Faculty Bibliography

OBJECTIVE: To assess the frequency of mutations in the CRX, GUCY2D, and RPE65 genes in patients with Leber congenital amaurosis (LCA). PATIENTS: One hundred seventy-six probands with a clinical diagnosis of LCA were from 9 countries, with the largest subgroup being 39 probands from India. METHODS: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of 3 genes (CRX, GUCY2D, and RPE65) known to be associated with LCA. RESULTS: Of the 176 probands, 28 (15.9%) harbored possible disease-causing mutations. The relative contribution of each gene to the total number of mutations was as follows: CRX, 2.8%; GUCY2D, 6.3%; and RPE65, 6.8%. No patients who harbored mutations in these genes had associated systemic abnormalities. Molecular diagnosis allowed definitive genetic counseling in a family affected with Best disease and LCA. CONCLUSIONS: Molecular diagnosis may be of benefit to patients affected with LCA. The relative paucity of mutations found in this study suggests that more LCA-associated genes remain to be discovered. CLINICAL RELEVANCE: Molecular diagnosis can confirm and clarify the diagnosis of LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations will be established. This will facilitate the counseling of patients on their visual prognosis and the likelihood of associated systemic anomalies

PURPOSE: To define the phenotypes of retinal degenerations associated with mutations in the gene encoding CRX (cone-rod homeobox), a photoreceptor-specific transcription factor. METHODS: Heterozygotes with the E168 [delta1 bp], E168 [delta2 bp], or G217 [delta1 bp] CRXgene mutation were studied clinically, with visual function tests, including rod and cone perimetry and electroretinography (ERG), and with optical coherence tomography (OCT). RESULTS: Clinical diagnoses included autosomal dominant cone-rod dystrophy in one family (E168 [delta1 bp] mutation) and simplex Leber congenital amaurosis in two families (E168 [delta2 bp], G217 [delta1 bp] mutations). In the family with the E168 [delta1 bp] mutation, two siblings had relatively mild disease expression in the third decade of life. The central retinas of these two patients had profound loss of rod and short wavelength cone function; long/middle wavelength cone thresholds were elevated at fixation, but there were greater paracentral than central abnormalities. Peripheral retinal dysfunction was evident by psychophysics and by maximum amplitude loss for rod- and cone-isolated ERG photoreceptor responses. OCT cross-sectional reflectance images showed decreased central retinal thickness consistent with photoreceptor loss. An additional member of this family (E168 [delta1 bp] mutation) and two other patients (representing E168 [delta2 bp] and G217 [delta1 bp] mutations) had a severe phenotype with retina-wide loss of function and islands of function remaining only in the temporal periphery. CONCLUSIONS: Truncation mutations in CRX are associated with retinopathies that share phenotypic features but vary in disease severity. The disease mechanism could involve abnormal photoreceptor development compounded by a disturbance in the maintenance of photoreceptors in the mature retina

To assess local retinal function in patients with retinitis pigmentosa (RP), multi-focal ERGs and local thresholds (static visual fields) were obtained on eight RP patients with visual acuities of 20/25 or better. All eight patients showed multi-focal responses with normal timing within the central 5 deg. However, there were few responses with normal timing in the areas outside the central 7.5 deg, except in the case of the only patient with a 30 Hz full-field response with normal timing. Since full-field ERGs are dominated by responses from the periphery, this finding supplies a foundation for the commonly observed delays in the full-field cone ERGs of patients with RP. With respect to amplitude, only two patients showed multi-focal responses with near normal amplitudes anywhere in the field. The loss of amplitude at any point was not a good predictor of visual sensitivity in the Humphrey visual field. On the other hand, all areas with normal timing had near normal sensitivity. Timing changes appear to be an early indication of local retinal damage to the cone system. Nearly all areas with sensitivity losses greater than 0.5 log unit, and some areas with near normal sensitivity, showed significantly delayed multi-focal ERGs. Finally areas with extreme sensitivity loss show multi-focal responses with a wide range of amplitudes and implicit times across patients, suggesting different mechanisms of disease action in different patients

PURPOSE: To determine whether the rod and cone photoreceptors are affected in patients with diabetic retinopathy. METHODS: Twelve patients with diabetes and varying levels of retinopathy and nine age-similar control observers participated in this study. Two-color (500 versus 650 nm) dark-adapted thresholds were measured as a function of retinal eccentricity. Full-field flash electroretinograms were obtained using brief, high-intensity flashes. Dark-adapted rod-isolated (Wratten 47B filter) and light-adapted cone-isolated (Wratten 26 filter) electroretinographic responses were measured as a function of flash intensity. The a-wave data were fitted with a model based on photopigment transduction to obtain values for the parameters of Rmax (the maximal response) and log S (sensitivity). Standard clinical 30-Hz flicker electroretinographic responses were also measured. RESULTS: Psychophysically measured dark-adapted thresholds were elevated primarily at eccentricities of 5 degrees and 10 degrees from the fovea. Analysis of rod and cone a-wave data showed that Rmax was normal in most of the patients, but log S was reduced. Analysis of b-wave and oscillatory potential parameters showed rod and cone postreceptoral abnormalities, including changes in the rod-isolated semisaturation constant (log k), cone-mediated 30-Hz flicker, and cone-isolated oscillatory potentials. The electrophysiological results were not significantly correlated with blood glucose or glycosylated hemoglobin level. CONCLUSIONS: The results provide evidence for rod and cone receptoral and postreceptoral deficits in patients with diabetic retinopathy. The photoreceptor changes are primarily in the log S (sensitivity) parameter and are attributed to transduction abnormalities

The purpose of this study was to determine the extent of peripheral visual deficits in patients with early age-related macular degeneration (ARMD) using electrophysiological and psychophysical techniques. Dark-adaptation curves, electro-oculograms (EOGs), and electroretinograms (ERGs) were obtained from patients with early ARMD and from normally sighted control subjects. The control subjects' data were used to calculate age-dependent 95% confidence intervals for each measure of visual function. For the control subjects, performance on all our measures of visual function decreased with age. For the patients with early ARMD, the cone system absolute thresholds, EOG ratios, and cone-dominated ERG amplitudes and implicit times were within the range of normal age-related changes. Rod system absolute thresholds, cone-rod break times, and rod-dominated electroretinographic measures were abnormal in some patients. These results suggest that when the effects of aging are taken into account, some patients classified as early ARMD may not show significant changes in peripheral retinal function with standard clinical tests

PURPOSE: To assess changes in measures of visual function in patients with retinitis pigmentosa (RP) over time. METHODS: Patients with RP and visual acuity of 20/40 or better and central visual fields of 10 degrees or larger were enrolled in a 9-year prospective study. The following measures of visual function were obtained annually over the follow-up period: visual acuity, Goldmann visual fields (V4e target), focal electroretinograms, and hue discrimination. RESULTS: Over the follow-up period, the averaged group data showed changes in all measures of visual function. The smallest amount of change occurred for visual acuity and hue discrimination, and the greatest amount of change occurred for visual field area. Examination of individual patient data over the follow-up period indicated that the rates of change varied among patients and that losses in function for one measure did not correlate well with losses on other measures. CONCLUSIONS: These results stress that although visual function deteriorated over time for this group of patients with RP, there were differences among our measures of visual function. Measures that primarily assess central retinal function change relatively slowly compared with measures that assess more peripheral retinal function