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Purpose: To evaluate the clinical and electrophysiologic findings in a family with two heterozygous sequence changes in the peripherin-retinal degeneration slow (RDS) gene., Methods: A family study was done of a pedigree obtained by screening for rhodopsin, peripherin/RDS, or rom-1 gene mutations in probands from families with hereditary retinal diseases. The patients consisted of three affected and four unaffected members from a family with cone dystrophy. Ophthalmoscopy, visual field testing, electroretinography, and DNA analysis were performed., Results: Denaturing gradient gel electrophoresis showed the presence of two different sequence changes in the RDS genes of this family. In three members with a retinal disease, the authors observed the substitution of phenylalanine for serine in codon 27 (serine-27-phenylalanine). The clinical and functional findings in these three patients were most consistent with autosomal-dominant cone dystrophy. Three other family members, unaffected with retinal disease, were found to show a substitution of serine for cysteine in codon 72 of the peripherin protein., Conclusion: A peripherin/RDS sequence change may produce a cone dystrophy with minimal ophthalmoscopic changes in the macula and limited peripheral degenerative changes. Caution is warranted to avoid ascribing nondisease-causing sequence polymorphisms in candidate genes as responsible for determining the development of a retinal disease phenotype.

Purpose: To establish the normal short-term range of variation in the measurement of visual acuity in patients with retinitis pigmentosa., Methods: Sixteen patients (31 eyes) with retinitis pigmentosa, whose visual acuity ranged from 20/25 to 20/200, participated in this prospective clinical study. The best-corrected visual acuity in undilated and in dilated conditions was recorded independently by two masked observers on two visits of each patient within a 2-week interval by means of the Early Treatment Diabetic Retinopathy Study charts (The Lighthouse, Long Island City, NY)., Results: Using mixed-model analysis, a reasonable upperbound for intervisit (intraobserver) variability of 6.0 letters for the visual acuity of patients with undilated pupils and 6.3 letters for the visual acuity of patients with dilated pupils and the corresponding maximum interobserver variability of visual acuity of 5.7 letters in patients with either undilated or dilated pupils on the Early Treatment Diabetic Retinopathy Study charts were computed. The overall average interobserver and intraobserver variability in visual acuity ranged from 1.3-2.3 letters., Conclusions: A change in visual acuity of seven letters or more on the standardized Early Treatment Diabetic Retinopathy Study charts may be considered important in patients with retinitis pigmentosa. For these patients with minor lens opacity, visual acuity measurements obtained with undilated and dilated pupils were similar. These findings help to establish guidelines for monitoring the response of visual acuity during any future therapeutic intervention trials or for determining substantial changes in visual acuity over time when the course of visual acuity loss in such patients is monitored.

Thirteen patients with cone-rod dystrophy were assigned into one of four previously described category subtypes according to clinical, electrophysiologic, and psychophysical criteria. The time course of rod dark adaptation was determined for each patient by means of a Goldmann-Weekers dark adaptometer. Nine of the 13 patients showed a normal time to return to their dark-adapted thresholds before bleaching, while four patients showed a prolonged recovery time. The four patients with a prolonged rod-recovery time were all from the same clinical subtype and showed a similar fundus appearance as well as similar electrophysiologic and psychophysical findings.

Background: Mutations in the human peripherin/retinal degeneration slow (rds) gene have been found in patients with macular dystrophies as well as in those with autosomal dominant retinitis pigmentosa. The authors studied the clinical features in members of two families with autosomal dominant retinitis pigmentosa and a previously unreported mutation in the peripherin/rds gene., Methods: Affected family members underwent a clinical ophthalmic examination and electrophysiologic and psychophysical testing. Available family members were evaluated for a mutation in the peripherin/rds gene., Results: A mutation in codon 216 of the peripherin/rds gene, resulting in a substitution of the amino acid serine for proline, was found to segregate with retinitis pigmentosa in these two families. Ocular features of this mutation include a later onset of more notable ophthalmoscopic, electrophysiologic, and psychophysical abnormalities of the retina, an atrophic-appearing foveal lesion, and extrafoveal atrophic and hyperpigmented degenerative retinal changes, which were found more posteriorly than usually seen in patients with retinitis pigmentosa. Visual field testing showed a partial ring scotoma or pear-shaped configuration of the remaining portions of the peripheral fields., Conclusion: A previously undescribed mutation in the peripherin/rds gene is responsible for an autosomal dominant retinitis pigmentosa phenotype. This phenotype tends to be associated with the development of an atrophic-appearing foveal lesion, more posterior distribution of pigmentary changes involving the vascular arcades, the presence of a partial ring scotoma or a pear-shaped configuration of the peripheral visual field, and a later onset of more extensive retinal structural and functional impairment.

Purpose: To determine the effectiveness of methazolamide for improving visual acuity and macular edema in patients with retinitis pigmentosa., Methods: Seventeen subjects with retinitis pigmentosa and chronic macular edema participated in a prospective, placebo-controlled, double-masked, crossover design study in which either methazolamide or a placebo was taken for 3 weeks. Visual acuity, fluorescein angiograms, and subjective impressions were obtained at baseline and after 3 weeks of treatment with each substance. A subgroup of subjects were enrolled in a more extended period of methazolamide treatment for an additional 3 months., Results: Methazolamide resulted in the improvement of angiographic macular edema in 9 of 17 subjects. As a group, visual acuity statistically improved with methazolamide. However, improvement in at least one eye, of between two and four lines more than while taking placebo, occurred in only three (undilated pupils) or four (dilated pupils) subjects. Subjective improvement during treatment with methazolamide but not placebo occurred in only one subject. An extended period of methazolamide treatment for an additional 3 months in a subgroup of patients did not result in additional beneficial effects on visual acuity. In fact, a partial rebound in the extent of macular edema was found., Conclusions: Although angiographic improvement of macular edema can occur in patients with retinitis pigmentosa treated with methazolamide, notable (between 3 and 4 lines) or even moderate (between 2 and 3 lines) visual acuity improvement was seen in relatively few patients. When methazolamide was administered in a placebo-controlled fashion, subjective improvement in visual function also was not readily apparent. A more substantial subjective improvement in visual function had occurred with the use of acetazolamide in five of six subjects who also had participated in a previous treatment trial with the use of acetazolamide.

Background: Prolongation in recovery of rod thresholds has been demonstrated in Stargardt's dystrophy. One possible explanation for this finding includes an impairment of vitamin A transport by the retinal pigment epithelium (RPE). By delivering an increased amount of vitamin A to the RPE, it might be possible to overcome a relative deficiency of vitamin A utilization or transport, and thus improve rod dark adaptation., Methods: Baseline dark-adapted rod final thresholds were measured for five patients with Stargardt's dystrophy after 60 minutes of dark adaptation. A full dark-adaptation curve was then measured after exposure to a bleaching light for 5 minutes. Time of recovery to within 0.2 log units of the prebleach dark-adapted rod threshold was determined. Each subject then took a 14- to 18-day course of oral vitamin A, 50,000 IU daily. Dark adaptation was then reassessed using the same pretreatment protocol., Results: Before treatment, all five patients had a prolongation of their rod recovery curve. There was no statistically significant difference between subjects in mean time taken to reach prebleach rod baseline thresholds before and after vitamin A treatment., Conclusions: These findings do not rule out the possibility that a delay in rod dark adaptation in Stargardt's dystrophy results from an inability to transport vitamin A from the RPE to photoreceptor cells. Nevertheless, a high dose of oral vitamin A taken for at least 14 days did not provide any objective improvement in dark-adaptation function in five such patients.

Purpose: To assess the effect of methazolamide on chronic macular edema in patients with retinitis pigmentosa in a double-masked, placebo-controlled, crossover study. Three subjects who had an initial improvement in their macular edema as demonstrated on fluorescein angiography received a continued course of methazolamide to assess its effect on macular edema., Methods: Seventeen subjects were enrolled in the initial study. On angiography, nine subjects demonstrated improvement in their macular edema with the use of methazolamide for 3 weeks; three of these continued receiving the drug at a dosage of 50 mg twice daily for either an additional 6 (one subject) or 12 (two subjects) weeks. All subjects were assessed at each visit with fluorescein angiography and on best corrected visual acuity, both undilated and dilated; a subjective impression was also documented., Results: After 6 and 12 weeks of treatment, all three subjects experienced a rebound of angiographic macular edema to some extent. The visual acuity varied only slightly (up to 7 letters) from both the baseline and most recent examinations after 6 and 12 weeks of treatment., Conclusion: Results from these few subjects suggest that at least a partial rebound of macular edema seen angiographically may occur with the continued use of methazolamide in patients with retinitis pigmentosa and chronic macular edema. Further study is required to determine if this rebound effect also occurs in treatment of other ocular disorders with chronic macular edema.

Two members of a family with autosomal dominant retinitis pigmentosa were found to have a cytosine-to-thymine mutation in the second nucleotide of codon 267 in the rhodopsin gene that resulted in a proline-to-leucine change. Two members of another family with autosomal dominant retinitis pigmentosa showed a guanine-to-thymine mutation in the first nucleotide of codon 190 in the rhodopsin gene that resulted in an aspartate-to-tyrosine change. Three members from a third family with autosomal dominant retinitis pigmentosa were also found to have a mutation in codon 190; however, this guanine-to-adenine mutation in the first nucleotide of codon 190 resulted in an aspartate-to-asparagine change. The relatively less severe functional retinal impairment in our patients with a transmembrane codon 267 rhodopsin gene mutation is generally comparable with that observed in a previously described codon 58 transmembrane mutation. The two families with different intradiscal codon 190 mutations showed a considerable difference in severity of their disease.

Three members of one family and one person from another family were found to have a guanine-to-adenine transition mutation in the first nucleotide of codon 106 in the rhodopsin gene that results in a glycine-to-arginine change. All affected members presented with a similar phenotype that included a regional predilection for pigmentary changes to occur in the inferior retina as well as visual field impairment predominantly in the superior hemisphere. The distribution of pigmentary changes, pattern of visual field loss, and substantial remaining electroretinographic amplitudes with normal implicit times were consistent with a form of "sector" retinitis pigmentosa. We documented the association of a distinct phenotype of autosomal dominant retinitis pigmentosa with a better visual prognosis and a specific rhodopsin gene mutation.

Six members of a family with autosomal dominant retinitis pigmentosa were found to have a cytosine-to-thymine transition mutation in the second nucleotide of codon 17 in the rhodopsin gene that resulted in a threonine to methionine change. Three members from another family with autosomal dominant retinitis pigmentosa showed a guanine-to-adenine transition mutation in the first nucleotide of codon 182 in the rhodopsin gene that resulted in a glycine to serine change. Each of these two mutations presented with a similar phenotype because both showed a regional predilection for pigmentary changes to occur in the inferior part of the retina as well as field impairment predominantly in the superior hemisphere. Electroretinographic amplitudes were more substantial than usually encountered in other forms of retinitis pigmentosa, a finding consistent with the better visual prognosis in patients with either of these two mutations. This article documents the association of two similar phenotypes of autosomal dominant retinitis pigmentosa with specific gene defects at a molecular level.

Eight members of a family with autosomal dominant retinitis pigmentosa were found to have a cytosine-to-guanine (C-to-G) transversion mutation in the second nucleotide of codon 58 of the rhodopsin gene, causing a substitution of the amino acid arginine for threonine. Five of these individuals were examined clinically. There was a distinct phenotypic expression of the gene defect within this family that included a regional predilection for pigmentary changes in the inferior and inferonasal parts of the retina, as well as field impairment predominantly in the superior hemisphere. Characteristic electroretinographic recordings and psychophysical threshold profiles also helped to identify this phenotype that, on a relative basis, causes less severe photoreceptor cell functional impairment than often occurs in other subtypes of retinitis pigmentosa. This report documents the association of a clinically recognizable phenotype in a family with autosomal dominant retinitis pigmentosa and a specific gene defect at the molecular level.

Using multipoint linkage analysis in 20 families segregating for X-linked retinitis pigmentosa (XLRP), the lod scores on a map of eight RFLP loci were obtained. Our results indicate that under the hypothesis of homogeneity the maximal multipoint lod score supports one disease locus located slightly distal to OTC at Xp21.1. Heterogeneity testing for two XLRP loci suggested that a second XLRP locus may be located 8.5 cM proximal to DXS28 at Xp21.3. Further heterogeneity testing for three disease loci failed to detect a third XLRP locus proximal to DXS7 in any of our 20 XLRP families.

The status of the blood-retinal barrier (BRB) in carriers of choroideremia and X-linked retinitis pigmentosa (XLRP) was determined by vitreous fluorophotometry (VF) and compared with that in female control subjects. Electroretinographic (ERG) amplitudes were measured to determine the overall functional integrity of retinal rods and cones. Comparison of the VF results showed an abnormal BRB in at least some carriers of XLRP, particularly those with peripheral fundus pigmentary changes, but not in carriers of choroideremia with even moderately extensive pigmentary changes. The abnormal BRB in XLRP carriers, with or without peripheral fundus pigmentary changes, was associated with at least moderate to moderately extensive reduction in scotopic ERG amplitudes, while the normal VF results in choroideremia carriers were associated with normal scotopic ERG amplitudes. However, in XLRP carriers, mild to modest reductions in ERG scotopic responses were seen in the presence of normal VF findings.

Twelve patients with retinitis pigmentosa and chronic macular edema were prospectively treated for 2-week periods with acetazolamide or a placebo in a masked, crossover study. Ten of the 12 patients had both subjective and objective improvement in visual acuity when treated with acetazolamide. Improvement was seen even in patients with an acuity as good as 20/25 at baseline as well as in patients with macular edema present for more than a decade. A dosage of 500 mg/d was found to be more effective than 250 mg/d. Six patients (50%) showed lessening of their macular edema on fluorescein angiography. This angiographically demonstrated improvement was predominantly due to less detectable leakage from retinal capillaries rather than from choroidal capillaries through the retinal pigment epithelium. Improvement in visual acuity was seen in some patients without a detectable change in the amount of angiographic fluorescein leakage.