Chapter 44 Inherited retinal disorders

Michel Michaelides, Graham E. Holder, Anthony T. Moore

STATIONARY RETINAL DYSFUNCTION SYNDROMES

Introduction

The inherited retinal disorders are a clinically and genetically heterogeneous group of conditions: many become symptomatic in childhood, occurring as an isolated abnormality in an otherwise healthy child. Some are associated with systemic abnormalities (see Chapter 45). Most of the genes causing the major childhood retinal dystrophies have been identified: the genotype–phenotype relationship is complex. There is considerable genetic heterogeneity for individual clinical disorders, and mutations in a single gene may give rise to several different phenotypes. Despite this, these disorders can be usefully divided clinically according to whether they:

1. Are stationary or progressive

2. Exhibit predominantly rod or cone involvement.

Stationary disorders present at birth or in the early months of life and are best referred to as dysfunction syndromes. Progressive conditions, which typically present later, are termed dystrophies.

Stationary retinal dysfunction syndromes

These include the forms of stationary night-blindness (rod dysfunction syndromes) and the cone dysfunction syndromes (stationary cone disorders).

Stationary night-blindness (rod dysfunction syndromes)

There are three main forms of stationary night-blindness; in congenital stationary night-blindness (CSNB) the fundus is normal or shows myopic changes. Fundus albipunctatus and Oguchi’s disease have a distinctive fundus appearance.

Congenital stationary night-blindness

Clinical findings

CSNB is characterized by night-blindness, variable visual loss, and a normal fundus. It may be inherited as an autosomal dominant (AD), autosomal recessive (AR), or X-linked (XL) disorder.

The visual acuity is usually normal or mildly reduced in the AD form, whereas mild to moderate central visual loss is common in the AR and XL subtypes. Other features of XL and AR CSNB include moderate to high myopia, nystagmus, strabismus, and paradoxical pupil responses. Fundus examination is usually normal but some patients have myopic fundi and pale or tilted optic disks (Fig. 44.1). Patients with AD CSNB usually present with symptomatic night-blindness, but in XL and AR CSNB, patients usually present in infancy with nystagmus, strabismus, and reduced vision. Nystagmus is not invariable and some patients are not diagnosed until late childhood or adulthood. The diagnosis is easily missed without electroretinography (ERG). XL and AR CSNB may be further subdivided into complete and incomplete forms. This differentiation was originally proposed in XL disease using electrophysiologic and psychophysical criteria and was subsequently shown to reflect genetically distinct disorders.

Fig. 44.1 X-linked congenital stationary night-blindness. Tilted optic disk with myopic fundus.

International Society for Clinical Electrophysiology of Vision (ISCEV) standard ERGs should be performed. This may not be possible in infants in whom a modified protocol is used (see Chapter 8). Four main responses are defined: a rod-specific ERG and a bright flash response performed under scotopic conditions, and two measures of cone function, a 30 Hz flicker ERG and a single flash photopic ERG. Both complete and incomplete CSNB show a “negative ERG”: the photoreceptor-derived a-wave in the bright flash response is normal, but there is selective reduction in the inner nuclear derived b-wave, such that it is smaller than the a-wave, indicating predominantly inner retinal dysfunction. In complete CSNB there is no detectable rod-specific ERG and a profoundly negative bright flash response. Cone ERGs show subtle abnormalities reflecting ON bipolar cell dysfunction (Fig. 44.2). There is a detectable rod-specific ERG in incomplete CSNB, and a profoundly negative bright flash response. Cone ERGs are much more abnormal than in complete CSNB, reflecting involvement of both ON- and OFF bipolar pathways. They show the characteristic triphasic appearance in the flicker response (see Fig. 44.2).

Fig. 44.2 Congenital stationary night-blindness. The left hand column traces (A) show data from a patient with “incomplete” CSNB (iCSNB); the center traces (B) are from a patient with “complete” CSNB (cCSNB); the right hand column traces (C) are from a representative normal subject. In iCSNB the rod ERG (DA 0.01) is mildly subnormal. The bright flash response (DA 11.0) is electronegative, with a normal a-wave confirming normal photoreceptor function, but a profoundly reduced b-wave. The 30 Hz flicker ERG (LA 30 Hz) is markedly subnormal and clearly shows the delayed double peak characteristically seen in iCSNB. The photopic single flash ERG (LA 3.0) shows marked reduction in the b : a ratio with simplification of the waveform and loss of the photopic oscillatory potentials, shown on ON-/OFF- response recording (200 ms orange stimulus on a green background) to reflect involvement of both ON- (depolarizing) and OFF- (hyperpolarizing) cone bipolar cell pathways. The PERG (pattern electroretinogram) is mildly subnormal in keeping with mild macular dysfunction. In cCSNB there is no detectable DA 0.01 response and the profoundly electronegative DA 11.0 ERG confirms the site of the dysfunction to be post-phototransduction. The LA 3.0 response shows a distinctive broadened a-wave and a sharply rising b-wave with a reduced b : a ratio and lack of photopic oscillatory potentials. This appearance indicates marked dysfunction of cone ON- bipolar cell pathways but preservation of the OFF- pathways. The profoundly negative ON- response, with preservation of the ON- a-wave and loss of the ON- b-wave, accompanied by a normal OFF- response supports this proposal. The broadened trough of the 30 Hz flicker ERG with a sharply rising peak is a manifestation of the same phenomenon. The PERG is almost undetectable. Overall, the findings in cCSNB are those of loss of ON- pathway function in both rod and cone systems.

ERG evidence of inner retinal rod system dysfunction may also occur in AD CSNB but in association with normal ISCEV cone ERGs. In other cases of AD CSNB, ERG rod responses are attenuated with normal cone responses, but the standard bright flash response does not have a negative waveform.

Molecular genetics and pathogenesis

Autosomal dominant CSNB

Mutations in the genes encoding three components of rod-specific phototransduction have been reported in AD CSNB: rhodopsin, the α-subunit of rod transducin and the rod cyclic guanosine monophosphate (cGMP) phosphodiesterase β-subunit (PDEβ).

X-linked CSNB

Two causative genes (CACNA1F and NYX) have been identified accounting for most families with XL CSNB. Incomplete CSNB is associated with mutation in CACNA1F, which encodes the retina-specific α_1F-subunit of the voltage-gated L-type calcium channel. The expression of CACNA1F appears limited to photoreceptors and is prominent in the synaptic terminals. Most mutations are inactivating truncation sequence variants. The loss of functional channels impairs the calcium flux into rod and cone photoreceptors required to sustain tonic neurotransmitter release from presynaptic terminals. This results in the inability to maintain the normal transmembrane potential of bipolar cells, so the retina remains in a partially light-stimulated state, unable to respond to changes in light-levels.

Complete CSNB is associated with mutation in NYX, the gene encoding the leucine-rich proteoglycan nyctalopin. Leucine-rich repeats are believed to be important for protein interactions, with many of the mutations identified within these repeats. Nyctalopin is expressed in photoreceptor inner segments, outer and inner nuclear layers, and ganglion cells. Nyctalopin may guide and promote the formation and function of the retinal ON- pathway.

Several genotype–phenotype studies have been performed in individuals with either CACNA1F or NYX mutations. There is considerable inter- and intra-familial phenotypic variability associated with CACNA1F mutations, even with an identical sequence variant,¹ suggesting that other genetic or environmental factors modify the phenotype. Although most patients with XL CSNB have non-progressive disease, Nakamura et al. reported two brothers with a CACNA1F mutation and progressive decline in vision with eventually undetectable rod and cone ERGs.² We have also infrequently observed slow progression in patients with XL CSNB. Patients with complete CSNB (NYX mutations) are invariably myopic and have more pronounced night-blindness.³

Oguchi’s disease

Clinical findings

Oguchi’s disease is a rare autosomal recessive stationary night-blindness with a greyish or green-yellow discoloration of the fundus at the posterior pole or extending beyond the arcades, which reverts to normal on prolonged dark adaptation (Mizuo phenomenon) (Fig. 44.3). Exposure to light then usually leads to the gradual reappearance of the abnormal discoloration in 10–20 minutes.

Fig. 44.3 Oguchi’s disease. Greyish or green-yellow discoloration of the fundus, which reverts to normal on prolonged dark adaptation (Mizuo phenomenon).

Most patients present with poor night vision. Visual acuity is normal or mildly reduced and photopic visual fields and color vision are normal. Although most cases are from Japan it occurs in other races.

Electrophysiology and psychophysics

There are two types of Oguchi’s disease depending on the dark adaptation findings:

Type 1: rod adaptation is markedly slowed; full recovery of sensitivity takes several hours and the absolute threshold is normal or only minimally elevated.

Type 2: there is no recognizable rod adaptation; the abnormal retinal appearance is less marked and the Mizuo phenomenon may be absent.

Most patients with Oguchi’s disease have a “negative” bright flash ERG, confirming the site of dysfunction to be post-phototransduction, as in XL CSNB. As opposed to fundus albipunctatus (below), the ERG remains abnormal even after prolonged dark adaptation.

Molecular genetics and pathogenesis

There is a truncating deletion in SAG, encoding arrestin, in patients with Oguchi’s disease. Reduced activity of arrestin is likely to result in prolonged activation of transducin and rod phosphodiesterase following light exposure. cGMP levels would thereby be maintained at a low level in even dim light exposure and the outer segment cation channels would remain closed resulting in prolonged rod hyperpolarization. The rods would behave as if they were light adapted and would be unresponsive to light at low levels of illumination, explaining the psychophysical abnormalities.

Null mutations in GRK1, encoding a second component of the rod phototransduction pathway, rhodopsin kinase (RK), have also been identified in Oguchi’s disease. The key function, of both RK and arrestin, in the normal deactivation and recovery of the photoreceptor after exposure to light, explains the delayed recovery in Oguchi’s disease. The consequences of these reported RK mutations have been assessed by expression studies in COS7 cells of wild-type and human mutant RK. The markedly reduced mutant RK activity supported their pathogenicity.⁶

Evidence from knockout mice models suggests that patients with SAG or GRK1 mutations may be more susceptible to light-induced retinal damage; it may therefore be advisable for patients to wear tinted spectacles.^7,⁸

Fundus albipunctatus

Clinical findings

This autosomal recessive form of stationary night-blindness has a characteristic fundus appearance with multiple white dots throughout the retina. Patients either present with night-blindness or an abnormal retinal appearance on routine fundoscopy. The visual acuity is usually normal and the condition non-progressive.

The deposits are discrete dull white lesions at the level of the retinal pigment epithelium (RPE). They are most numerous in the mid-periphery and are usually absent at the macula; the optic discs and retinal vessels are normal. Fluorescein angiography shows multiple areas of hyperfluorescence, which may not directly correlate to the deposits seen clinically. In some patients there is good correlation between the white dots and increased autofluorescence on fundus autofluorescence imaging, but not in others. The differential diagnosis is from other causes of flecked retina (see Chapter 48).

Electrophysiology and psychophysics

Dark adaptation is severely delayed in fundus albipunctatus (FA), reflecting abnormal regeneration of rhodopsin. The rod-cone break is delayed and full rod adaptation may take many hours. Rod ERGs are markedly abnormal, with the rod-specific ERG (DA 0.01) being undetectable under standard conditions, but becoming normal following prolonged dark adaptation (Fig. 44.4). The dark-adapted bright flash ERG (DA 11.0), which after standard dark adaptation arises in dark-adapted cones, can have a low b : a ratio; a red flash stimulus under dark adaptation shows a normal cone component but an undetectable rod component and prevents confusion with a form of CSNB associated with a negative ERG. To confirm the diagnosis of FA it is necessary to exceed the ISCEV ERG standard recommendations for dark adaptation considerably. Most but not all patients with RDH5 mutations show full recovery of rod function with extended dark adaptation. This contrasts with the findings in retinitis punctata albescens (see below), related to mutation in RLBP1, and usually allows the distinction between the two disorders.

Fig. 44.4 Fundus albipunctatus. The DA 0.01 ERG is undetectable following a standard period of dark adaptation and the DA 11.0 response is reduced with additional reduction in the b:a ratio. However, following an extended period of dark adaptation both DA 0.01 and DA 11.0 responses are completely normal in keeping with delayed regeneration of rhodopsin.

There are two forms of FA, one in which cone ERGs are normal, and a rarer form described as fundus albipunctatus with cone dystrophy and negative ERG.⁹

Molecular genetics and pathogenesis

Mutations in three genes (RDH5, RLBP1, and RPE65), encoding components of the visual cycle, have been identified to date. The gene RDH5 encodes 11-cis-retinol dehydrogenase, a component of the visual cycle. Recombinant mutant 11-cis retinol dehydrogenases have reduced activity compared with recombinant enzyme with wild-type sequence.¹⁰ The phenotype of patients with RDH5 mutations is variable, including normal or reduced cone responses.¹¹ The function of the protein product of RDH5 is consistent with the delay in the regeneration of photopigments characteristic of the disorder.

Mutations have also been reported in RLBP1, encoding the cytosolic cellular retinaldehyde binding protein (CRALBP). Retinitis punctata albescens is usually associated with RLBP1 mutations (see below). CRALBP has been localized to the RPE Müller cells, and ciliary epithelium. It can select 11-cis-retinaldehyde from a mixture of retinoids and protect it from photoisomerisation, suggesting a possible role in the generation of 11-cis-retinoids in the visual cycle; in keeping with the phenotypic features of FA.

Sequence variants in RPE65 have also been identified in patients with a retinal appearance similar to FA.¹² Reduced fundus autofluorescence has been observed in patients with RPE65 and RDH5 mutations,^11,¹² supporting the belief that disruption of retinoid recycling in the RPE is essential for the development of FA.

Stationary cone disorders (cone dysfunction syndromes)

The cone dysfunction syndromes include congenital color vision disorders where there is normal visual acuity but defective color vision, and the various forms of cone dysfunction associated with reduced central vision and often nystagmus and photophobia (Table 44.1).¹³

Table 44.1 Summary of the cone dysfunction syndromes

Disorders of color vision with normal visual acuity

Color vision in humans is trichromatic; there are three classes of cone photoreceptor that contain visual pigments maximally sensitive at 560 nm (L-cones (red)), 535 nm (M-cones (green)) and 440 nm (S-cones (blue)). The genes for the protein component (opsin) of the red and green cone pigments are on the long arm of the X chromosome, and the blue cone opsin gene on chromosome 7. About 8% of men and 0.5% of women have a red–green color vision defect, which is associated with abnormalities of the red and green cone opsin genes. Tritanopia is an uncommon autosomal dominant disorder in which there is a specific deficiency of blue cone sensitivity associated with mutations of the blue cone opsin gene.

This group of disorders, their clinical characteristics, and the molecular pathology are reviewed elsewhere.¹⁴

Achromatopsia

Achromatopsia is genetically heterogeneous and characterized by an absence of functioning cones in the retina.¹³ It may occur in complete (typical) and incomplete (atypical) forms.

Complete achromatopsia (rod monochromatism)

Clinical and histopathologic findings

The usual presentation is with reduced vision, nystagmus, and marked photophobia in infancy. The incidence is approximately 1 in 30 000. Parents often comment that vision is much better in dim illumination. Pupil reactions are sluggish or may show paradoxical constriction in the dark. High hyperopic refractive errors may be present and the fundi are normal. The nystagmus and photophobia, marked in infancy, may improve with age.

The visual acuity is usually 6/60 and there is complete color blindness. Peripheral visual fields are normal but a small central scotoma can often be detected. Achromatopsia is generally a stationary disorder but slow deterioration and macular atrophy may occur.^15,¹⁶

Histopathologic studies have demonstrated cone-like structures in the retina,^17,¹⁸ which have also been observed in vivo using adaptive optics imaging, albeit to a variable degree.¹⁶ This is promising with regard to gene replacement therapy.

Electrophysiology and psychophysics

The dark adaptation curve is monophasic with no evidence of a cone contribution and spectral sensitivity studies show that rods mediate threshold under both photopic and scotopic conditions; there is no evidence of a Purkinje shift. Electroretinography (Fig. 44.5) shows normal rod-derived ERGs but no detectable cone-derived responses.

Fig. 44.5 ERGs from a patient with rod monochromacy (A), a patient with S-cone monochromacy (B), and a representative normal (C). The rod-specific (DA 0.01) and bright flash ERGs (DA 11.0) show no definite abnormality in either of these cone dysfunction syndromes. The 30 Hz flicker ERG (*LA 30 Hz) is undetectable in both, but the single flash photopic ERG (LA 3.0) is small and late, typical of S-cone origins. Note that the scale for the photopic ERGs in the two patients differs from that in the normal subject better to illustrate the low amplitude LA 3.0 response in the S-cone monochromat.

Molecular genetics and pathogenesis

Achromatopsia is recessively inherited and genetically heterogeneous. Four genes have been identified, CNGA3, CNGB3, GNAT2 and PDE6C; all encoding components of cone phototransduction.

CNGA3 and CNGB3 code for the α- and β-subunits of the cGMP-gated (CNG) cation channel in cone cells, respectively. In the dark, cGMP levels are high in cone photoreceptors, therefore enabling cGMP to bind to the α- and β-subunits of CNG channels, resulting in them adopting an open conformation and permitting influx of cations, with consequent cone depolarization. When light is applied, activated photopigment interacts with transducin, a three-subunit guanine nucleotide binding protein, stimulating the exchange of bound GDP for GTP. The cone α-transducin subunit (encoded by GNAT2), which is bound to GTP, is then released from its β- and γ-subunits and activates cGMP-phosphodiesterase by removing the inhibitory γ-subunits from the active site of this enzyme, which is formed by two α-subunits (encoded by PDE6C). cGMP-phosphodiesterase lowers the concentration of cGMP in the photoreceptor, which results in closure of cGMP-gated cation channels.

More than 60 disease-causing mutations in CNGA3 have been identified in patients with achromatopsia; with four mutations (Arg277Cys, Arg283Trp, Arg436Trp, and Phe547Leu) accounting for approximately 40% of all mutant CNGA3 alleles.¹⁹ By comparison, far fewer mutations have been identified in CNGB3; with the 1 base-pair frameshift deletion, 1148delC (Thr383fs), accounting for up to 80% of CNGB3 mutant disease chromosomes.^20,²¹ The majority of CNGA3 mutations identified to date are missense mutations, indicating that there is little tolerance for substitutions with respect to functional and structural integrity of the channel polypeptide. In contrast, the majority of CNGB3 alterations are nonsense mutations.

About 70% of achromatopsia results from mutations of CNGA3 and CNGB3, with GNAT2 and PDE6C each accounting for less than 1%;^19,^20,²¹ further causative genes remain to be discovered.

Incomplete achromatopsia

Clinical findings

The presentation and clinical findings in infancy are similar to the complete form of achromatopsia, but the visual prognosis may be better. Visual acuity is often in the range 6/24–6/36 and there may be some residual color perception. This form is also inherited as an autosomal recessive trait.

Molecular genetics and pathogenesis

As in the complete form, mutations in CNGA3 have been identified in individuals with incomplete achromatopsia.¹⁹ The mutations identified are all missense mutations, located throughout the channel polypeptide including the transmembrane domains, ion pore, and cGMP-binding region. Only three of these, Arg427Cys, Arg563His, and Thr565Met, are exclusively found in patients with incomplete achromatopsia.¹⁹ Therefore, in the majority of cases of incomplete achromatopsia, other factors may influence the phenotype such as modifier genes or environmental factors. The missense variants identified in incomplete achromatopsia must be compatible with residual channel function since the phenotype is milder than in complete achromatopsia. Mutations in PDE6C have also been identified in incomplete achromatopsia.²²

Mutations in CNGB3 or GNAT2 have not been reported in association with incomplete achromatopsia. However all GNAT2 mutations to date, and the vast majority of CNGB3 mutants, result in premature termination of translation, and thereby truncated and probably non-functional phototransduction proteins. Therefore an incomplete achromatopsia phenotype is unlikely to be compatible with these genotypes, which are predicted to encode mutant products lacking any residual function.

S-cone monochromatism (blue cone monochromatism)

Clinical findings

Blue cone monochromatism (BCM) is an X-linked recessive disorder, affecting approximately 1 in 100 000 individuals, in which affected males have normal rod and blue (S) cone function but lack red (L) and green (M) cone function. The clinical features are similar to complete achromatopsia but less severe. Affected infants have photophobia and develop small amplitude rapid nystagmus in early infancy. They are usually myopic, in contrast to achromatopsia (Fig. 44.6). The nystagmus reduces with time.

Fig. 44.6 Blue cone monochromatism. Pale tilted optic disk with myopic fundus.

BCM is generally accepted to be a stationary disorder but deterioration and the development of macular atrophy may occur.^23,^24,^25,²⁶

Electrophysiology and psychophysics

Achromatopsia and BCM may be differentiated by the mode of inheritance, findings on psychophysical testing and electrophysiology. There is some preservation of the single flash photopic ERG (LA 3.0) in BCM (Fig. 44.5), and specialised spectral ERG techniques to measure S-cone ERGs can also be used (see Fig. 44.5). Female carriers of X-linked BCM may have abnormal cone ERGs and mild anomalies of color vision.

Color vision tests that probe the tritan color axis, such as the Hardy, Rand and Rittler® (HRR) plates, are necessary in order to distinguish between achromatopsia and BCM; with relative preservation of tritan discrimination in BCM. Blue cone monochromats display fewer errors along the vertical axis in the Farnsworth 100-hue test (fewer tritan errors), and may display protan-like patterns on the Farnsworth D-15.

Molecular genetics and pathogenesis

Mutation analyses have established the molecular basis for BCM.²⁴ The mutations in the L- and M-opsin gene array cause BCM to fall into two main classes:

1. A normal L- and M- pigment gene array is inactivated by a deletion in the locus control region (LCR), located upstream of the L-pigment gene. A deletion here abolishes transcription of all genes in the pigment gene array and therefore inactivates both L- and M-cones.

2. The LCR is preserved but changes within the L- and M-pigment gene array lead to loss of functional pigment production. The most common genotype in this class consists of a single inactivated L/M hybrid gene. The first step in this second mechanism is unequal crossing over reducing the number of genes in the array to one, followed in the second step by a mutation that inactivates the remaining gene. The most frequent inactivating mutation that has been described is a thymine-to-cytosine transition at nucleotide 648, which results in a cysteine-to-arginine substitution at codon 203 (Cys203Arg), a mutation known to disrupt the folding of cone opsin molecules.

The data suggest that 40% of BCM genotypes are a result of a one-step mutational pathway that leads to deletion of the LCR. The remaining 60% of BCM genotypes comprise a heterogeneous group of multi-step pathways. Studies have not detected the genetic alteration that would explain the BCM phenotype in all assessed individuals.²⁴ In one study the structure of the opsin array did not reveal the genetic mechanism for the disorder in 9 of 35 affected patients²⁴ which may suggest genetic heterogeneity yet to be identified in BCM.

Oligocone trichromacy

Oligocone trichromacy is characterized by reduced visual acuity (6/12 to 6/24), mild photophobia, normal fundi, reduced cone ERGs with normal rod responses, and normal color vision.¹³ Patients have been described both with and without nystagmus. These patients may have a reduced number of normal functioning cones (oligocone) with preservation of the three cone types in the normal proportions, thereby permitting trichromacy. High-resolution quantitative retinal imaging supports this.²⁷

Color vision testing either reveals normal or slightly elevated color discrimination thresholds. Slightly elevated discrimination thresholds are compatible with a reduction in cone numbers.

Oligocone trichromacy is inherited as an autosomal recessive trait; the molecular genetic basis is unknown. Patients with either RGS9/R9AP mutations (“bradyopsia”; see below) or oligocone trichromacy have very similar clinical phenotypes, characterized by stationary cone dysfunction with normal color vision.²⁸ The distinctive electrophysiologic features associated with RGS9 and R9AP mutations enable directed genetic screening.

RGS9/R9AP retinopathy (bradyopsia)

Clinical findings

Bradyopsia is a stationary cone dysfunction syndrome with onset in early childhood; it is characterized by mild photophobia, markedly delayed dark and light adaptation, moderately reduced visual acuity, normal color vision, and normal fundi. Some patients report difficulty seeing moving objects. It is not possible clinically to distinguish bradyopsia from oligocone trichromacy; however there are pathognomonic findings on extended electrophysiologic assessment.²⁸

Electrophysiology

The rod-specific ERG (DA 0.01), the red flash ERG under dark adaptation (which has both a cone and rod component), and the single bright white flash (DA 11.0) with inter-stimulus interval (ISI) of 2 minutes are normal. The DA 11.0 ERGs with an ISCEV standard ISI of 20 seconds show amplitude reduction, which becomes progressively less severe with increasing ISI, consistent with delayed recovery following the flash. The pattern electroretinogram (PERG) and standard 30 Hz flicker ERG (LA 30 Hz) are usually undetectable. A residual low amplitude standard photopic single flash ERG (LA 3.0) is usually recorded.

The electrophysiologic findings are distinctive for the disorder, needing more extended testing than in the ISCEV ERG standard protocol which shows normal dark-adapted responses, an undetectable 30 Hz flicker ERG, and a severely reduced LA 3.0 ERG suggesting incomplete achromatopsia. However, ERGs to a red flash under dark adaptation, which in a normal subject gives an early cone system derived response and a later rod system derived response, show that dark-adapted cones retain good function and rule out achromatopsia.

Molecular genetics and pathogenesis

Mutations in both RGS9 and R9AP have been associated with bradyopsia, with no sequence variants in either of these genes identified in subjects with oligocone trichromacy.²⁸

To turn off the visual response, each of the activated phototransduction molecules has to be deactivated; α-transducin and cGMP-phosphodiesterase are simultaneously deactivated by the hydrolysis of the α-transducin bound GTP to GDP. This GTPase activity is substantially accelerated by RGS9, a GTPase activating protein that binds to the Gβ5 subunit and to R9AP, a membrane anchor protein. RGS9 and R9AP have a critical role in the recovery phase of visual transduction. RGS9 is anchored to photoreceptor outer segment disk membranes by R9AP; required for the correct targeting and localization of RGS9 in photoreceptors and enhances RGS9 activity up to 70-fold.

Bornholm eye disease

Clinical findings

Bornholm eye disease is an X-linked disorder with moderate to high myopia and astigmatism, impaired visual acuity, moderate optic nerve hypoplasia, thinning of the RPE in the posterior pole with visible choroidal vasculature, and abnormal cone ERGs.²⁹ Affected members in this single family were all deuteranopes, with a stationary natural history; however a similar phenotype has also been published in association with protanopia.^30,³¹ This disorder is therefore best characterized as an X-linked cone dysfunction syndrome with myopia and dichromacy.

Molecular genetics and pathogenesis

Linkage analysis has mapped the locus to Xq28, in the same chromosomal region as the L/M opsin gene array. Perhaps molecular genetic analysis of the opsin array will reveal mutations accounting for both the cone dysfunction and the color vision phenotype or rearrangements within the opsin gene array may be found to account for the color vision findings, whilst the cone dysfunction component of the disorder may be ascribed to mutation within an adjacent but separate locus.

Progressive retinal dystrophies

Rod–cone dystrophies

The rod–cone dystrophies (retinitis pigmentosa (RP)) are a clinically and genetically heterogeneous group of disorders with progressive loss of rod and later cone photoreceptor function leading to severe visual impairment. RP usually occurs as an isolated retinal abnormality, but it may also be seen with systemic abnormalities (see Chapter 45).

Leber’s congenital amaurosis

Clinical findings

Leber’s congenital amaurosis (LCA) is a severe congenital or early infant-onset non-syndromic retinal blindness described by Theodore Leber in 1869. He characterized the disorder by a searching nystagmus, abnormal pupil responses, minimal if any vision beyond infancy, and a normal fundus appearance initially, followed by the development of pigmentary changes. He later described a milder form of the same disease which has had several names, including early onset severe retinal dystrophy (EOSRD), severe early childhood onset retinal dystrophy (SECORD), and early onset retinitis pigmentosa. LCA/EOSRD is the most common inherited cause of severe visual impairment in children, accounting for 10–18% of children in institutions for the blind.

Severe visual impairment is from birth or the first few months of life with roving eye movements or nystagmus and poor pupillary light responses. Eye-poking, the “oculodigital” sign, is common (Fig. 44.7). Fundus examination may be normal but a variety of abnormal fundus appearances may be present such as disk pallor, vessel attenuation, or mild peripheral pigmentary retinopathy. There may also be disk drusen, optic disk edema or pseudopapilledema (Fig. 44.8), a flecked retina, maculopathy, or nummular pigmentation. Affected infants often have high hyperopia, or less commonly high myopia, suggesting some interference with emmetropization.

Fig. 44.7 Leber’s congenital amaurosis. Eye-poking, the “oculodigital sign” is very common but of unknown cause; it results in atrophy of orbital fat and enophthalmos.

Fig. 44.8 Leber’s congenital amaurosis. High hypermetropia and pseudopapilloedema.

Although most patients have normal fundi in infancy, signs of a pigmentary retinopathy appear in later childhood with optic disk pallor and retinal arteriolar narrowing. Other late signs, which may be related to eye-poking, include enophthalmos, keratoconus, and cataract. Eventual vision is in the region of 3/60 to perception of light, with progression not observed in all cases.

Following the discovery of many disease-causing genes (below) it has sometimes been possible to identify characteristic associated phenotypes (Figs 44.9 to 44.12): RDH12-associated disease is characterized by bone spicule pigmentation and maculopathy (Fig. 44.9) and CRB1-associated disease has nummular pigmentation, maculopathy, relative preservation of para-arteriolar RPE, with retinal thickening and loss of lamination on optical coherence tomography (Figs 44.10 and 44.11).