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Background: Leber congenital amaurosis (LCA) is an infrequently encountered congenital form of retinitis pigmentosa with marked genetic and clinical heterogeneity. Thus far, 10 genes have been identified in this disorder since 1996. In the future, LCA may become treatable by gene and/or pharmacological intervention, and these therapies will likely be gene specific, giving major significance to rapid gene identification and gene-phenotype studies., Objective: To test the hypothesis that parents of patients with LCA have identifiable electroretinographic and psychophysical changes. SUBJECTS, MATERIALS, AND METHODS: Complete eye examinations and electroretinographic studies were performed on 2 sets of parents whose offspring were diagnosed as having LCA and who were found to carry a mutation in 1 of the 10 LCA genes-GUCY2D. One set of parents also underwent static perimetry threshold measurements., Results: We found that single flash-light-adapted a- and b-wave amplitudes, 30-Hz flicker, or both cone signals were significantly decreased in amplitude in 4 heterozygotes, while 2 parents showed delayed 30-Hz flicker implicit times. Electroretinographic rod-mediated signals were normal in 2 of the heterozygotes, but subnormal in 2. Static perimetry testing showed normal thresholds in the 2 heterozygotes tested., Main Outcome Measures: Single flash-light-adapted a- and b-wave amplitudes and implicit times, 30- or 32-Hz flicker amplitudes and implicit times, rod-mediated signals, and dark-adapted, rod-mediated thresholds., Conclusions: Some carrier parents of patients with LCA and a GUCY2D mutation develop measurable, cone and possibly rod abnormalities most consistent with a mild cone-rod dysfunction. This correlates well with the known retinal expression pattern of GUCY2D, which is considerably higher in cone compared with rod photoreceptor cells.

Ten rhodopsin mutations have been found in a screen of 282 subjects with retinitis pigmentosa (RP), 76 subjects with Leber congenital amaurosis, and 3 subjects with congenital stationary night blindness. Eight of these mutations (gly51-to-ala, val104-to-ile, gly106-to-arg, arg135-to-gly, cys140-to-ser, gly188-to-glu, val209-to-met, and his211-to-arg) produce amino acid substitutions, one (gln64-to-ter) introduces a stop codon, and one changes a guanosine in the intron 4 consensus splice donor sequence to thymidine. Cosegregation of RP with gln64-to-ter, gly106-to-arg, arg135-to-gly, cys140-to-ser, gly188-to-glu, his211-to-arg, and the splice site guanosine-to-thymidine indicates that these mutations are likely to cause retinal disease. Val104-to-ile does not cosegregate and is therefore unlikely to be related to retinal disease. The relevance of gly51-to-ala and val209-to-met remains to be determined. The finding of gln64-to-ter in a family with autosomal dominant RP is in contrast to a recent report of a recessive disease phenotype associated with the rhodopsin mutation glu249-to-ter. In the present screen, all of the mutations that cosegregate with retinal disease were found among patients with RP. The mutations described here bring to 35 the total number of amino acid substitutions identified thus far in rhodopsin that are associated with RP. The distribution of the substitutions along the polypeptide chain is significantly nonrandom: 63% of the substitutions involve those 19% of amino acids that are identical among vertebrate visual pigments sequenced to date.

DNA samples from 161 unrelated patients with autosomal dominant retinitis pigmentosa were screened for point mutations in the rhodopsin gene by using the polymerase chain reaction and denaturing gradient gel electrophoresis. Thirty-nine patients were found to carry 1 of 13 different point mutations at 12 amino acid positions. The presence or absence of the mutations correlated with the presence or absence of retinitis pigmentosa in 174 out of 179 individuals tested in 17 families. The mutations were absent from 118 control subjects with normal vision.

Patients with certain systemic deficiencies in the degradation of glycosaminoglycans (GAGs) often suffer from a retinal degeneration similar to that seen in retinitis pigmentosa. This applies to mucopolysaccharidosis (MPS) types I, II, and III, but not to type VI. The retinal pigment epithelium (RPE) is thought to contribute significantly to the synthesis and degradation of proteoglycans in the interphotoreceptor matrix. This raises the possibility that a defect in the synthesis or degradation of GAGs by the RPE may be related to some forms of retinal degeneration. In the present work, RPE from normal and RP donors was investigated for the capacity to correct deficiencies in GAG degradation by cultured skin fibroblasts from patients with different forms of MPS. A cross-correction technique was used in which abnormal increases in the incorporation of 35S-sulfate into GAGs by MPS fibroblasts was measured in the absence or presence of RPE cultures. RPE from normal donors corrected the defects in GAG degradation of fibroblasts from patients with MPS I, II, and III, but not MPS VI. The RPE from four donors with retinitis pigmentosa (one autosomal dominant, one sex-linked, and two isolated cases) and one donor with an unclassified isolated retinal degeneration demonstrated the same capacities to correct the MPS deficiencies as did normal RPE. Therefore, although retinitis pigmentosa is a heterogeneous disorder with several possible etiologies, no evidence was found in these five patients for a defect in GAG degradation that resembles the deficiencies of MPS patients.

Bilateral symmetry of disorders of vision is examined in 60 typical patients with retinitis pigmentosa. We observed a very high degree of interocular congruence in the patterns of both kinetic visual field defects and threshold profiles and in abnormalities of foveal colour discrimination and visual acuity. Abnormalities of foveal colour vision are highly correlated with the extent of visual field loss.

A brother and sister, born to consanguineous parents, had pigmentary retinopathy in a pericentral distribution. The retinopathy was noted in infancy when the siblings were examined for strabismus. The optic disks, maculae, and retinal vessels were normal. There was mild reduction in amplitude of both scotopic and photopic electroretinographic responses. Both patients had moderate hyperopic astigmatism and esotropia. The fundus and visual acuity remained unchanged over periods of nine and 13 years in the brother and sister, respectively. Results of ocular examinations on the father, mother, and an older sister were normal. These findings support an autosomal recessive mode of inheritance in this family with pericentral pigmentary retinopathy.

We report the results of cataract extraction in 26 eyes of 16 patients with retinitis pigmentosa or Usher's syndrome. There was no unusual incidence of intraoperative or postoperative complications in this group. After adequate preoperative counseling, and after we made certain that the patients' expectations were in line with anticipated results, 15 of our 16 patients were satisfied with the surgical outcome. Four patients who had a conventional cataract extraction with postoperative contact lens wear in one eye and an intraocular lens implanted in the other eye preferred the eye with the implant. There was no evidence that intraocular lens implantation interfered with the post-cataract-extraction care of the patients.

Retinal abnormalities associated with hearing loss may be inherited alone or with additional manifestations. Environmental insults, such as rubella embryopathy, may also cause these abnormalities. We studied 13 patients with retinal abnormalities and hearing loss. Five had Usher's syndrome (retinitis pigmentosa and hearing impairment), one had crystalline retinopathy, two had associated enamel dysplasias, two had clumped pigmentary retinopathy, and three had Amalric-Diallinas syndrome. Our findings suggest considerable heterogeneity of syndromes involving retinal abnormalities and hearing loss.