

carrier mild reduction or delay in b-wave response

EOG: subnormal (absent light rise) DA: prolonged useful in early cases when diagnosis uncertain; female carriers

of XL disease often have abnormal results

VF: progressive loss, usually ring scotoma, progresses to small central field


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Acetazolamide PO: CME Future: gene replacement therapy, retinal cell transplantation, humoral factors

II. ASSOCIATED SYSTEMIC DISEASE (SECONDARY RP)A. Refsum disease (Phytanoyl-COA Hydroxylase deficiency)

AR TRIAD: Increased serum Phytanic acid, Peripheral neuropathy, Palpitations Investigation: elevated fasting serum phytanic acid or reduced phytanic acid

oxidase activity in cultured fibroblasts

RP: often without bone spicules, nyctalopia, reduced ERG Infantile: dysmorphic facies, mental handicap, hepatomegaly and deafness Adult: cerebellar ataxia, polyneuropathy, deafness, anosmia, cardiopathy and

ichthyosis

Treatment: low-phytanic acid, low-phytol diet (minimise milk products, animalfats and green leafy vegetables)

B. Bassen-Kornzweig syndrome (Hereditary Abetalipoproteinaemia) AR (usually without bone spicules) TRIAD: Abetalipoproteinaemia, Acanthocytosis, Ataxia Abetalipoprotein not synthesised: fat malabsorptioon and fat-soluble vitamin

(AEK) deficiency

GI symptoms: failure to thrive, fat intolerance, steathorrhea Neurological: spinocerebellar ataxia Ocular: nyctalopia, progressive restriction of EOM, ptosis, strabismus,

nystagmus

I i i


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Systemic TRIAD: Obesity (truncal), Polydactyly, Hypogonadism; puffy handswith indistinct knuckles, renal anomalies (urethral reflux with pyelonephritis

and kidney damage), Learning disability (special education support)

Differential Diagnosis of RP and Renal disease

Alport syndrome Alstrom syndrome Familial juvenile nephronophthisis (AR) Senior-Loken syndrome (AR) Type II membranoproliferative glomerulonephritis


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E. Usher syndrome Accounts for 5% of profound deafness in children and 50% of combined deaf-

blindness Prevalence: 3 per 100,000 Inheritance: AR (type 1 and 2); 11 types with known chromosome location (9

cloned genes)

Protein: present in hair cells of inner ear and photoreceptor cells Fundus: salt and pepper pigmentation, OA Ocular: miosis, cataract, orbital fat atrophy Systemic: premature ageing beginning in infancy, dwarfism, skeletal

abnormalities, deafness, photosensitivity, mental disability and early death

Classification Incidence Onset Deafness

Type 1 75% 1st

decade Congenital, profound, vestibular dysfunction

Type 2 23% 2nd

decade Congenital, partial, normal vestibular function

Type 3 2% Late Progressive hearing loss and vestibular dysfunction

Differential Diagnosis of Ocular Associations and Hearing Loss

Systemic disease and RP

Alport syndrome

Alstrom syndrome

Cockayne syndrome

l i d l i h i i l

Uveitis

Congenital syphilis

Congenital rubella

VKH


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Systemic: asymptomatic till age 8-15 months; progressive renal failure, growthretardation, renal rickets and hypothyroidism

Treatment: cysteamine (reacts with cysteine to form a mixed disulphide thatcan leave the lysosome) may be beneficial

III. LEBER CONGENITAL AMAUROSISA. Aetiology

1.Definition Infantile to early childhood form of RP Commonest genetic cause of visual impairment in infants and children Severe mutations result in LCA i.e. rod-cone dystrophy; mild mutations lead to

later-onset cone-rod dystrophy

Primary LCA: 9 known monogenic forms Complicated LCA: systemic disease resulting in severe LCA (seizures, CNS and

mental detioration, usually with an obvious decline in school performance)

Prognosis: very poor2.Inheritance

Usually AR Genetically very heterogenous: 14 gene loci identified

a. CEP290: 15%b. GUCY2D: 12%

%


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Differentiates LCA from dystrophic disease (reduced ERG with age) Requires repeating at a later stage as there is maturation of the normal ERG

response in the first year of life e.g. delay ERG till 6 months or repeat after thistime

C. Associations1.Ocular

High refractive errors: usually hyperopia

Strabismus Keratoconus Keratoglobus Cataract

2.Systemic Mental disability (most children have normal intelligence) Deafness Epilepsy and CNS anomalies Renal anomalies Skeletal malformations Endocrine dysfunction

DIFFERENTIAL DIAGNOSIS


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IV. CONE DYSTROPHIESA. Aetiology

1.Definition No evidence of rod dysfunction or predominant progressive cone deficiency

(cone-rod dystrophy)

2.Inheritance Sporadic: most common Mutations described in 12 genes: AD usually or XL less often AD:

a. GUCA1A (guanylate cyclase activator 1A) calcium-binding proteindefect expressed in photoreceptor OS (6p21.1)

b. GUCY2D (17p13.1) XLR:

a. Adult-onsetb. Tapetal retinal reflex: bright green or golden fundus reflexc. Mizuo-Nakamura phenomenon: fundus appearance changes with DA

B. Clinical1.Symptoms

Bilateral gradual reduced central and colour vision in 2nd-4th decade f d h l (d bl d ) d h h b (l h


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Bardet-Biedl syndrome

Hallervorden-Spatz syndrome

LCA

Batten disease (Neuronal Ceroid Lipofuscinosis)

AD olivopntocerebellar ataxia

Stargardt disease (advanced)

Cone and cone-rod dystrophy

Fenestrated sheen macular dystrophy

Central areolar choroidal dystrophy

Toxic retinopathy (chloroquine, clofazimine)

C. Cone-Rod Dystrophies1.Definition

Cones affected proportionately more than rods and both are abnormal Depends on mutation severity: severe mutations result in LCA whilst less severe

result in cone-rod dystrophy

Associated Genes

ABCA4: Stargardt ALMS1: Alstrom SCA7: AD spinocerebellar ataxia GUCY2D: LCA CRX: RP or LCA

2.Clinical Expanding central scotomata Progressive severe VA loss Nyctalopia and dyschromatopsia Late: bone-spicule hyperpigmentation and fundus atrophy


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MACULAR DYSTROPHIES

I. STARGARDT DISEASE (JUVENILE MACULAR DEGENERATION)A. Aetiology

Definition Most common hereditary macular dystrophy (7% of all retina dystrophies) Common cause of central VA loss < 50 years Bilateral, symmetric, progressive condition Triad: macular atrophy, flecks and dark choroid Fundus flavimaculatus: variant of same disease

a. Often presents in adulthood, may be an incidental finding, visionmay not be impaired

b. Flecks: widely scattered throughout fundus Inheritance

AR: most common AD pedigrees reported Gene mutations:

a. ABCA4: 1p21-22; encodes retina specific ATP-binding cassette(ABC) transporter protein expressed by rod OS

b. STGD4c. ELOVL4: AD; 6q; photoreceptor-specific component of FA

elongation

d. RDS/peripherin


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C. Management Investigations

AF: may be present OCT: characteristic thinning of PR layer FFA: dark choroid or midnight fundus (blockage of choroidal

fluorescence secondary to increased lipofuscin in RPE) present in 80%

ICG: hypofluorescent spots ERG: typically normal in early stages; normal to sub-normal photopic;

normal scotopic

EOG: subnormal in advanced Prognosis

Maculopathy: poor VA loss: rapid progression beyond 6/12; stabilizes at 6/60 CNV: uncommon

II. VITELLIFORM DEGENERATIONSA. Best disease (Juvenile-onset vitelliform macular dystrophy)

Definition Second most common macular dystrophy EOG is always abnormal but the retina may initially appear normal


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Serous detachment

Other Signs CNV: 20% of patients Subretinal haemorrhage Hyperopia esophoria/esotropia

Investigations EOG: always abnormal showing a severe loss of light response during all

stages; typically < 1.5 and often near 1.1; abnormal in carriers

ERG: normal OCT: material within RPE FFA: corresponding hypofluorescence due to blockage; hyperfluorescence

if CNV

Treatment No effective treatment Prognosis: good until 5th decade; VA loss due to CNV, scarring or GA CNV: PDT, Anti-VEGF, laser

B. Adult-onset Definition

Most common adult-onset vitelliform disorder Belongs to pattern dystrophy group Foveal lesions: smaller, do not show similar evolutionary changes


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Definition

Generic term including several retinal dystrophies Exhibit various morphological yellow, orange or grey macular deposits Lesions associated with accumulation of lipofuscin at RPE level Clinical pattern can vary among affected family members or even between

the 2 eyes of one patient and can evolve from one pattern to another

Inheritance Usually present in isolation; typically in midlife Described in association with

a. Myotonic dystrophyb. Kjellin syndrome: spastic paraplegia and dementiac. Pseudoxanthoma elasticum

Common Characteristics

AD inheritance: mostly associated with RDS/peripherin gene mutations

Variable expression Bilateral symmetrical involvement Relatively benign course: small risk of CNV Normal ERG Occasionally abnormal EOG: consistent with diffuse RPE disorder


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B. Clinical Symptoms

Central vision is good if drusen are discrete and extrafoveal Increased risk of AMD

Signs Drusen

a. Radiating pattern: yellow-white, elongated (2nd decade), oftenconfluent

b. Typically extend beyond vascular arcade and nasal to the discc. Honeycomb pattern develops

RPE degeneration, GA and occasional CNV (4th-5th decade) Investigations

FA: hyperfluorescent (more numerous than seen clinically) ERG: normal EOG: subnormal (advanced disease)

V. SORSBY (PSEUDOINFLAMMATORY) MACULAR DYSTROPHYA. Aetiology

Definition Also known as hereditary haemorrhagic macular dystrophy Very rare condition; bilateral VA loss in 5th decade from subfoveal CNV


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OTHER MACULAR DYSTROPHIES

Benign concentric annular MD

AD; mild VA loss in adult

Bulls eye maculopathy

Paracentral ring scotoma

Annular window defect on FA

Dominant CMO

AD; gene locus on 7p

1st

-2nd

decade with gradual VA loss

Bilateral CMO (INL)Flower-petal leakage on FA

Unresponsive to systemic CAI

Sjogren-Larsson syndrome

Neurocutaneous disorder: congenital ichthyosis, spasticity, convulsions, mental

disability, early death

AR: 7p11; fatty aldehyde dehydrogenase defiency

Bilateral glistening yellow-white crystalline macular deposits (?pathognomonic)

Cataract, colobomatous microphthalmos, RP

VEP: abnormal

Familial ILM dystrophy

AD; presentation in 3rd

-4th

decadeGlistening inner retinal surface

ERG: reduced b-wave


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CHOROIDAL DYSTROPHIES

I. DIFFUSE DYSTROPHYA. Choroideraemia

1.Definition Progressive, diffuse degeneration of choroid, RPE and PR Underlying defect probably in rod photoreceptors

2.Inheritance XLR with locus on Xq21.2 (CHM gene): stop mutation prevents normal

production of Rab escort protein (REP-1) localised to RPE

Female carriers: 50% of sons develop choroideraemia; 50% of daughtersare carriers

3.Symptoms Nyctalopia: 2nd-3rd decade Constricted VF Female carrier: VA, peripheral VF and ERG are usually normal

4.Signs Mid-peripheral RPE abnormalities (may mimic RP) RPE atrophy: central and peripheral spread (foveal sparing till late) End-stage: choroidal vessels over bare sclera, vascular attenuation and OA Female carrier: mild, patchy moth-eaten peripheral RPE atrophy and

mottling


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Enzyme deficiency: ten-fold elevation of ornithine levels in plasma, urine,CSF and aqueous humour which is toxic to RPE and choroid

2 clinical subtypes:a. Pyridoxine (vitamin B6) responsive: less sever and more slowly

progressive clinical course

b. Pyridoxine non-responsive2.Inheritance

AR with gene locus on 10q26 More common in Finland

3.Symptoms Myopia and nyctalopia: 1st-2nd decade

4.Signs Mid-peripheral depigmented spots associated with diffuse pigmentary

mottling

Generalised hyperpigmentationof remaining RPE differentiates it fromchoroideraemia

Characteristic scalloped and sharply demarcated circular/oval areas of CRatrophy numerous crystals at posterior pole Coalescence of atrophic areas with peripheral and central spread (foveal

sparing till late)

Vascular attenuation and vitreous degeneration, Other: myopia, astigmatism, early-onset cataracts (PSC), CMO or ERM

5.Investigations


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Demarcated macular atrophy of RPE and choriocapillaris Normal full-field ERG reponse Differences in onset and progression Differentiated from toxoplasmosis, AMD or Bulls eye maculopathy

A. Central Areolar Choroidal Dystrophy (CACD) AD with gene locus on 17p RDS/peripherin gene mutations affecting arginine residue Gradual central VA loss: 3rd-4th decade Prognosis: poor with SVL by 6th-7th decade Non-specific foveal granularity RPE atrophy and loss of choriocapillaris at macula GA atrophy with prominence of large choroidal vessels CNV: rare

B. North Carolina Macular Dystrophy Very rare non-progressive condition: stabilizes in teenage years VA usually better than anticipated clinically (6/6 to 6/60) AD with complete penetrance but highly variable expression MCDR1 gene on 6q16


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INNER RETINAL AND VITREORETINAL DYSTROPHIES

I. JUVENILE X-LINKED RETINOSCHISISA. Aetiology

1.Definition Bilateral progressive maculopathy peripheral retinoschisis (50%) Splitting of NFL from rest of NSR (vs. acquired retinoschisis where splitting

occurs at OPL)

Differential diagnosis

Congenital

Degenerative peripheral retinoschisis

No known inheritance pattern

SecondaryVitreoretinal traction

Myopic degeneration with staphyloma

RVO

2.Inheritance XL i.e. mainly affects males


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Subretinal exudate RD (rare)

Traumatic rupture of foveal schisis

C. Management1.Investigations

OCT: schisis spaces in middle layers; assess progression of maculopathy ERG: normal in isolated maculopathy; negative waveform i.e. decreased b-

wave amplitude and normal a-wave in peripheral schisis

EOG: normal in isolated maculopathy; subnormal in advanced peripherallesions

FA: mild window defect but NOT leakage2.Treatment

Avoid contact sports and boxing Treatment of associated refractive error, strabismus and amblyopia LVA and genetic counselling Topical CAI: may reduce foveal thickening and cyst-like spaces

II. STICKLER SYNDROMEA. Aetiology

1.Definition Hereditary arthro-ophthalmopathy Disorder of collagen tissue


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Ocular Features

High non-progressive myopia (most common)

Early childhood

Vitreous liquefaction (hallmark)

Optically empty vitreous (STL1) except for vitreous veils

i.e. retrolenticular and circumferential equatorial

membrane extends into vitreous cavity

Fibrillary and beaded vitreous (STL2)

RetinaRD: 50% in 1

stdecade (secondary to multiple or giant

tears, lattice degeneration and PVR)

RPE hyperplasia, vascular sheathing, sclerosis

Lens

Presenile cataract: frequently non-

progressive peripheral cortical wedge or

fleck opacities

Ectopia lentis: uncommon

Glaucoma (5-10%)

Congenital angle anomaly

Neuro-ophthalmological (less frequent)Ptosis

Strabismus

III. WAGNER SYNDROMEA. Aetiology

1.Definition Erosive vitreoretinopathy Similar changes to Stickler but not associated with systemic abnormalities

2.Inheritance AD with gene locus on 5q12-q14


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IV. FAMILIAL EXUDATIVE VITREORETINOPATHYA. Aetiology

1.Definition Slowly progressive condition (Criswick-Shepens syndrome) Failure of vascularisation of the temporal retinal periphery Similar to ROP but NOT associated with low birth weight and prematurity

2.Inheritance Type 1: AD (chromosome 11) with high penetrance and variable expression Type 2: XLR (NDP gene involved in Norrie disease)

B. Clinical1.Signs

Vitreous: degeneration and peripheral vitreo-retinal attachmentsassociated with areas of white without pressure

Vessels: abrupt termination in scalloped pattern at temporal equator;tortuosity, telangiectasia and neovascularisation

Ridge: fibrovascular proliferation and vitreoretinal traction Temporal dragging: macula and disc

2.Differential Diagnosis ROP Coats

3.Complications


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NR2E3 at 15q23: ligand-dependent transcription factorB. Clinical

1.Symptoms Nyctalopia and decreased central VA in childhood

2.Signs Pigmentary changes: along vascular arcades or midperiphery nummular

(circular) yellow pigment clumps (rather than bone spicule)

Cystoid maculopathy: without leakage on FA or schisis Goldmann-Favre: vitreous degeneration and peripheral retinoschisis

3.Differential Diagnosis RP XLRS

4.Investigations ERG: S-cone hyperfunction; severe M- and L-cone impairment; non-

recordable rod function VF: peripheral to mid-peripheral loss

VI. NORRIE DISEASE1.Definition

XLR: NDP gene mutation encoding for the protein norrin Characteristics: globular, severely dystrophic retina with pigmentary


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SYSTEMIC DISEASES WITH PIGMENTARY RETINOPATHIES

Systemic Disease

Autosomal Recessive

Bardet-Biedl syndrome

Usher syndrome

Familial juvenile nephronophthisis (renal-retinal dysplasia)

Bietti corneoretinal crystalline dystrophy

Friedrich ataxia (spinocerebellar ataxia)

Homocystinuria

MannosidosisMucopolysachharidosis (Heparan sulphate accumulation only is

associated with RP)

Hurler (IH) Sheie (IS) Sanfilippo (III)Batten disease (neuronal ceroid lipofuscinosis)

Haltia-Santavuori: infantile Jansky-Bielschowsky: late infantile( onset 2-4 years) Lake-Cavanagh: early juvenile (onset 4-6 years) Spielmeyer-Vogt: juvenile (onset 6-8 years)Peroxisome disorders

Neonatal adrenoleukodystrophy Refsum disease Zellweger syndrome (cerebrohepatorenal)

Autosomal Dominant

Alagille syndrome (Arteriohepatic dysplasia)

Charcot-Marie Tooth

Myotonic dystrophy (Steinert disease)

Oculodentodigital dysplasia

Olivopontocerebellar atrophy

Stickler syndrome (arthro-ophthalmopathy)

Waardenburg syndromeWagner syndrome

XL Recessive

Incontinentia pigmenti (Bloch-Sulzberger syndrome)

Alport syndrome

Mucopolysachharidosis II (Hunter)

PelizaeusMerzbacher disease

Mitochondrial Disorders(Myopathy)Kearns-Sayre syndrome

CPEO , atypical RP, heart block

NARP syndrome: neurogenic muscle weakness, ataxia

and RP

MELAS: mitochondrial encephalomyopathy, lactic

acidosis and stroke


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Syndrome

Ocular

SystemicAnterior Posterior

Alagille syndrome

(Arteriohepatic dysplasia)

Posterior embryotoxon

Axenfeld anomaly

Myopia

RP Intrahepatic cholestatic

syndrome

Congenital heart disease

Flattened facies and bridge

of nose

Bony abnormalities

Charcot-Marie Tooth RP and OA Degeneration of lateralhorn of spinal cord

Myotonic dystrophy (Steinert

disease)

Christmas tree cataract Retinal degeneration

Pattern dystrophy

ERG: subnormal/abnormal

Muscle wasting

Oculodentodigital dysplasia Congential cataract

Coloboma

Thin nose with hypoplastic

alae and narrow nostrils

Abnormality of 4th

and 5th

fingersHypoplastic dental enamel

Olivopontocerebellar

atrophy

Possible external

ophthalmoplegia

Retinal degeneration (peripheral

and/or macular)

Cerebellar ataxia

Stickler syndrome (arthro-

ophthalmopathy)

Progressive myopia Myopic retinal degeneration

RD common

ERG: subnormal/abnormal

Joint hypermobility

Arthritis


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Syndrome

Ocular


Bardet-Biedl syndrome RP with severely diminished

or extinguished ERG

Progressive VF loss

Obesity

Polydactyly

Hypogenitalism

Mild mental disability

Bietti corneoretinal

crystalline dystrophy

Crystals in limbal

cornea

Yellow-white crystals limited

to posterior pole

Round subretinal pigmentConfluent loss of

choriocapillaris on FA

Friedrich ataxia Retinal degeneration and OA Spinocerebellar degeneration

Limb incoordination

Nerve deafness

Homocystinuria Myopia

Lens subluxation or

dislocationGlaucoma

Fine pigmentary or cystic

retinal degeneration

Marfanoid appearance

Cardiovascular abnormalities

(thrombosis)Mental disability

Mannosidosis Storage material in retina Macroglossia

Large head and ears, flat nose

Skeletal abnormality

Hepatosplenomegaly

Mucopolysaccharidosis I H Early corneal RP and OA Gargoyle facies


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Syndrome

Ocular


Incontinentia pigmenti

(Bloch-Sulzberger

syndrome)

Conjunctival pigmentation

Cataract

Nystagmus

Strabismus

Patchy mottling

Falciform retinal fold

Cicatricial RD

OA

Death in male fetus

Triphasic dermopathy: skin

pigmentation (lines and

whorls)

Alopecia

Dental anomalies

CNS involvement

Alport syndrome Anterior lenticonous

Posterior polymorphous

corneal dystrophy

Cataract

Yellowish punctate flecks

Normal ERG

Glomerular BM collagen type

IV abnormality (CRF)

Sensorineural deafness

Mucopolysachharidosis II

(Hunter)

No corneal clouding Retinal arteriolar

narrowing

ERG: subnormal

Coarse facies

Short stature

Mild clinical course

Mental disability

PelizaeusMerzbacher

disease

Possible RP with absent

foveal reflex

Inflantile progressive

leukodystrophy

Cerebellar ataxia and limb

spasticity

Mental disability

Kearns Sayre syndrome Progressive external

ophthalmoplegia

Atypical RP with normal to

abnormal ERG

Heart block


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Ptosis


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Disorder DeficiencyOcular


Gangliosidosis GM1

Infantile (Type I) All 3 Beta-galactosidase isoenzymes(hexosaminidase A, B and C)

Corneal cloudingTortuous

conjunctival vessels

High myopia

CRS in 50%Pendular nystagmus

OA

Papilloedema

Hurler-like faciesKyphosis

Hypotonia

Congestive heart failure

Severe cerebral degeneration

Death by age 2

Gangliosidos GM2

Tay-Sachs disease (Type I) Hexosaminidase A (most common

ganglioside storage disease)

CRS in 100% by 6

months

nystagmus

OA after 1 year

Blind by 2 years

More common if Ashkenazi Jewish descent (100x) or

French Canadian

Progressive neurological deterioration: paralysis and

dementia

Death by age 2-4

Sandhoff disease (Type II) Hexosaminidase B Indistinguishable Indistinguishable

Mucolipodosis

Type 1 (Sialidosis) Corneal clouding

Punctate lens

opacities

CRS

OA

Severe (< age 2): severe Hurler-like facies,

hepatosplenomegaly, deafness, death in early childhoood

Late-onset (< age 7): myoclonus and seizures; normal life

span

Niemann-Pick

Type A: acute neuronopathic Corneal clouding

(subtle)

CRS in 50% Severe CNS deterioration

Massive hepatosplenomegalyDeath by age 4

Type B: chronic neuronopathic (Sea-

blue histiocyte syndrome)

CRS

Bulls eye

maculopathy

Hepatosplenomegaly

Lungs and BM involvement

CNS disease does NOT occur

Longer survival


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ALBINISM

Type C: chronic neuropathic Gaze palsy

Abnormal eye

movements

NO CRS

Others

Farber disease Ceramidase Nodular cornealopacity

Pingueculum-like

lesion

CRS Hoarseness, aphoniaDermatitis

Lymphadenopathy

Renal and cardiopulmonary disease

Gaucher disease

(chronic non-neuropathic adult)

CRS

Mid-peripheral white

lesions

NO CNS involvement

Liver, spleen, LN, skin and BM involvement

Disease Inheritance Ocular Systemic

OCA1A AR: 11q14-21

TYR (tyrosinase) gene Tyrosinase-

negative or inactive(complete)Hair bulb incubation test negative:

incubate with L-DOPA; reliable only >

5 years

Iris: thin, pale blue, characteristic pink reflex

(diaphanous)

Frequently myopic astigmatism; positive anglekappa; strabismus

VA: < 6/60; photophobia

Nystagmus: pendular, horizontal, increases in bright

light; lessens with age; head nodding

Foveal hypoplasia; lack of perimacular arcades;

prominent choroidal vessels

White hair and skin t hroughout life

Skin does NOT tan

All forms of OCA: increased risk of skin neoplasia (BCC and SCC)before 4

thdecade

Temporal nerve fibres decussate rather than project to ipsilateral

LGB (absent stereopsis)

Asymmetric VEP: predominance in response to monocular

stimulation; absence of misrouting excludes diagnosis of albinism

OCA1B AR: 11q14-21 TYR gene Tyrosinase Complete albinism at birth White hair and skin at birth


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CONGENITAL AND STATIONARY RETINAL DISEASE

(Yellow variant) positive; hair bulb positive (minimially

active)

Iris transillumination

Photophobia

Nystagmus

Albinotic fundal reflex

Increasing pigmentation with yellow-red hair and light normal skin

that tans

OCA2 AR: 15q11.2-q12

OCA2 gene (formerly P gene)

Most prevalent worldwideHigh frequency inAfrican population

Iris: blue, yellow or brown (age and race dependent)

Pigment: pupil and limbus

Transillumination minimal to absent in dark-skinnedModerate-severe VF defect

VA: 6/24 -6/36; photophobia

Hair and skin colour might be white at birth, darkening over time,

but typically born with some pigment

Hyperkeratosis and freckling in exposed areas

OCA3

(Red, Rufous or

temperature

sensitive)

AR: 9p; TYRP1 (tyrosinase-related

protein 1) gene

Occurs mainly in African descent

Iris: blue to brown

Transillumination

Nystagmus; strabismus

Retinal hypopigmentation

Mild vision loss

Skin and hair red brown

Freckles and areas of hypopigmentation

OCA4 AR: MATP (membrane-associated

transporter protein) gene

Same as OCA2 Same as OCA2

OA1

(Netteship-Falls)

XLR: Xp22.3

OA1 gene

(uncommonly AR)

Marked iris and choroidal pigment deficiency

Nysagmus; myopic astigmatism

Foveal hypoplasia

Tessellated or mosaic fundus

VA: 6/18 to 6/120

Carrier female: mosaic fundus

Normal pigmentation elsewhere

Melanocytes: normal in size and number in eyes and skin (skin

biopsy)

Giant melanocytes: abnormal melanosomes within melanocytes

Occasional hypopigmented cutaneous macules

More lightly pigmented than relatives

Chediak-Higashi AR: 1q42-43

LYST gene

Mild OCA (silver hair)

Diminished uveal and retinal pigmentation

Photophobia; nystagmus

Recurrent infections: early death

Neutropenia, anaemia, thrombocyopaenia

Lymphoproliferative syndrome (accelerated phase):

hepatosplenomegaly, lymphadenopathy, leukaemia

Hermansky-Pudlak AR: 10q2

HPS1 gene

High frequency in Puerto Rico

Iris: blue-gray to brown (age and race dependent);

normal or cartwheel effect

Mild to severe nystagmus and photophobiaMild-moderate VA loss

Platelet bleeding disorder (mild)

Pulmonary interstitial fibrosis, granulomatous colitis, renal failure

Hair and skin colour: variableLysosomal storage disease of reticulo-endothelial system: Ceroid

storage


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I. COLOUR VISION (CONE) ABNORMALITIES

Classification of Hereditary Colour Vision Defects

Trichromatism

(use abnormal proportions of 3 primary colours)

Normal

Deuteranomalous

Protanomalous

Tritanomalous

XR

XR

AD

92

5

1

0.0001

Dichromatism

(match any colour with only 2 primary colours)

Deuteranopia

Protanopia

Tritanopia

Abnormal green sensitive cone pigment: confuse red and

green

Abnormal red-sensitive cone pigment: confuse red and

green

Abnormal blue-sensitive cone pigment: confuse blue and

yellow

XR

XR

AD

1

1

0.001

Monochromatism(Achromatopsia)

Presentation: congenital nystagmus, poorcentral VA, photoaversion and hemeralopia (day

blindness0

ERG: absent cone response; relatively normalrod response

DA: no cone plateau or cone-rod break

Typical (rod monochromatism)

Atypical (blue-cone monochromatism)

True colour blindness: no cone function (shades of grey)VA: 6/18 to 6/60

Nystagmus: present in childhood; improves with age

Misdiagnosed as ocular albinism

Genes: CNGA3, CNGB3, GNAT2

Only blue-sensitive cones; reduced in number and normally

absent from fovea

Clinically indistinguishable from rod monochromatism: FH,

CV or ERG required

AR

XR

0.0001

?

II. NIGHT VISION (ROD) ABNORMALITIESA. CSNB with Normal fundi

1.Definition Life-long stable abnormality of scotopic vision (abnormal rods)


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Presentation: nystagmus, decreased VA or myopia In spite of poor rod vision, both amount and rate of rhodopsin regeneration following a bright light bleach are normal indicates communication failure between proximal PR end and BPC vs. RP which involves PR loss

2.Inheritance XL: most common; Xp11 AD: typified by French Nougaret pedigree; rhodopsin gene mutation AR

3.Clinical AD: non-progressive nyctalopia alone AR and XL: VA normal to occasionally 6/60, significant myopia (most cases of reduced VA, tilted disc and temporal pallor) and

nystagmus

Fundus: usually normal except for myopic changes4.Investigations

ERG: loss of retinal on-response with negative ERG DA: typically 2-3 log units above normal

ERG Classification

Schubet-Bornshein

abnormalityAR

and XL

Negative ERG (most common)

Maximal dark-adapted response: large a-wave but absent or much reduced b-wave

Photopic cone ERG also shows some abnormalities

Complete: very poor rod function;

psychophysical thresholds mediated by

cones

Incomplete: some rod function; elevated DA

threshold

Riggs abnormality AD Much rarer

Reduction in amplitude but normal waveform of the photopic response

which, under scotopic conditions, manifested only a slight increase in

amplitude.

B. CSNB with Abnormal fundi1.Fundus albipunctatus


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Disorder of visual pigment regeneration: mutation in gene for 11-cis-retinol dehydrogenase Recovery of normal rhodopsin levels after intense light exposure may take several hours Nyctalopia with minimal rod ERG Dark adaptation for several hours results in normal ERG VA and CV typically good, though often not normal Fundus: yellow-whitish dots in posterior pole sparing fovea radiating towards periphery Differential diagnosisa. Retinitis punctate albescens: RP variant, arteriolar narrowing and severely depressed ERG that does not recover with DA

b. Fleck retina of Kandori: larger, patch like flecks with less nyctalopia2.Oguchi disease

Very slow DA but rhodopsin regeneration is normal Physiologic defect: retinal circuitry rather than visual pigments Mutations: arrestin on 2q (Japanese) and rhodopsin kinase (European) Mizuo-Nakamura phenomenon: golden-yellow i ridescent sheen after light exposure that disappears after DA

3.Enhanced S-cone Photopic ERG response resembles scotopic Signs: ring of RPE degeneration often seen in region of vascular arcades, CMO ERG: greatly magnified blue-cone signal; very week red-green cone function; rod function deficient May overlap with Goldmann-Favre syndrome

Documents

Hereditary Dystrophies