Functional characterisation and serial imaging of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity.

AIM: To characterise and monitor abnormal fundus autofluorescence (AF) in patients with retinitis pigmentosa (RP) who have good visual acuity. METHODS: 21 patients with a clinical diagnosis of RP were examined. All had rod-cone dystrophy (ISCEV standard electroretinograms (ERGs)), visual acuity of 6/9 or better, and manifested a parafoveal ring of high density fundus AF. Repeat AF imaging was performed after periods of between 2 years and 5 years in 12 patients. Pattern ERG (PERG) and multifocal ERG (mfERG) were performed in 20 cases. Visual fields (VF), photopic and scotopic fine matrix mapping and small field PERGs were performed in representative cases. RESULTS: The rings of high density AF varied in size between patients (from 4 degrees -16 degrees diameter). MfERGs showed relative preservation over the central macular area, correlating with the size of AF ring and with PERG and psychophysical data. Progressive constriction of the AF ring was demonstrated at follow up in three patients. Serial PERG, mfERG, and VFs, performed in one of these cases, showed evidence of deterioration concordant with ring constriction. CONCLUSIONS: High density rings of AF, seen in some patients with RP with good visual acuity, demarcate areas of preserved central photopic function. MfERGs correlate with the area encircled by high density AF and the PERG data. The size of the ring of AF can show progressive constriction accompanied by increasing macular dysfunction.

A detailed study of the phenotype of an autosomal dominant cone-rod dystrophy (CORD7) associated with mutation in the gene for RIM1.

AIM: To characterise the phenotype of an autosomal dominant cone-rod dystrophy (CORD7) associated with the Arg844His mutation in RIM1. METHODS: Eight members of a four generation, non-consanguineous British family were examined clinically and underwent electrophysiological testing, automated dark adapted perimetry, dark adaptometry, colour vision assessment, colour fundus photography, fundus fluorescein angiography (FFA), and fundus autofluorescence (AF) imaging. RESULTS: The majority of affected individuals described a progressive deterioration of central vision, night vision, and peripheral visual field usually between the third and fourth decades. The visual acuity ranged from 6/6 to 3/60. Colour vision testing showed mild to moderate dyschromatopsia in the majority of individuals. Fundus changes comprised a range of macular appearances varying from mild retinal pigment epithelial (RPE) disturbance to extensive atrophy and pigmentation. In some individuals retinal vessels were attenuated and in two subjects peripheral areas of retinal atrophy were present. An absent or severely reduced PERG was detected in all subjects, indicative of marked macular dysfunction. Full field ERG showed abnormal rod and cone responses. AF imaging revealed decreased macular AF centrally surrounded by a ring of increased AF in the majority of individuals. "Bull's eye" lesions were present in two individuals, comprising of a ring of decreased perifoveal AF bordered peripherally and centrally by increased AF. Photopic sensitivity testing demonstrated elevated central visual field thresholds with additional superior greater than inferior peripheral field loss. There were rod and cone sensitivity reductions in the central and peripheral visual fields, with the inferior retina being more affected than the superior. CONCLUSIONS: The detailed phenotype is described of the autosomal dominant cone-rod dystrophy, CORD7, which is associated with a point mutation in RIM1, a gene encoding a photoreceptor synaptic protein. The pattern of disease progression and long term visual outcome facilitates improved genetic counselling and advice on prognosis. Such phenotypic data will be invaluable in the event of future therapy.

Acute zonal occult outer retinopathy: towards a set of diagnostic criteria.

BACKGROUND: Individuals with acute zonal occult outer retinopathy (AZOOR) present with initially progressive scotomata and photopsia. Characteristically, the extent of the visual field defect is unexplained by fundal examination, but there is marked retinal dysfunction evident electrophysiologically. It is the authors' experience that a group of patients exhibit characteristic clinical and electrophysiological abnormalities, which serve as criteria for a working diagnosis. METHODS: A retrospective observational case series of 28 patients were identified with the clinical diagnosis of AZOOR who shared similar abnormal electrophysiology. Details of the history and ophthalmic findings were obtained from the case notes. RESULTS: Electrophysiology demonstrated a consistent pattern of dysfunction both at the photoreceptor/retinal pigment epithelial complex but also at inner retinal levels, essentially comprising a delayed 30 Hz flicker ERG and a reduction in the EOG light rise. CONCLUSION: This study determines diagnostic criteria applicable to a group of patients with AZOOR, typically those with classic symptomatology. Electrophysiological testing can help avoid lengthy, costly, and potentially invasive investigations, and the unnecessary use of immunosuppressive therapy.

En face optical coherence tomography: a new method to analyse structural changes of the optic nerve head in rat glaucoma.

AIM: To investigate en face optical coherence tomography (eOCT) and its use as an effective objective technique for assessing changes in the glaucomatous rat optic nerve head (ONH) in vivo, and compare it with confocal scanning laser ophthalmoscopy (cSLO). METHODS: 18 Dark Agouti (DA) rats with surgically induced ocular hypertension were imaged with eOCT and cSLO at regular intervals. Assessment included three dimensional (3D) topographic reconstructions, intensity z-profile plots, a new method of depth analysis to define a "multilayered" structure, and scleral canal measurements, in relation to the degree of intraocular pressure (IOP) exposure. RESULTS: The increased depth resolution of the eOCT compared to the cSLO was apparent in all methods of analysis, with better discrimination of tissue planes. This was validated histologically. eOCT demonstrated several significant changes in imaged rat ONH which correlated with IOP exposure, including the area of ONH (p<0.01), separation between retinal vessel and scleral layers (p<0.05), and anterior scleral canal opening expansion (p<0.05). CONCLUSION: eOCT appears to be effective in assessing rat ONH, allowing detailed structural analysis of the multilayered ONH structure. As far as the authors are aware, this is the first report of scleral canal expansion in a rat model. They suggest eOCT as a novel method for the detection of early changes in the ONH in glaucoma.

A detailed phenotypic study of "cone dystrophy with supernormal rod ERG".

AIMS: To characterise the detailed phenotype of "cone dystrophy with supernormal rod ERG" in a case series of 10 patients. METHODS: 10 affected patients were examined clinically and underwent colour fundus photography, with nine undergoing detailed electrophysiological testing. Five patients were assessed further with fundus autofluorescence (AF) imaging, automated photopic and dark adapted perimetry, and dark adaptometry. Detailed colour vision assessment was performed in six subjects. Blood samples were taken from four patients for DNA extraction and mutation screening of NR2E3 was undertaken. RESULTS: The onset of symptoms was in the first and second decades of life. Subjects presented with reduced central vision and marked photophobia. All individuals were myopic and colour vision testing revealed severely reduced colour discrimination predominantly along the red-green axes; tritan colour vision was relatively well preserved. Nyctalopia is a later feature of the disorder. Funduscopy and AF imaging revealed a range of macular appearances. There was electrophysiological evidence of marked macular dysfunction, reduced and delayed cone responses, and supernormal and delayed rod responses. Photopic and dark adapted perimetry revealed central scotomata with widespread peripheral sensitivity loss. No disease causing sequence variants in NR2E3 were identified. CONCLUSIONS: The largest case series to date has been described of the clinical, psychophysical and electrophysiological characteristics of this unusual cone dystrophy with supernormal rod responses. Electrophysiological data were consistent with a post-phototransduction, but pre-inner nuclear layer, site of dysfunction. While the definitive diagnosis can only be made with electrophysiological testing, several characteristics that may increase suspicion of this diagnosis are presented.

High-titer recombinant adeno-associated virus production from replicating amplicons and herpes vectors deleted for glycoprotein H.

Production of high-titer rAAV is essential for in vivo clinical application. One limiting factor may be the failure of existing systems to replicate the packaging genome in such a way that expression of Rep and Cap proteins is coordinately amplified. DISC-HSV (disabled single-cycle virus) is a genetically modified herpes simplex virus (HSV) that by deletion of glycoprotein H (gH) is infectious only if propagated in a complementing cell line. In this study, we have used DISC-HSV as a helper for rAAV replication, and have simulated to some extent the amplication of the rep and cap genomes seen in wtAAV infection by incorporating both these and vector sequences in HSV amplicons. Facilitated production of AAV Rep and Cap proteins translates into a considerably improved recovery of rAAV, which transduces cells of the neuroretina in vivo with high efficiency. The potential for contamination with infectious herpes particles is eliminated by the use of noncomplementing (gH-) cell lines to propagate the virus, and by standard purification methods. The use of DISC-HSV and herpes-derived amplicons for production of rAAV may be a useful strategy for future in vivo studies and for clinical application.

Long-term effect of acetazolamide in a patient with retinitis pigmentosa.

The authors studied the therapeutic effect of acetazolamide on a patient with autosomal dominant retinitis pigmentosa complicated by retinal edema. In addition to reduction of macular edema and some improvement of central vision, they found an unexpected progressive increase in extrafoveal retinal sensitivity with prolonged medication. It is proposed that the therapeutic effect is mediated by alteration of retinal pigment epithelial function and that disturbed polarity is restored to a more normal state.

Experimental myopia in chicks: ocular refraction by electroretinography.

Application of devices that degrade the retinal image has been reported to produce enlargement of the ocular globe in young domestic chicks. Two such device types (domes and arches) were applied to 3-day-old chicks. The domes affected the entire visual field whereas the arches affected only the lateral field. A third group wore a thin circumorbital ring to control for possible mechanical impediments to growth. Untreated control chicks comprised a fourth group. At ages ranging from 3 to 7 wk, the chicks were refracted in their lateral visual fields with a Maxwellian view optometer based on Scheiner's principle, which yields an objective assessment of the refractive state of the photoreceptor image plane. One to seven measurements were taken from each of 48 urethane-anesthetized chicks. These indicated that the mean refractive states of the untreated eyes and the ring eyes were -0.20 D and -0.19 D, respectively, which did not differ significantly from emmetropia. In contrast, the mean refractive states of the arch eyes and the dome eyes were -4.11 D and -14.88 D, respectively, which differed significantly from emmetropia and from each other. The results indicate that early retinal image degradation can result in the relatively rapid development of a substantial myopia in these experimental animals.

A morphological analysis of experimental myopia in young chickens.

Devices that degrade vision were applied to the left eyes of 3-day old chicks. The dome device affected the entire visual field, and the arch device, only the lateral field. Control chicks wearing a circumorbital ring and untreated chicks were also examined. The dome device produced -15D and the arch device -4D of mean refractive error, while the ring and untreated chicks were emmetropic. Morphological measurements were made from macrophotographs of the intact and hemisected eyes fixed as for electron microscopy. The effects of the devices were analysed from the mean differences between the left (treated) and right (control) eyes. Nearly linear growth of the normal eye was found during the period in which measurements were taken (age 20-55 days). The ring device did not affect eye growth. The arch device significantly increased the dorsoventral equatorial diameter of the eye. The dome device had the greatest effect, and resulted in increases in both axial length and equatorial diameter during the treatment period. Dome eyes had a bulging cornea, increased anterior chamber depth, more open angle, and greater corneal diameter than controls. The axial length and equatorial diameter of the posterior segment also were increased. Two inflammatory responses of the eye were found, particularly in dome eyes; about 50% of treated eyes exhibited choroidal swelling, and vitreal clouding was found less frequently. The association between inflammation and excessive accommodation in producing the observed changes is discussed.

Functional loss in age-related Bruch's membrane change with choroidal perfusion defect.

During a prospective study of age-related macular degeneration, evidence of diffuse Bruch's membrane disease was sought using fluorescein angiographic evidence of a prolonged choroidal filling phase. Dark-adapted static perimetry was done on eight eyes with this angiographic sign and on six eyes with a similar number of drusen but no manifest choroidal perfusion abnormality. Scotopic threshold was measured using the Humphrey automated perimeter and fine matrix mapping. In eyes without delayed choroidal perfusion, no discrete areas of increased threshold were found compared with the background sensitivity. By contrast, in seven of the eight eyes with fluorescein angiographic evidence of prolonged choroidal filling, discrete areas of scotopic threshold elevation (up to 3.4 log units) were recorded; these corresponded closely to regions of choroidal perfusion abnormality. It was postulated that diffuse deposits of abnormal material might account for both the perfusion abnormality and functional loss by acting as a diffusion barrier between the choriocapillaris and the retinal pigment epithelium.

Fundus autofluorescence in age-related macular disease imaged with a laser scanning ophthalmoscope.

PURPOSE: To image and quantify the spatial distribution of fundus autofluorescence in normal subjects, to determine its age dependence, and to document the deviation from normal in patients with age-related macular disease. METHODS: Using a confocal laser scanning ophthalmoscope (cLSO), the intensity and spatial distribution of fundus autofluorescence was studied in 33 normal subjects, 97 eyes with drusen only, and 111 eyes with visual loss caused by age-related macular disease. RESULTS: Fundus autofluorescence intensity in normal subjects was highest at the posterior pole and dipped at the fovea. Autofluorescence increased with age at the posterior pole. Fundus in eyes with age-related maculopathy showed localized high autofluorescence that did not correspond with drusen. Linear pigmentation at the level of the retinal pigment epithelium (RPE), whether detached or flat, fluoresced brightly, whereas plaques of melanin did not. Areas of low and high levels of autofluorescence were seen in lesions containing choroidal new vessels. In areas of geographic atrophy, autofluorescence was low. CONCLUSIONS: The spatial distribution of background fundus autofluorescence and the correlation of autofluorescence with age in normal subjects imply that autofluorescence is derived from lipofuscin at the level of the RPE. Focal accumulation of autofluorescent material occurs at the level of the RPE in patients with drusen, but the drusen do not show marked increases in autofluorescence. It is likely that melanolipofuscin accounts for the high levels of autofluorescence, corresponding to linear pigmentation at the level of the RPE. Low-intensity autofluorescence occurs in the presence of retinal photoreceptor loss, and variable levels over disciform lesions probably relate to variations in metabolic activity of the RPE.

Abnormal dark adaptation and rhodopsin kinetics in Sorsby's fundus dystrophy.

Scotopic visual thresholds and time courses for dark adaptation were determined in eight patients with Sorsby's fundus dystrophy. Rhodopsin regeneration also was recorded in two. All patients had poor night vision and a visible yellow deposit at the level of Bruch's membrane that was confluent in the posterior pole. In retinal regions with the yellow deposit, scotopic thresholds were elevated, the rod-cone break was delayed or indistinct, the time courses for the rod portion of the dark adaptation curve was prolonged, and rhodopsin regeneration was slow in the one patient in whom measurements were made. In regions of ophthalmoscopically normal retina, dark adaptation was affected minimally, and in one patient, rhodopsin was regenerated at a normal rate. It was hypothesized that the abnormal dark adaptation and rhodopsin kinetics might be caused by reduced metabolic exchange across a thickened Bruch's membrane.

Scaling the hill of vision: the physiological relationship between light sensitivity and ganglion cell numbers.

PURPOSE: Differential light sensitivity (DLS) in white-on-white perimetry is used as a measure of ganglion cell function to estimate the amount of neuronal damage in glaucoma. The physiological relationship between DLS and ganglion cell numbers is poorly understood. Within small retinal areas, brightness information is summated, so that A * L = C, or A = C/L, where A is target area, L is threshold luminance, and C is a constant. In larger illuminated areas, as with a Goldmann size III target in perimetry, summation is incomplete, so that A(k) = C/L, where k is the coefficient of summation, and 0 < k < 1. This study tests the hypothesis that the target area (A) can be represented by the number of underlying ganglion cells (G) to give G(k) = C/L. METHODS: Normative human data for ganglion cell density within 30 degrees of retinal eccentricity were taken from the literature and corrected for lateral displacement of ganglion cells from the fovea to estimate ganglion cell receptive field density (g). The number of ganglion cell receptive fields within a Goldmann size III target (G) was calculated from target area (A) and receptive field density (g) [G = A (g)]. Normative data for DLS in the central 30 degrees (Humphrey 30-2) were taken from the literature. The coefficient summation (k) was measured empirically at each Humphrey 30-2 test point in 8 normal subjects. The relationship between DLS and G was investigated by plotting DLS as decibels (dB) against G and DLS as 1/L (1/Lamberts) against G(k). The physiological relationship was extrapolated to glaucomatous ganglion cell loss by calculating hypothetical cell losses for 3 and 6 dB sensitivity defects at each test point. RESULTS: Spatial summation increased with eccentricity. The relationship between DLS (dB) and G was curvilinear. The relationship between DLS (1/L) and G(k) was linear (r2 = 0.73). The extrapolation to glaucomatous ganglion cell loss indicated that a proportionally greater loss of ganglion cells is required in the central compared with peripheral visual field for equal losses in dB sensitivity. CONCLUSIONS: The number of underlying ganglion cells, adjusted for local spatial summation, is better reflected by the DLS scale of 1/L than by dB. If spatial summation is unchanged in glaucoma, this scale more accurately reflects the amount of neuronal damage.

Intrafamilial variation of phenotype in Stargardt macular dystrophy-Fundus flavimaculatus.

PURPOSE: To evaluate the intrafamilial phenotypic variation in Stargardt macular dystrophy-Fundus flavimaculatus (SMD-FFM). METHODS: Thirty-one siblings from 15 families with SMD-FFM were examined. Age of onset, visual acuity, and clinical features on fundus examination and fundus autofluorescence images, including presence or absence of central and peripheral atrophy and distribution of flecks, were recorded. In addition, electrophysiological studies were undertaken. RESULTS: Large differences between siblings in age of onset (median, 12 years; range, 5-23 years) were observed in six of the 15 families studied, whereas in 9 families differences in age of onset between siblings were small (median, 1 year; range, 0-3 years). Visual acuity varied two or more lines among siblings in nine families. In 10 families (67%) siblings were found to have different clinical appearance on fundus examination and fundus autofluorescence images, whereas in 5 families (33%), affected siblings had similar clinical features. Electrodiagnostic tests were performed on affected members of 12 families and disclosed similar qualitative findings among siblings. In nine families there was loss of central function only; in two, global loss of cone function; and in one, global loss of cone and rod function. CONCLUSIONS: In this series, although differences in age of onset, visual acuity, and fundus appearance were observed between siblings, electrophysiological studies demonstrated intrafamilial homogeneity in retinal function. The findings are difficult to reconcile with expression studies showing ABCR transcripts in rod photoreceptors but not in cones.

In vivo fundus autofluorescence in macular dystrophies.

OBJECTIVE: To document the deviation from normal of fundus autofluorescence in patients with inherited macular dystrophies. METHODS: The intensity and spatial distribution of fundus autofluorescence was documented in 118 patients with inherited macular dystrophies by means of a confocal laser scanning ophthalmoscope, and the images were compared with the fundus appearance and fluorescein angiograms. RESULTS: Background autofluorescence appears to be elevated in all forms of macular dystrophies examined. The pale deposits at the level of the retinal pigment epithelium in disorders such as Best disease, adult vitelliform macular dystrophy, and fundus flavimaculatus were consistently associated with higher levels of autofluorescence than the background signal. There was no strong correlation between the intensity of autofluorescence and the fluorescein angiographic sign of a dark choroid. Increased levels of autofluorescence were present in a subject with a mutation known to cause macular dystrophy but in whom there were no manifest ophthalmoscopic or functional abnormalities. CONCLUSIONS: All dystrophies examined have in common accumulation of autofluorescent material in the retinal pigment epithelium to a greater degree than that seen with age. The abnormal high background autofluorescence associated with inherited macular dystrophies confirms the impression derived from histological studies that these disorders affect the entire retinal pigment epithelium. The lack of correlation between autofluorescence and the presence of a dark choroid implies that there may be different fluorophores in different disorders. The pale deposits at the level of the retinal pigment epithelium-Bruch membrane seen in macular dystrophies have similar autofluorescence characteristics. This technique may be useful in detecting the abnormal phenotype in early disease.

Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus.

OBJECTIVE: To determine if phenotypic subtypes exist in Stargardt macular dystrophy-fundus flavimaculatus (SMD-FFM). METHODS: A cross-sectional study of 63 patients with autosomal recessive SMD-FFM was undertaken. The age of onset, duration of symptoms, visual acuity, and clinical features on fundus examination, color fundus photographs, and fundus autofluorescence images were recorded. Electrophysiological tests, including pattern, focal, and full-field electroretinogram (ERG), electro-oculogram, and color-contrast sensitivity measurement, were also performed. RESULTS: Based on electrophysiological attributes (ERG), patients with SMD-FFM could be classified into 3 groups. In group 1, there was severe pattern ERG abnormality with normal scotopic and full-field ERGs. In group 2, there was additional loss of photopic function, and in group 3, there was loss of both photopic and scotopic function. Differences in scotopic or photopic function among groups were not explained on the basis of differences in age of onset or duration of disease. CONCLUSIONS: Patients with SMD-FFM can be classified into 3 groups based on the absence or presence of generalized loss of either photopic or photopic and scotopic function. It appears that these 3 groups may represent distinct phenotypic subtypes in SMD-FFM.

Laser treatment in subjects with high-risk clinical features of age-related macular degeneration. Posterior pole appearance and retinal function.

OBJECTIVES: To verify that a few laser lesions in the posterior pole can cause drusen to resolve in patients with age-related macular degeneration, and to document central retinal sensitivity as drusen resolve. DESIGN: In a pilot study, 12 patients considered to be at high risk for sight-threatening complications from age-related macular degeneration were treated with 12 argon laser lesions in the posterior pole, with review for 12 to 24 months. RESULTS: Choroidal neovascularization developed in 1 patient 8 months after treatment, with consequent loss of central vision. In 9 of the remaining 11 patients, high-risk characteristics of drusen were reduced. Four patients had retinal pigment epithelial depigmentation, and all maintained 20/40 visual acuity at 12 months. One patient lost 3 lines of vision due to geographic atrophy after 12 months. Scotopic retinal threshold was elevated before treatment in 8 patients, compared with an age-matched comparison group. Of these, 4 patients underwent retesting 3 to 6 months after treatment, and all had improved thresholds, but only 1 patient sustained the improvement at 12 months. At 12 months, 3 of the 8 patients showed an improvement in their mean retinal threshold. Of those in whom the mean retinal threshold worsened, the mean elevation in threshold was not more than 0.6 log units. CONCLUSIONS: A few laser lesions in the posterior pole leads to resolution of drusen. There does not appear to be an increased risk for choroidal neovascularization. Retinal threshold measurements show no indication of geographic atrophy at 1 year, but cannot be excluded as a late outcome. Laser treatment may reduce the risk for profound sight-threatening lesions in age-related macular degeneration.

Clinical features in affected individuals from 21 pedigrees with dominant optic atrophy.

OBJECTIVE: To assess phenotypic variation of affected individuals from British families with autosomal dominant optic atrophy. DESIGN: Eighty-seven patients from 21 families showing evidence of linkage to chromosome 3q were identified via the Genetic Clinic of Moorfields Eye Hospital, London, England. Genetic linkage analysis was carried out with markers from chromosome 3q28-qter. Patients underwent clinical examination and psychophysical and electrophysiological testing. RESULTS: Best-corrected visual acuity ranged from 20/20 (6/6 m) to light perception. Although visual acuity was not significantly worse in older patients in the group (chi2=3.20, df=4, P>.50), it did deteriorate with age in one third of the families. Subtle or temporal pallor of the optic disc occurred in 96 (55%) of 174 eyes and total atrophy in 76 (44%). Tritanopia was found in 6 (7.5%) of 80 patients; 65 (81.2%) had a mixed color deficit. A cecocentral scotoma was found in the vast majority. Peripheral motion detection threshold was elevated in areas of visual field with raised mean surround sensitivity but not elsewhere. Pattern visual evoked potentials were of reduced amplitude and delayed. Pattern electroretinograms showed a reduced N95 component in keeping with primary ganglion cell dysfunction. CONCLUSIONS: There is wide intrafamilial and interfamilial phenotypic variation in autosomal dominant optic atrophy, with visual function in some, but not all, families deteriorating with age. There is evidence of degeneration of the ganglion cell layer predominantly from central retina, but this is not the exclusive result of either parvocellular or magnocellular cell loss.

Dominant retinitis pigmentosa associated with two rhodopsin gene mutations. Leu-40-Arg and an insertion disrupting the 5'-splice junction of exon 5.

OBJECTIVE: To determine the phenotypes of two families in which retinitis pigmentosa cosegregates with a rhodopsin (RHO) gene mutation: a leucine-to-arginine change at codon 40 (Leu-40-Arg) in one family, and a 150-base pair insertion that disrupts the RHO 5'-splice junction of exon 5 in another. PATIENTS: Three affected members of each family. RESULTS: The Leu-40-Arg mutation was associated with the onset of night blindness in the first decade of life. By the fourth decade, severe retinal functional loss was evident on dark-adapted static threshold perimetry, and electroretinographic responses were absent or barely detectable. In contrast, the RHO 150-base pair insertion was associated with the later onset of mild night vision difficulties; in two individuals, mild night vision difficulties were first noticed in the second decade while a third, a 25-year-old woman, was asymptomatic. Dark-adapted static threshold perimetry of this latter individual revealed a "regional" or class 2 pattern of retinal functional loss associated with equal loss of rod and cone electroretinographic responses. CONCLUSION: The RHO Leu-40-Arg mutation causes symptomatic retinal dysfunction by the end of the first decade while the insertion disrupting the 5'-splice junction of RHO exon 5 causes later onset "regional" or class 2 retinal dysfunction.

Autosomal dominant cone and cone-rod dystrophy with mutations in the guanylate cyclase activator 1A gene-encoding guanylate cyclase activating protein-1.

OBJECTIVE: To describe the phenotype in 3 families with dominantly inherited cone and cone-rod dystrophy with mutations in guanylate cyclase activator 1A (GUCA1A), the gene-encoding guanylate cyclase activator protein-1 (GCAP-1). METHODS: Phenotypic characterization with psychophysical and electrophysiological evaluation and confocal laser scanning ophthalmoscopy was performed in 2 families with a Tyr99Cys mutation and 1 family with a Pro50Leu mutation. Haplotype analysis was performed in the families with Tyr99Cys mutation. RESULTS: The families with a Y99C mutation were shown to be ancestrally related. Decreased visual acuity and loss of color vision occurred after the age of 20 years, followed by progressive atrophy of the central 5 degrees to 10 degrees. Electrophysiological testing revealed generalized loss of cone function, with preservation of rod function. Abnormal rod and cone sensitivities were confined to the central 5 degrees to 10 degrees. Confocal laser scanning ophthalmoscopy imaging showed abnormalities of autofluorescence in early disease. Subjects with a Pro50Leu mutation demonstrated marked variability in expressivity from minimal abnormalities of macular function to cone-rod dystrophy. CONCLUSIONS: The phenotype associated with the Y99C mutation in GUCA1A is distinctive, with little variation in expression. By contrast, that associated with the P50L mutation demonstrates variable expressivity. CLINICAL RELEVANCE: Phenotype-genotype correlation in these 2 mutations demonstrates 2 different phenotypes.