Childhood Stationary Retinal Dysfunction Syndromes 11 Michel Michaelides, Anthony T

Home , Cone dystrophy, Dichromacy, Oguchi disease

Childhood Stationary Retinal Dysfunction Syndromes 11 Michel Michaelides, Anthony T. Moore

| Core Messages 11.1 ∑ The stationary retinal dysfunction syn- Introduction dromes represent an important cause of childhood visual impairment The inherited retinal disorders can be classified ∑ This heterogeneous group of disorders are according to their natural history (stationary or inherited as autosomal recessive, autoso- progressive), the mode of inheritance (autosomal dominant or X-linked (XL) recessive mal dominant (AD), autosomal recessive (AR), traits X-linked recessive (XL), or mitochondrial) and ∑ They can be usefully divided into rod dys- principal site of dysfunction within the retina function syndromes (congenital stationary (retinal pigment epithelium, rod or cone pho- night blindness, Oguchi disease, fundus toreceptor,or inner retina).This classification is albipunctatus) and cone dysfunction syn- undertaken by careful clinical history and ex- dromes (complete achromatopsia, incom- amination, and with the assistance of detailed plete achromatopsia, blue cone monochro- psychophysical and electrophysiological assess- matism, oligocone trichromacy and XL ment. cone dysfunction with dichromacy) Major advances have been made in the field ∑ Presentation is at birth or in early infancy, of retinal molecular genetics in the last decade, often associated with nystagmus with identification of the causative genes un- ∑ Rod dysfunction syndromes usually, derlying most inherited retinal disorders, but not always, have symptomatic night especially those associated with the stationary blindness. Central visual function is variably dysfunction syndromes. At present routine mo- affected. Rod-specific ERGs are absent/ lecular diagnostic testing is only available for a reduced, with variable less severe abnor- few disorders but the numbers will increase as malities of the cone ERG advances are made in the technology of genetic ∑ Cone dysfunction syndromes usually analysis. present with photophobia, reduced visual This chapter aims to discuss the stationary acuity and colour vision disturbance. dysfunction syndromes and for convenience Cone ERGs are abnormal with normal rod they have been divided into those conditions responses characterised principally by either rod or cone ∑ The underlying molecular genetic basis photoreceptor dysfunction. The phenotypes of the majority of the retinal dysfunction identified within these two groups will be de- syndromes is now well characterised, scribed and an outline of our current under- allowing molecular genetic diagnosis standing of the molecular biology underpin- and the potential for future treatment ning their pathogenesis will be provided. strategies. 180 Chapter 11 Childhood Stationary Retinal Dysfunction Syndromes RDH5 GRM6 RHO GNAT1 PDE6B NYX CACNA1F GRK1 SAG RDH5 or myopic or the throughout the throughout the level retina at of the RPE retina at the level the level retina at of the RPE reduced myopic or X-linked XL recessive mild reduction or phenomenon autosomal dominant, autosomal With cone cone With dystrophy Autosomal recessive Often normal – Absent Reduced white Multiple scattered dots specific ERG) specific Incomplete CSNB X-linked (detectable rod-specific ERG) 6/18–6/60 Often myopia Present Markedly normal Usually AD Summary of dysfunction the rod syndromes autosomal recessive, autosomal Rod dysfunction Rod syndrome Subtype stationary Congenital of Mode acuity Visual Autosomal Refractive 6/12–6/60 inheritance Nystagmus Cone Often myopia Present Fundi Reduced normal Usually error Mutated function gene(s) night blindness (AR CSNB) stationary Congenital night blindness (AD CSNB) stationary Congenital Complete blindness night (XL CSNB) X-linked recessive Autosomal CSNB Normal 6/12–6/60 dominant rod- (absent Often myopia Present Fundus –albipunctatus Reduced normal Usually Absent dystrophy cone Without Normal Autosomal recessive Often normal normal Usually – Absent myopic or Normal white Multiple scattered dots Oguchi disease Autosomal Often normal – Absent Normal Mizuo–Nakamura AR Table 11.1. 11.1 Introduction 181 some locussome CNGA3 CNGB3 GNAT2 14 Chromosome CNGA3 (b) Single inactivated L/M inactivated hybrid gene hybrid crimination hypermetropia tance Typical Typical achromatopsia achromatopsia X-linked incomplete incomplete X-linked Summary of dysfunction syndromes the cone Locus control region control Locus Complete Rod mono- Autosomal 6/36–6/60OftenPresentmono- Absent Autosomal Usually Rod Complete achromatopsia chromatism recessive hypermetropia normal Cone dysfunction Cone syndrome Alternative names of Mode Visual Refractive inheri- Nystag- acuity Colour error Fundi gene(s) Mutated and myopiadichromacy mus vision chromo- or astigmatism protanopia Incomplete Atypical Autosomal 6/24–6/36OftenPresent Residual Autosomal Atypical Incomplete Usually achromatopsia cone Blue monochromatism achromatopsia achromatopsia atypical X-linked recessive X-linked 6/24–6/36 Often myopia hypermetropia Present Residual Usually (a) Deletion normal tritan dis- normal of the LCR Oligocone Oligocone Autosomal 6/12–6/24Equal incidence Usually Normal Normal – Usually incidence 6/12–6/24Equal Autosomal Oligocone Oligocone trichromacy dysfunc- cone X-linked tion with syndrome Bornholm syndrome disease eye X-linked recessive 6/12–6/36 high to Moderate Absent Deute- of and myopia Myopic absent Xq28 with myopia or ranopia LCR Table 11.2. 182 Chapter 11 Childhood Stationary Retinal Dysfunction Syndromes

there is always a detectable rod-specific ERG in 11.2 incomplete CSNB and cone ERGs are much Stationary Retinal Dysfunction Syndromes more abnormal than in complete CSNB, reflecting involvement of both ON- and OFF- bipolar These disorders are subdivided on the basis of pathways. whether rod or cone photoreceptors are pre- AR CSNB is phenotypically very similar to dominantly involved. These conditions are XLCSNB, both clinically and on ERG testing. summarised in Tables 11.1 and 11.2. In most families with AD CSNB, affected individuals show attenuated rod responses but normal cone responses on ERG testing, without 11.2.1 evidence of a negative waveform on maximal Rod Dysfunction Syndromes response testing. Inner retinal dysfunction has (Stationary Night Blindness) been reported in a few cases.

Three forms of stationary night blindness are Molecular Biology recognised: congenital stationary night blindness (CSNB), fundus albipunctatus and Oguchi AD CSNB disease. Consistent with clinical and electrophysiological findings, mutations in genes encoding three 11.2.1.1 components of the rod-specific phototransduc- Congenital Stationary Night Blindness tion cascade have been reported in association with AD CSNB: namely rhodopsin [10], the Clinical Features and Electrophysiology a-subunit of rod transducin [11] and the rod cGMP phosphodiesterase b-subunit [15]. CSNB is characterised by night blindness, variable visual loss and usually normal fundi, XL CSNB although some patients have pale or tilted optic Two genes (CACNA1F and NYX) have been im- discs. CSNB may be inherited as an AD, AR or plicated in XL CSNB.Incomplete CSNB is associ- XL disorder; with XL inheritance being most ated with mutation in CACNA1F, which encodes a common. Patients with AD CSNB usually pres- the retina-specific 1F-subunit of the voltage- ent with nyctalopia and have normal visual acu- gated L-type calcium channel expressed in the ity [36]; whereas in XL and AR, CSNB presenta- outer nuclear layer, inner nuclear layer, and gan- tion is usually in infancy with nystagmus, glion cell layer [5, 38]. The majority of the muta- moderate to high myopia, strabismus, reduced tions reported are inactivating truncation se- central vision, and in some cases paradoxical quence variants. The loss of functional channels pupil responses (pupillary dilatation to bright impairs the calcium flux into rod and cone pho- light) [34]. toreceptors required to sustain tonic neuro- XL CSNB is further subdivided into the com- transmitter release from presynaptic terminals. plete and incomplete forms. Patients with com- This may result in the inability to maintain the plete CSNB are myopic and have more pro- normal transmembrane potential of bipolar nounced night blindness. Both complete and cells, such that the retina remains in a partially incomplete CSNB show a negative type of ERG, light-stimulated state, unable to respond to in that the photoreceptor derived a-wave in the changes in light levels. Although most patients maximal response is usually normal,but there is with XL CSNB have nonprogressive disease, two selective reduction in the inner nuclear derived brothers with a mutation in CACNA1F have been b-wave so that it is smaller than the a-wave. In described who showed progressive decline in vi- complete CSNB, the rod-specific ERG is more sual function and eventually had a nonrecord- severely affected and is often nonrecordable [2]. able rod and cone ERG [29]. Cone ERGs show mild abnormalities reflecting Complete CSNB is associated with mutation ON- bipolar pathway dysfunction. In contrast, in NYX, the gene encoding the leucine-rich pro- 11.2 Stationary Retinal Dysfunction Syndromes 183 teoglycan nyctalopin [6, 35]. Leucine-rich re- cascade and thereby restoring photoreceptor peats are believed to be important for protein sensitivity after exposure to light. In Oguchi dis- interactions and the described mutations fre- ease the rods therefore behave as if they are light quently involve these regions. It has been sug- adapted and thus unresponsive to light at low gested that nyctalopin plays a role in the devel- levels of illumination. The key function, of both opment and function of the ON- pathway rhodopsin kinase and arrestin,in the normal de- within the retina, consistent with observed elec- activation and recovery of the photoreceptor af- trophysiological findings. ter exposure to light, is entirely consistent with the delayed recovery seen in Oguchi disease. Ev- AR CSNB idence from knock-out mice models suggests Mutations in GRM6, the gene encoding the glu- that patients with RK or arrestin mutations may tamate receptor mGluR6, have been identified be more susceptible to light-induced retinal in patients with AR CSNB [12]. This neurotrans- damage; it may therefore be advisable to encour- mitter receptor is present in the synapses of age patients to wear tinted spectacles,thereby re- ON- bipolar cell dendrites, mediating synaptic stricting excessive light exposure [8, 9]. transmission from rod and cone photoreceptors to these second-order neurones. 11.2.1.3 Fundus Albipunctatus 11.2.1.2 Oguchi Disease Clinical Features and Electrophysiology

Clinical Features and Electrophysiology Fundus albipunctatus (FA) has an AR mode of inheritance with a highly characteristic fundus This rare AR form of stationary night blindness appearance with multiple white dots scattered was first described in Japanese patients but has throughout the retina at the level of the RPE been subsequently reported in Europeans [22] (Fig. 11.1). The white deposits are most numerous and African-Americans [41]. Most patients in the mid-periphery and are usually absent from present with poor night vision. Visual acuity is the macula. Patients either present with night usually normal or only mildly reduced and pho- blindness or because the abnormal retinal ap- topic visual fields and colour vision are normal. pearance is noted on routine ophthalmoscopy. In Oguchi disease, a characteristic greyish or Visual acuity is usually normal and the condition green-yellow discolouration of the fundus is is nonprogressive in the majority of affected indi- seen, which reverts to normal on prolonged viduals.The rod-specific ERG is undetectable un- dark adaptation (Mizuo–Nakamura phenome- der standard conditions, but becomes normal non) [22]. The abnormal appearance may be following prolonged dark adaptation, in direct confined to the posterior pole or extend beyond contrast to Oguchi disease. Two forms of FA have the vascular arcades. Most patients with Oguchi been described, the common form in which cone disease have a negative waveform maximal ERGs are normal, and a second type described as ERG, confirming the site of dysfunction to be FA with cone dystrophy and negative ERG [28]. post-phototransduction, as observed in XL and AR CSNB.In direct contrast to fundus albipunc- Molecular Biology tatus, the ERG remains abnormal even after prolonged dark adaptation. Mutations in RDH5, the gene encoding 11-cis retinol dehydrogenase, a component of the Molecular Biology visual cycle involved in recycling the chromo- phore 11-cis retinal, have been identified in FA Nonsense mutations have been identified in two with or without cone dystrophy [43]. The func- rod phototransduction proteins, arrestin [14] tion of the protein product of RDH5 is consis- and rhodopsin kinase (RK) [44],both involved in tent with the delay in the regeneration of pho- terminating activation of the phototransduction topigments characteristic of the disorder. 184 Chapter 11 Childhood Stationary Retinal Dysfunction Syndromes

Fig. 11.1. Fundus albipunctatus. Characteristic fundus appearance with multiple white dots scattered throughout the retina at the level of the RPE

vision and complete colour blindness. The usu- 11.2.2 al presentation is with reduced vision (6/36– Cone Dysfunction Syndromes 6/60), nystagmus and marked photophobia in infancy. Vision is usually better in mesopic These different syndromes encompass a wide conditions. Pupil reactions are sluggish or may range of clinical, electrophysiological and psy- show paradoxical pupil responses. Hyperme- chophysical findings [25]. Presentation is in in- tropic refractive errors are common and fundus fancy or at birth, usually with photophobia, nys- examination is generally normal. The nystag- tagmus, reduced central vision, and normal rod mus, although marked in infancy, may improve function. The cone dysfunction syndromes in- with age, as can the photophobia. Rod-specific clude complete and incomplete achromatopsia, ERGs are normal but there are no detectable blue cone monochromatism, oligocone trichro- cone-derived responses. macy,and XL cone dysfunction with dichromacy. Incomplete achromatopsia is less common than the complete subtype and has a milder 11.2.2.1 phenotype. The presentation and clinical find- Achromatopsia – Complete and Incomplete ings of incomplete achromatopsia in infancy are similar to complete achromatopsia, but visual Achromatopsia refers to a genetically heteroge- acuity is usually in the range 6/24 to 6/36 and neous group of autosomal recessive stationary there often is some residual colour perception. retinal disorders in which there is an absence of functioning cones in the retina [25]. They are Molecular Biology characterised by reduced central vision, poor colour vision, photophobia, pendular nystag- Three achromatopsia genes have been identi- mus and usually normal fundi, and may occur fied, CNGA3, CNGB3,and GNAT2; which all en- in complete (typical) and incomplete (atypical) code components of the cone-specific photo- forms. transduction cascade. Mutations in all three genes have been reported in association with Clinical Features and Electrophysiology complete achromatopsia, whereas only mutations in CNGA3 have been identified in incom- Complete achromatopsia (previously known as plete achromatopsia. rod monochromatism), has an incidence of ap- CNGA3 and CNGB3, code for the a- and proximately 1 in 30,000, is inherited as an auto- b-subunits of the cGMP-gated (CNG) cation somal recessive trait and results in impaired channel in cone cells. In the dark, cGMP levels 11.2 Stationary Retinal Dysfunction Syndromes 185 are high in cone photoreceptors, therefore en- tions of achromatopsia [17, 19, 21, 39, 42]. The abling cGMP to bind to the a- and b-subunits of phenotype of a large consanguineous family CNG channels, resulting in them adopting an with GNAT2 inactivation has been reported open conformation and permitting an influx of [23]. The findings of note were clinical evidence cations, with consequent cone depolarisation. of progressive deterioration in older affected in- On exposure to light, activated photopigment dividuals, residual colour vision, and relative initiates a cascade culminating in increased preservation of S-cone ERGs in all subjects. cGMP-phosphodiesterase activity, thereby low- ering the concentration of cGMP in the pho- 11.2.2.2 toreceptor, which results in closure of CNG Blue Cone Monochromatism cation channels and consequent cone hyper- (S-Cone Monochromatism) polarization. More than 50 disease-causing mutations Clinical Features and Electrophysiology in CNGA3 have been identified in patients with achromatopsia [21, 42], with the majority Blue cone monochromatism (BCM) is an XL re- being missense sequence variants, indicating cessive disorder, affecting fewer than 1 in that there is little tolerance for substitutions 100,000 individuals, in which affected males with respect to functional and structural in- have normal rod and blue (S) cone function but tegrity of the channel polypeptide. Four muta- lack red (L) and green (M) cone function. The tions (Arg277Cys, Arg283Trp, Arg436Trp and clinical features are similar to incomplete Phe547Leu) account for approximately 40% of achromatopsia. Affected infants are photopho- all mutant CNGA3 alleles [42]. By comparison, bic and develop fine rapid nystagmus in early approximately only 12 mutations have been infancy. In keeping with achromatopsia, the identified in CNGB3 [17, 19, 39], with the nystagmus often reduces with time. They are majority being nonsense variants. The most usually myopic (a common finding in XL retinal frequent mutation of CNGB3 identified to date disorders), with a visual acuity of 6/24–6/36. By is the 1-base-pair frameshift deletion, 1148delC comparison, subjects with achromatopsia more (Thr383 fs), which accounts for up to 80% of commonly have a hypermetropic refractive CNGB3 mutant disease chromosomes [17, 19]. It error. Fundi are usually normal in BCM or have is currently proposed that approximately 25% changes consistent with myopia. Female carri- of achromatopsia results from mutations of ers of BCM may have abnormal cone ERGs and CNGA3 [42] and 40–50% from mutations of mild anomalies of colour vision. CNGB3 [17, 19]. Achromatopsia and BCM may be differenti- Mutations within a third gene, GNAT2,which ated by the mode of inheritance, findings on encodes the a-subunit of cone transducin, have psychophysical and electrophysiological test- also been shown to cause achromatopsia [1, 20]. ing, and via molecular genetic analysis. In con- In cone cells, light activated photopigment in- trast to achromatopsia, there is some preserva- teracts with transducin, a three subunit guanine tion of the single flash photopic ERG in BCM nucleotide binding protein, stimulating the ex- and normal S-cone function can be demon- change of bound GDP for GTP. All the GNAT2 strated using specialised spectral ERG tech- mutations identified to date result in premature niques. On colour vision testing, good residual translation termination and in protein-trunca- tritan discrimination is consistent with BCM, tion at the carboxy-terminus. Mutations in this with the Farnsworth 100-Hue test, Berson gene are thought to be responsible for less than plates, Hardy, Rand and Rittler plates all having 2% of patients affected with this disorder, sug- been used successfully. gesting the presence of further genetic hetero- BCM is generally a stationary disorder geneity in achromatopsia. but progressive deterioration, with or without The phenotype associated with mutations in the development of macular pigmentary the two cation channel protein genes appears to changes, has been reported in some patients be in keeping with previous clinical descrip- [3, 13, 27, 30]. 186 Chapter 11 Childhood Stationary Retinal Dysfunction Syndromes

Molecular Biology 11.2.2.3 Oligocone Trichromacy The underlying molecular genetic basis of BCM involves inactivation of the L- and M-opsin Clinical Features and Electrophysiology genes located at Xq28 [3, 4, 27,30, 31]. The mutations in the L- and M- pigment gene array caus- Oligocone trichromacy is an unusual cone dys- ing BCM fall into two classes: function syndrome in which patients are be- 1. In the first class,a normal L- and M- pigment lieved to have a reduced number of normal gene array is inactivated by a deletion in the functioning cone photoreceptors (oligocone locus control region (LCR),located upstream syndrome), with preservation of the three cone of the L- pigment gene. A deletion in this re- types in the normal proportions, thereby per- gion abolishes transcription of all genes in mitting trichromacy [18, 40]. the pigment gene array and therefore inacti- The disorder is characterised by reduced vates both L- and M- cones. visual acuity from infancy (6/12 to 6/24), mild 2. In the second class of mutations, the LCR is photophobia, normal fundi, and abnormal cone preserved but changes within the L- and M- ERGs, but normal colour vision [18, 24, 32, 40]. pigment gene array lead to loss of functional Normal colour vision is a unique finding in pigment production. The most common the cone dysfunction syndromes. Rod-specific genotype in this class consists of a single in- ERGs are normal. Patients usually have no nys- activated L/M hybrid gene. The first step in tagmus. On detailed psychophysical testing, this second mechanism is unequal crossing some subjects have slightly elevated colour dis- over reducing the number of genes in the crimination thresholds, compatible with a re- array to one, followed in the second step by a duction in cone numbers [18, 24]. mutation that inactivates the remaining Cone ERG findings in patients with oligo- gene. The most frequent inactivating muta- cone trichromacy were found to be poorly con- tion that has been described is a thymine-to- cordant in a recent case series [24]. Cone 30-Hz cytosine transition at nucleotide 648, which flicker ERG responses were absent or markedly results in a cysteine-to-arginine substitution reduced in two siblings, who additionally at codon 203 (Cys203Arg), a mutation known showed a photopic b-wave of shortened implic- to disrupt the folding of cone opsin mole- it time; suggesting some preservation of the cules. cone OFF- pathway, as the implicit time of the OFF- response in normal subjects is similar to Approximately 40% of blue cone monochromat that in these patients. Other patients showed genotypes are a result of a one-step mutational clearly present, but delayed and reduced cone pathway that leads to deletion of the LCR, with 30-Hz flicker ERGs, with some showing a mild- the remaining 60% comprising a heteroge- ly electronegative maximal response, suggestive neous group of multi-step pathways [3, 4, 27, 30, of inner retinal abnormality. Cone system im- 31]. Nevertheless, a significant minority of sub- plicit time changes are not expected in restrict- jects are not found to have disease-causing ed disease, and in addition are more usually as- alterations to the opsin array [3, 31], suggesting sociated with generalised dysfunction, rather genetic heterogeneity yet to be identified in than loss of function related to a reduction in BCM. Patients with a progressive phenotype photoreceptor numbers [24]. This phenotypic have not been found to have a particular geno- heterogeneity suggests that there may be more type to account for the progression [3, 4, 27, 31]. than one disease mechanism and therefore more than one disease-causing gene associated with the oligocone phenotype. It has previously 11.2 Stationary Retinal Dysfunction Syndromes 187 been proposed that these patients have a re- 11.2.2.4 duced number of retinal cones that function X-Linked Cone Dysfunction Syndrome normally. That may apply to central cones, but with Dichromacy and Myopia recent electrophysiological data suggest that remaining peripheral cones do not function Clinical Features and Electrophysiology normally [24]. Previous reports have suggested this disor- A stationary XL cone dysfunction syndrome der to be stationary, but there is clinical evi- has been described consisting of moderate to dence of progression in one family that has been high myopia, astigmatism, moderately reduced investigated, consisting of two affected brothers acuity (6/12 to 6/36), dichromacy (deuterano- whose grandmother had evidence of bull’s-eye pia or protanopia), normal or myopic fundi maculopathy and abnormal cone ERGs with (Fig. 11.2) and abnormal cone ERGs but normal normal rod responses [24]. However, until mo- rod responses [16, 26, 45]. Nystagmus is not ob- lecular genetic data become available it can not served in affected subjects. This disorder was be proven that the grandmother’s cone dysfunc- first reported in a large five-generation Danish tion is the same disorder as that of the two family that had its origins on the Danish island brothers. of Bornholm. The syndrome was therefore named Bornholm eye disease (BED) [16]. Af- Molecular Biology fected members in that family were found to be deuteranopes on detailed colour vision testing. Oligocone trichromacy is likely to be inherited Subsequently, further families have been iden- as an autosomal recessive trait, but the molecu- tified with similar characteristics and with lar genetic basis of the disorder is unknown. either deuteranopia or protanopia [26, 45, un- Since oligocone trichromacy may have a devel- published data]. opmental component, genes involved in retinal photoreceptor differentiation, when cone num- Molecular Biology bers are being determined, may represent good candidate genes.Since electrophysiological test- Linkage analysis performed in the original BED ing suggests that the site of abnormality may family has mapped the locus to Xq28, in the not be exclusively at the level of the photorecep- same chromosomal region as the L-/M- opsin tor, genes expressed preferentially in the inner gene array [37]. The association of protanopia retina may represent alternative candidates. or deuteranopia with cone dysfunction indi-

Fig. 11.2. X-linked cone dysfunction syndrome with dichromacy and myopia.Myopic fundi with tilted optic discs 188 Chapter 11 Childhood Stationary Retinal Dysfunction Syndromes

cates a potential role for opsin gene mutations been suggested to successfully alleviate photo- in the aetiology of this disorder. However, mo- phobia in patients with cone disorders [33]. lecular analysis of the opsin gene array, whilst Advances in molecular biology have led to revealing changes that are consistent with the the identification of many of the causative ge- colour vision defects associated with this syn- netic mutations, which should offer new thera- drome (dichromacy), failed to identify alter- peutic prospects. In the stationary retinal dys- ations that also potentially account for the cone function syndromes, histopathological or high dysfunction [26, 45]. resolution in vivo microscopy data are often not It is therefore possible that rearrangements yet available; however, the evidence to date sug- within the opsin gene array account for the gests that photoreceptor cells remain present in colour vision findings, whilst the cone dysfunc- these disorders, and could therefore potentially tion component of the disorder may be ascribed be targeted in the future with directed gene to mutation within an adjacent but separate therapy. locus. To date however, the only cone dystrophy (COD2) that maps to an adjacent region (Xq27), displays a different phenotype [7].Nevertheless, 11.4 it is becoming increasingly well recognised in Conclusions retinal molecular genetics that disparate phenotypes can be caused by both different muta- The stationary retinal dysfunction syndromes tions in the same gene, and even the same mu- presenting in childhood comprise a group of tation in the same gene. disorders that are both clinically and genetical- It is of note that a similar XL cone dysfunc- ly heterogeneous. Their clinical, psychophysical tion syndrome without dichromacy has not and electrophysiological phenotypic features been described, so it would appear that this are now well characterised, and in most cases form of cone dysfunction is only seen in associ- the causative genes have been identified. Per- ation with dichromacy. This observation may haps not surprisingly these genes mainly en- suggest that the cone dysfunction arises from a code proteins involved in either the cone or rod mutation in a gene that only causes cone dys- phototransduction pathway. Gene therapy function when expressed in dichromats. treatment trials will be shortly commencing for the rod–cone dystrophy Leber congenital amau- rosis (see Chap. 10); if successful, we may be at 11.3 the beginning of an exciting time when these Management of Stationary Retinal stationary retinal dysfunction syndromes, Dysfunction Syndromes which represent an important cause of childhood blindness, may finally be treatable. The stationary retinal dysfunction syndromes are currently not amenable to any form of treat- Summary for the Clinician ment. However, all patients and their families ∑ See Tables 11.1 and 11.2 benefit from genetic counselling, educational and occupational advice, and supportive meas- ures such as the provision of appropriate spec- tacle correction and low vision aids, and the treatment of concurrent ocular problems such as myopia or cataracts. Photophobia is often a prominent symptom in the cone disorders and therefore tinted spectacles or contact lenses may be beneficial to patients,in terms of both improved comfort and vision. For example, red contact lenses have References 189

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