Introduction
The hereditary retinal dystrophies are a group of disorders that exert their major effect on the retinal pigment epithelium–photoreceptor complex and choriocapillaris to cause a range of visual symptoms. In individuals with a retinal dystrophy, mutation in different genes (genetic heterogeneity) can cause the same clinical phenotype. In addition, mutations in the same gene can cause different phenotypes (phenotypical heterogeneity). A monogenetic retinal dystrophy can develop at any age and the genetic abnormality can usually be determined using modern techniques. Identifying the precise mutation aids genetic counselling and can facilitate enrolment in a clinical trial.
Generalized photoreceptor dystrophies
Retinitis pigmentosa
Genetics:
typical retinitis pigmentosa (RP) is a group of retinal dystrophies initially mainly affecting the rod photoreceptor cells and subsequently cones (rod–cone dystrophy). It can be sporadic or inherited as AD, AR, or X-L; many cases are due to mutation in the rhodopsin gene. X-L has the worst prognosis with severe visual loss by the 4th decade; AR and sporadic cases have a more favourable course with retention of central vision until the 5th or 6th decade or later and AD disease has the best outlook.
Diagnosis
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Presentation : decreased peripheral and night vision; age of onset is variable.
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Signs : (a) mid-peripheral RPE atrophy and intraretinal perivascular ‘bone-spicule’ pigmentary changes together with mild arteriolar narrowing ( Fig. 15.1A ), (b) gradual increase in density and extent of the pigmentary change, (c) gliotic ‘waxy’ pallor of the optic discs ( Fig. 15.1B ), (d) the macula may show atrophy, epiretinal membrane formation or CMO.
Fig. 15.1
Retinitis pigmentosa: (A) intraretinal mid-peripheral ‘bone-spicule’ pigmentary changes, (B) ‘waxy’ disc pallor.
( Figure 15.1A courtesy of P. Saine.)
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Electroretinogram (ERG) : reduced scotopic rod and combined responses in early disease; later, photopic responses reduce and eventually the ERG is extinguished.
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Electro-oculogram (EOG) : subnormal with an absence of the light rise.
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Perimetry : small mid-peripheral scotomas gradually coalesce, leaving a tiny central island (‘tunnel vision’), that may eventually be extinguished.
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Ocular associations : (a) posterior subcapsular cataract, (b) open angle glaucoma, (c) myopia, (d) keratoconus, (e) Coats disease, (f) disc drusen.
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Atypical RP : either closely related to typical RP or representing incomplete forms of the disease (e.g. cone–rod dystrophy, sector RP, RP sine pigmento).
Treatment:
associations such as cataract and glaucoma are amenable to treatment; CMO may respond to systemic acetazolamide.
Important systemic associations
RP, often atypical, may be associated with the following:
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Bassen–Kornzweig syndrome (abetalipoproteinaemia) : AR lipoprotein abnormality with malabsorption of fat-soluble vitamins causing failure to thrive followed by severe spinocerebellar ataxia. Blood microscopy shows ‘thorny’ red cells (acanthocytosis) ( Fig. 15.2A ). Treatment with large doses of vitamins A, D, E and K may prevent visual loss.
Fig. 15.2
Systemic associations: (A) acanthocytosis in Bassen–Kornzweig syndrome, (B) polydactyly in Bardet–Biedl syndrome.
(From Salmon JF, Kanski’s Clinical Ophthalmology: A Systematic Approach , 9th edition. Oxford, UK: Elsevier; 2020.)
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Refsum disease : AR enzyme deficiency resulting in phytanic acid accumulation; there are distinct infantile and adult types. Early detection and a diet low in phytanic acid can arrest progression of the potentially severe neurological and other features.
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Kearns–Sayre syndrome : mitochondrial inheritance; chronic progressive external ophthalmoplegia associated with systemic problems (see Chapter 19 ).
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Bardet–Biedl syndrome : genetically heterogeneous condition with systemic features including mental handicap, polydactyly ( Fig. 15.2B ); fundus often shows a bull’s-eye maculopathy due to cone–rod dystrophy.
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Usher syndrome : AR, but genetically heterogeneous; accounts for approximately 5% of all cases of profound deafness in children and approximately half of all cases of combined deafness and blindness.
Progressive cone dystrophy
Definition:
an usually sporadic dystrophy predominantly affecting the cone system. In some cases, there is no evidence of rod dysfunction, whereas in others rod dysfunction subsequently develops but cone deficiency still predominates (cone–rod dystrophy).
Diagnosis
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Presentation : in 2nd to 4th decades with impaired central and colour vision.
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Signs : the macula may show (a) virtually normal appearance, (b) nonspecific pigmentary changes or (c) bull’s-eye configuration ( Box 15.1 , Fig. 15.3A ); geographic atrophy subsequently ensues with VA of 6/60 or worse.
Box 15.1
Other causes of bull’s-eye macular appearance
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Chloroquine maculopathy
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Advanced Stargardt disease
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Fenestrated sheen macular dystrophy
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Benign concentric annular macular dystrophy
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Bardet–Biedl syndrome
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Lipofuscinosis
Fig. 15.3
Cone dystrophy: (A) bull’s eye appearance, (B) FAF showing annular pattern concentric with the fovea.
( Figure 15.3B courtesy of Chris Barry, Lions Eye Institute, Perth, Australia.)
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ERG : photopic responses are subnormal or unrecordable and flicker fusion frequency is reduced, but rod responses are preserved until late.
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EOG : normal to subnormal.
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FAF : is often the key diagnostic test showing various annular patterns concentric with the fovea ( Fig. 15.3B ).
Leber congenital amaurosis
Definition:
severe AR condition affecting the retina, presenting in childhood. It is the most common genetic cause of visual impairment in children and at least 20 different forms have been identified, each with slightly different symptoms and speed of progression.
Diagnosis
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Presentation : perinatal night blindness and poor peripheral vision leading to blindness, associated with nystagmus or roving eye movements.
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Signs : (a) absent or sluggish pupillary light reflexes, (b) mild pigmentary retinopathy may be seen initially, followed by (c) coloboma-like fundus lesions ( Fig. 15.4A ), optic atrophy, severe arteriolar narrowing and macular pigmentation.
Fig. 15.4
Leber congenital amaurosis: (A) coloboma-like macular atrophy in late disease, (B) ‘oculodigital’ syndrome.
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‘ Oculodigital syndrome’ : constant rubbing of the eyes causing enophthalmos is characteristic ( Fig. 15.4B )
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ERG : usually nonrecordable even in early cases.
Stargardt disease and fundus flavimaculatus
Definition:
Stargardt disease and fundus flavimaculatus (FFM) are variants of the same disease, characterized by diffuse accumulation of lipofuscin within the RPE. Commonest form of macular dystrophy. Inheritance is usually AR with a mutation in the ABCA 4 gene; mutations in at least two other genes. Symptoms may be disproportionate to visible fundus changes.
Diagnosis
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Presentation : in the 1st and 2nd decades, occasionally later, with gradual impairment of central vision. Some patients may remain asymptomatic until late, especially with predominantly peripheral changes (FFM pattern).
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Maculopathy : (a) the macula may be normal initially and then show nonspecific mottling or an oval ‘snail-slime’ or ‘beaten-bronze’ appearance ( Fig. 15.5A ), with (b) progression to geographic atrophy or bull’s-eye maculopathy.
Fig. 15.5
Stargardt disease: (A) ‘beaten-bronze’ maculopathy, (B) pisciform flecks, (C) FA showing generalized ‘dark choroid”, (D) OCT showing RPE and retinal atrophy, sparing the macula.
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