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Importance: The p.Asp67Tyr genetic variant in the GJA3 gene is responsible for congenital cataracts in a family with a high incidence of glaucoma following cataract surgery., Objective: To describe the clinical features of a family with a strong association between congenital cataracts and glaucoma following cataract surgery secondary to a genetic variant in the GJA3 gene (NM_021954.4:c.199G>T, p.Asp67Tyr)., Design, Setting, and Participants: This was a retrospective, observational, case series, genetic association study from the University of Iowa spanning 61 years. Examined were the ophthalmic records from 1961 through 2022 of the family members of a 4-generation pedigree with autosomal dominant congenital cataracts., Main Outcomes and Measures: Frequency of glaucoma following cataract surgery and postoperative complications among family members with congenital cataract due to the p.Asp67Tyr GJA3 genetic variant., Results: Medical records were available from 11 of 12 family members (7 male [63.6%]) with congenital cataract with a mean (SD) follow-up of 30 (21.7) years (range, 0.2-61 years). Eight of 9 patients with congenital cataracts developed glaucoma, and 8 of 8 patients who had cataract surgery at age 2 years or younger developed glaucoma following cataract surgery. The only family member with congenital cataracts who did not develop glaucoma had delayed cataract surgery until 12 and 21 years of age. Five of 11 family members (45.5%) had retinal detachments after cataract extraction and vitrectomy. No patients developed retinal detachments after prophylactic 360-degree endolaser., Conclusions and Relevance: The GJA3 genetic variant, p.Asp67Tyr, was identified in a 4-generation congenital cataract pedigree from Iowa. This report suggests that patients with congenital cataract due to some GJA3 genetic variants may be at especially high risk for glaucoma following cataract surgery. Retinal detachments after cataract extraction in the first 2 years of life were also common in this family, and prophylactic retinal endolaser may be indicated at the time of surgery.

Importance: High-dose and long-duration opioid prescriptions remain relatively common among children and adolescents, but there is insufficient research on the association of state laws limiting the dose and/or duration of opioid prescriptions (referred to as opioid prescribing cap laws) with opioid prescribing for this group., Objective: To examine the association between state opioid prescribing cap laws and the receipt of opioid prescriptions among children and adolescents., Design Setting and Participants: This repeated cross-sectional study used a difference-in-differences approach accounting for staggered policy adoption to assess the association of state opioid prescribing cap laws in the US from January 1, 2013, to December 31, 2019, with receipt of opioid prescriptions among children and adolescents. Analyses were conducted between March 22 and December 15, 2021. Data were obtained from the OptumLabs Data Warehouse, a national commercial insurance claims database. The analysis included 482 118 commercially insured children and adolescents aged 0 to 17 years with full calendar-year continuous insurance enrollment between 2013 and 2019. Individuals were included for every year in which they were continuously enrolled; they did not need to be enrolled for the entire 7-year study period. Those with any cancer diagnosis were excluded from analysis., Exposure: Implementation of a state opioid prescribing cap law between January 1, 2017, and July 1, 2019. This date range allowed analysis of the same number years for both pre-cap and post-cap data., Main Outcomes and Measures: Outcomes of interest included receipt of any opioid prescription and, among those with at least 1 opioid prescription, the mean number of opioid prescriptions, mean morphine milligram equivalents (MMEs) per day, and mean days' supply., Results: Among 482 118 children and adolescents (754 368 person-years of data aggregated to the state-year level), 245 178 (50.9%) were male, with a mean (SD) age of 9.8 (4.8) years at the first year included in the sample (data on race and ethnicity were not collected as part of this data set, which was obtained from insurance billing claims). Overall, 10 659 children and adolescents (2.2%) received at least 1 opioid prescription during the study period. Among those with at least 1 prescription, the mean (SD) number of filled opioid prescriptions was 1.2 (0.8) per person per year. No statistically significant association was found between state opioid prescribing cap laws and any outcome. After opioid prescribing cap laws were implemented, a -0.001 (95% CI, -0.005 to 0.002) percentage point decrease in the proportion of youths receiving any opioid prescription was observed. In addition, percentage point decreases of -0.01 (95% CI, -0.10 to 0.09) in high-dose opioid prescriptions (>50 MMEs per day) and -0.02 (95% CI, -0.12 to 0.08) in long-duration opioid prescriptions (>7 days' supply) were found after cap laws were implemented., Conclusions and Relevance: In this cross-sectional study, no association was observed between state opioid prescribing cap laws and the receipt of opioid prescriptions among children and adolescents. Alternative strategies, such as opioid prescribing guidelines tailored to youths, are needed., Competing Interests: Conflict of Interest Disclosures: Dr Bicket reported receiving grants from the Centers for Disease Control and Prevention, the Michigan Department of Health and Human Services, and the National Institutes of Health and personal fees from Alosa Health and axialHealthcare outside the submitted work. No other disclosures were reported., (Copyright 2022 Stone EM et al. JAMA Health Forum.)

Importance: Mutations in the myocilin (MYOC) gene are the most common molecularly defined cause of primary open-angle glaucoma that typically occurs in patients with high intraocular pressures (IOP). One MYOC mutation, p.Gln368Ter, has been associated with as many as 1.6% of primary open-angle glaucoma cases that had a mean maximum recorded IOP of 30 mm Hg. However, to our knowledge, the role of the p.Gln368Ter mutation in patients with normal-tension glaucoma (NTG) with an IOP of 21 mm Hg or lower has not been investigated., Objective: To evaluate the role of the p.Gln368Ter MYOC mutation in patients with NTG., Design, Setting, and Participants: In this case-control study of the prevalence of the p.Gln368Ter mutation in patients with NTG, cohort 1 was composed of 772 patients with NTG and 2152 controls from the United States (Iowa, Minnesota, and New York) and England and cohort 2 was composed of 561 patients with NTG and 2606 controls from the Massachusetts Eye and Ear Infirmary and the NEIGHBORHOOD consortium. Genotyping was conducted using real-time polymerase chain reaction that was confirmed with Sanger sequencing, the imputation of genome-wide association study data, or an analysis of whole-exome sequence data. Data analysis occurred between April 2007 and April 2018., Main Outcomes and Measures: Comparison of the frequency of the p.Gln368Ter MYOC mutation between NTG cases and controls with the Fisher exact test., Results: Of 6091 total participants, 3346 (54.9%) were women and 5799 (95.2%) were white. We detected the p.Gln368Ter mutation in 7 of 772 patients with NTG (0.91%) and 7 of 2152 controls (0.33%) in cohort 1 (P = .03). In cohort 2, we detected the p.Gln368Ter mutation in 4 of 561 patients with NTG (0.71%) and 10 of 2606 controls (0.38%; P = .15). When the cohorts were analyzed as a group, the p.Gln368Ter mutation was associated with NTG (odds ratio, 2.3; 95% CI, 0.98-5.3; P = .04)., Conclusions and Relevance: In cohorts 1 and 2, the p.Gln368Ter mutation in MYOC was found in patients with IOPs that were 21 mm Hg or lower (NTG), although at a frequency that is lower than previously detected in patients with higher IOP. These data suggest that the p.Gln368Ter mutation may be associated with glaucoma in patients with normal IOPs as well as in patients with IOPs that are greater than 21 mm Hg.

Importance: Stargardt disease is a phenotypically diverse macular dystrophy caused by the autosomal recessive inheritance of mutations in ABCA4. Pseudodominant transmission occurs more often than might be expected because of the relatively high carrier frequency of pathogenic ABCA4 variants. Genetic characterization of affected individuals permits a more precise understanding of these genotype-phenotype associations., Observations: In this case series, we explore the clinical courses and genotypes of a woman and her 2 daughters with pseudodominant transmission of Stargardt disease. The mother had choroidal neovascularization that was treated with bevacizumab. Both daughters exhibited worse vision than their mother, despite lacking choroidal neovascularization, because of the extent of photoreceptor and retinal pigment epithelium atrophy in the macula. Genetic testing confirmed pseudodominant inheritance and the presence of 3 ABCA4 alleles within the family., Conclusions and Relevance: These cases emphasize the clinical relevance of recognizing pseudodominant transmission and the resultant phenotypic variability. Differing degrees of visual impairment in these patients emphasize the need to continue refining our understanding of how individual ABCA4 mutations contribute to phenotype.

Age-related macular degeneration is a very common condition that is caused by a complex interplay of genetic and environmental factors. It is likely that, in the future, genetic testing will allow physicians to achieve better clinical outcomes by administering specific treatments to patients based on their genotypes. However, improved outcomes for genotyped patients have not yet been demonstrated in a prospective clinical trial, and as a result, the costs and risks of routine genetic testing currently outweigh the benefits for patients with age-related macular degeneration.

Importance: Screening for splice site mutation c.828+3A>T in the peripherin 2 (PRPH2) gene should be a high priority in families with highly variable retinal dystrophies. The correction of missplicing is a potential therapeutic target., Objective: To determine the prevalence, genetic origin, and molecular mechanism of a donor c.828+3A>T mutation in the PRPH2 (peripherin 2, retinal degeneration slow) gene in individuals with retinal dystrophies., Design, Setting, and Participants: Case-control study that took place at the University of Texas Health Science Center, the University of Iowa, and the Retina Foundation of the Southwest, from January 1, 1987, to August 1, 2014, including affected individuals from 200 families with a diagnosis of autosomal dominant retinitis pigmentosa, 35 families with unspecified macular dystrophies, and 116 families with pattern dystrophy. Participants were screened for the c.828+3A>T mutation by restriction-enzyme digest, single-strand conformational polymorphism screening, or bidirectional sequencing. Haplotypes of polymorphic markers flanking the PRPH2 locus and sequence variants within the gene were determined by denaturing gel electrophoresis or automated capillary-based cycle sequencing. The effect of the splice site mutation on the PRPH2 transcript was analyzed using NetGene2, a splice prediction program and by the reverse transcription polymerase chain reaction of illegitimate transcripts from peripheral white blood cells., Main Outcomes and Measures: Results of testing for splice site mutation, haplotypes, and alternate transcripts., Results: The PRPH2 mutation was found in 97 individuals of 19 independently ascertained families with a clinical diagnosis of retinitis pigmentosa, macular dystrophy, and/or pattern dystrophy. All affected individuals also shared a rare haplotype of approximately 644 kilobase pairs containing the c.828+3A>T mutation, which extends from the short tandem repeat polymorphism D6S282 to c.1013G>A (rs434102, a single-nucleotide polymorphism) in exon 3 of PRPH2, suggesting this mutation is from a common ancestor and is a founder mutation. It has a prevalence of 2% in families diagnosed as having autosomal dominant retinitis pigmentosa and 10% in families with variable clinical diagnosis of pattern, macular, and retinal dystrophies. Individuals with the c.828+3A>T mutation expressed a PRPH2 transcript not found in control participants and that was consistent with abnormal splicing., Conclusions and Relevance: The PRPH2 c.828+3A>T splice site mutation is a frequent cause of inherited retinal dystrophies and is owing to the founder effect. The likely cause of disease is the missplicing of the PRPH2 message that results in a truncated protein product. Identifying the genetic etiology assists in more accurate management and possible future therapeutic options.

Importance: The effects of position on retinal and choroidal structure are absent from the literature yet may provide insights into disease states such as age-related macular degeneration (AMD)., Objective: To evaluate the effect of postural change on retinal and choroidal structures in healthy volunteers and patients with non-neovascular AMD., Design, Setting, and Participants: Prospective observational case series at an academic tertiary care retina service from September 2013 to April 2014 involving 4 unaffected volunteers (8 eyes) and 7 patients (8 eyes) with intermediate AMD. Healthy volunteers selected for the study had no evidence of ocular disease. Patients with AMD were required to have at least 10 intermediate-sized drusen., Exposures: Spectral-domain optical coherence tomography with enhanced depth imaging in upright (sitting) and supine positions. Stable imaging was achieved using a rotating adjustable mechanical arm that we constructed to allow the optical coherence tomography transducer to rotate 90°. The Iowa Reference Algorithms were used to quantify choroid and choriocapillaris thicknesses., Main Outcomes and Measures: Changes in sitting and supine position central macular thickness (in micrometers), total macular volume (in cubic millimeters), choroidal thickness (in micrometers), and choriocapillaris-equivalent thickness (CCET, in micrometers)., Results: Choriocapillaris-equivalent thickness was thinner in healthy participants (9.89 μm; range, 7.15-12.5 μm) compared with patients with intermediate AMD (16.73 μm; range, 10.31-27.38 μm) (P = .02); there was no difference in overall choroidal thickness between the 2 groups (P = .38). There was a 15% CCET reduction among healthy participants when transitioning from a sitting (9.89 μm) to supine (8.4 μm; range, 6.92-10.7 μm) position (P = .02) vs a CCET reduction of 11.1% from sitting (16.73 μm) to supine (14.88 μm; range, 8.76-20.8 μm) positioning (P = .10) in patients with intermediate AMD., Conclusions and Relevance: Intermediate AMD appears to be associated with an increase in CCET and with a lack of positional responses that are observed in the CCET of normal eyes. Our results suggest that although outer portions of the choroid do not appear to be responsive to modest positional or hydrostatic pressure, the choriocapillaris capacity is, and this is measurable in vivo. Whether this physiologic deviation that occurs in AMD is related to atrophy, inflammation, or changes in autoregulatory factors or growth factors remains to be determined.

Objective: To evaluate changes in visual acuity (VA) over time in patients with Leber congenital amaurosis (LCA) and mutations in the CEP290 gene., Methods: Visual acuity was determined at the initial and most recent visits of 43 patients with LCA and CEP290 mutations. The main outcome measures included the best-corrected VA at the initial and most recent visits, as well as the correlation between age and VA., Results: At the initial visit, 14 patients had measurable chart VA in the better-seeing eye, 25 patients had nonmeasurable chart VA, and 4 young patients did not have VA assessed. At the most recent visit, 15 patients had measurable chart VA and 28 had nonmeasurable chart VA. The average interval between the 2 visits was 10.4 years (range, 2-47 years). For patients with measurable chart VA, the median logMAR value at the initial visit (0.75; range, 0.10-2.30) and at the most recent visit (0.70; range, 0.10-2.00) did not differ significantly (P> .05). There was no significant relationship between VA and age., Conclusions: Patients with LCA and CEP290 mutations had a wide spectrum of VA that was not related to age or length of follow-up. Severe VA loss was observed in most, but not all, patients in the first decade. These data will help clinicians provide counseling on VA changes in patients with CEP290 mutations and could be of value for future treatment trials.

OBJECTIVE To review the effect of the fluocinolone acetonide implant in subjects with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV), an inherited autoimmune uveitis. METHODS A retrospective case series was assembled from patients with ADNIV who received fluocinolone acetonide implants. Visual acuity and features of ADNIV, including inflammatory cells, neovascularization, fibrosis, and cystoid macular edema, were reviewed. RESULTS Nine eyes of 5 related patients with ADNIV with uncontrolled inflammation were reviewed. Follow-up ranged from 21.7 to 56.7 months. Visual acuity at implantation ranged from 20/40 to hand motion. Preoperatively, 8 eyes had vitreous cells (a ninth had diffuse vitreous hemorrhage). Eight eyes had cystoid macular edema, 7 had an epiretinal membrane, and 3 had retinal neovascularization. Following implantation, vitreous cells resolved in all eyes and neovascularization regressed or failed to develop. Central macular thickness improved in 4 eyes. During the postoperative course, however, visual acuity continued to deteriorate, with visual acuity at the most recent examination ranging from 20/60 to no light perception. There was also progressive intraocular fibrosis and phthisis in 1 case. Four eyes underwent cataract surgery. Six of the 7 eyes without previous glaucoma surgery had elevated intraocular pressure at some point, and 3 of these required glaucoma surgery. CONCLUSIONS The fluocinolone acetonide implant may inhibit specific features of ADNIV such as inflammatory cells and neovascularization but does not stabilize long-term vision, retinal thickening, or fibrosis. All eyes in this series required cataract extraction, and more than half required surgical intervention for glaucoma. Further studies may identify additional therapies and any benefit of earlier implantation.

Objective: To determine the safety and efficacy of subretinal gene therapy in the RPE65 form of Leber congenital amaurosis using recombinant adeno-associated virus 2 (rAAV2) carrying the RPE65 gene., Design: Open-label, dose-escalation phase I study of 15 patients (range, 11-30 years of age) evaluated after subretinal injection of the rAAV2- RPE65 vector into the worse-functioning eye. Five cohorts represented 4 dose levels and 2 different injection strategies., Main Outcome Measures: Primary outcomes were systemic and ocular safety. Secondary outcomes assayed visual function with dark-adapted full-field sensitivity testing and visual acuity with Early Treatment Diabetic Retinopathy Study charts. Further assays included immune responses to the vector, static visual fields, pupillometry, mobility performance, and optical coherence tomography., Results: No systemic toxicity was detected; ocular adverse events were related to surgery. Visual function improved in all patients to different degrees; improvements were localized to treated areas. Cone and rod sensitivities increased significantly in the study eyes but not in the control eyes. Minor acuity improvements were recorded in many study and control eyes. Major acuity improvements occurred in study eyes with the lowest entry acuities and parafoveal fixation loci treated with subretinal injections. Other patients with better foveal structure lost retinal thickness and acuity after subfoveal injections., Conclusions: Gene therapy for Leber congenital amaurosis caused by RPE65 mutations is sufficiently safe and substantially efficacious in the extrafoveal retina. There is no benefit and some risk in treating the fovea. No evidence of age-dependent effects was found. Our results point to specific treatment strategies for subsequent phases., Application to Clinical Practice: Gene therapy for inherited retinal disease has the potential to become a future part of clinical practice., Trial Registration: clinicaltrials.gov Identifier: NCT00481546.

Objective: To characterize the seroreactivity against retinal proteins in patients with posterior uveitis, retinal disease of noninflammatory origin, and healthy controls., Methods: Patients with posterior uveitis (n = 47), molecularly confirmed photoreceptor degenerations (n = 11), and healthy controls (n = 33) received dilated fundus examinations at the University of Iowa. Aqueous-soluble and detergent-soluble fractions of human retina were separated by gel electrophoresis and transferred to polyvinylidene fluoride membranes. Membranes were probed with patient serum samples to detect IgG, IgA, and IgM human antibodies that react with retinal antigens. The number of bands detected by Western blot was counted, and their molecular weights were determined., Results: Antibodies recognizing retinal proteins were found in healthy controls, in patients with posterior uveitis, and in patients with molecularly confirmed heritable retinal degenerations. In healthy controls, 42% of individuals had circulating autoantibodies that recognized retinal proteins. Healthy controls had a low odds ratio of serum reactivity to soluble antigens (0.7; 95% confidence interval [CI], 0.4-1.2). Patients with inflammatory retinal diseases and inherited retinal diseases had 4.89 (95% CI, 2.25-10.64; P < .001) and 2.71 (95% CI, 1.19-6.16; P = .02) times more activity against soluble retinal antigens compared with controls., Conclusions: Healthy control patients exhibited a significantly higher level of background autoantibody activity against retinal proteins than previously reported. Antibody activity in healthy controls was primarily directed against membrane-bound retinal proteins, whereas in patients with pathologic retinal conditions, antibodies targeting nonmembrane-bound retinal proteins predominate.

Objectives: To report a child with early-onset autosomal recessive Best vitelliform macular dystrophy and compound heterozygous BEST1 mutations, the management of a choroidal neovascular membrane with intravitreal bevacizumab in the proband, the benefits of amblyopia therapy in the fellow eye, and the findings in the parents, carriers of heterozygous BEST1 mutations., Methods: A 5-year-old white girl presented with monocular visual acuity loss and bilateral vitelliform macular lesions. Her parents were also examined. Examinations included electro-oculograms (EOGs), electroretinograms, imaging studies, and BEST1 gene testing. Interventions included off-label treatment with intravitreal bevacizumab in the left eye and amblyopia therapy in the right eye., Results: The proband presented with visual acuity of 20/200 OD with an atypical subfoveal vitelliform scar and 20/16 OS with asymptomatic vitelliform deposits. Subfoveal choroidal neovascularization developed at age 6 years, causing marked vision loss (20/200 OS). Visual acuity recovered to 20/20 OS after serial intravitreal bevacizumab injections. Amblyopia therapy improved visual acuity to 20/50 OD. The proband showed subnormal EOG Arden ratios and mild electroretinogram changes. Molecular testing showed missense BEST1 mutations (R141S and R141H) in the proband. Unlike dominant Best vitelliform macular dystrophy, in the heterozygous parents EOGs were normal and minimal autofluorescence changes were seen., Conclusions: Choroidal neovascularization treatment with bevacizumab was associated with vision restoration. Amblyopia treatment also yielded significant benefit. Patients presenting with vitelliform lesions should be screened for BEST1 mutations, even when parents have normal EOG and imaging results., Clinical Relevance: Prompt recognition and treatment of choroidal neovascularization and amblyopia management effectively restores vision. Awareness and recognition of recessive inheritance permits correct diagnosis and counseling.

Objective: To investigate whether mutations in NPHP5 can cause Leber congenital amaurosis (LCA) without early-onset renal disease., Methods: DNA samples from 276 individuals with nonsyndromic LCA were screened for variations in the NPHP5 gene. Each had been previously screened for mutations in 8 known LCA genes without identifying a disease-causing genotype., Results: Nine of the 276 LCA probands (3.2%) harbored 2 plausible disease-causing mutations (7 different alleles) in NPHP5. Four of these have been previously reported in patients with Senior-Loken syndrome (F141del, R461X, H506del, and R489X) and 3 are novel (A111del, E346X, and R455X). All 9 patients had severe visual loss from early childhood but none had overt renal disease in the first decade of life. Two patients were diagnosed with nephronophthisis in the second decade. Retinal imaging studies showed retained photoreceptor nuclei and retinal pigment epithelium integrity mainly in the cone-rich central retina, a phenotype with strong similarities to that of NPHP6 disease., Conclusions: Mutations in NPHP5 can cause LCA without early-onset renal disease. Abnormalities observed in the photoreceptor outer segments (a cilial structure) may explain the severe visual loss in NPHP5 -associated LCA. Clinical Relevance  The persistence of central photoreceptor nuclei despite severe visual loss in NPHP5 disease is encouraging for future therapeutic interventions.

Objective: To describe the clinical, molecular, and serologic findings of a case in which autoimmune retinopathy and early-onset heritable retinal degeneration were both considered in the differential diagnosis., Methods: A 3-year-old girl had clinical findings suggestive of a childhood-onset retinal degeneration. Samples of DNA and serum were collected. The coding regions of 11 genes associated with Leber congenital amaurosis were sequenced. The patient's serum reactivity to soluble and insoluble fractions of human retinal protein was compared with that of healthy control subjects (n = 32), patients with inflammatory eye disease (n = 80), and patients with molecularly confirmed retinal degenerations (n = 11). Two-dimensional gel electrophoresis and mass spectrometry were used to identify a protein that corresponded to a reactive band on Western blot., Results: No plausible disease-causing mutations were identified in any of the retinal disease genes tested. However, the patient's serum showed reactivity to a single retinal antigen of approximately 47 kDa. Two-dimensional gel electrophoresis and mass spectrometry revealed the major reactive species to be neuron-specific enolase (NSE). Autoantibodies targeting NSE were not observed in any healthy control subjects or patients with inflammatory eye disease. However, anti-NSE activity was found in 1 child with molecularly confirmed Leber congenital amaurosis., Conclusion: This patient's clinical and laboratory findings coupled with the recently discovered role of anti-NSE antibodies in canine autoimmune retinopathy suggest that autoantibodies targeting NSE are involved in the pathogenesis of her disease., Clinical Relevance: Infection or inflammation within the retina early in life may lead to an autoimmune phenocopy of early-onset inherited retinal degeneration.

Objective: To clinically phenotype an inherited macular dystrophy with peculiar intraretinal pigment spots, cysts, and hemorrhage in a 24-year-old female proband and her family., Methods: Extended family members of the proband underwent dilated fundus examination, optical coherence tomography, and, in selected cases, fluorescein angiography and electroretinography., Results: Seventeen family members, representing 3 generations and ranging in age from 5 to 64 years, were clinically examined. Visual acuities ranged from 20/20 to 20/200. Amblyopia and strabismus were frequently present in affected individuals. Consistent with an autosomal dominant pattern of inheritance, 7 family members had multiple central macular cystic spaces and flat, round, densely pigmented spots within the retina. There were right-angle vessels and telangiectasis in the central macula. Two subjects showed evidence of active macular neovascularization with leakage on fluorescein angiography at ages 7 and 24 years, which was responsive to either focal laser or a single injection of bevacizumab. In those cases examined, multifocal electroretinography showed a diminished foveal response., Conclusions: This spotted cystic neovascular macular dystrophy appears to represent a new autosomal dominant retinal condition. Because these patients are at risk for choroidal neovascularization, identification of the responsible gene may provide insight into the mechanisms of pathological neovascularization.

Objective: To study the phenotypic characteristics of patients with a novel p.E292K mutation in BEST1., Methods: Affected individuals underwent ophthalmic examination and testing that included photography, autofluorescence, optical coherence tomography, and electrophysiological testing. Their DNA was analyzed for BEST1 mutations., Results: Five patients aged 5 to 59 years who expressed the p.E292K mutation in BEST1 were identified in 3 families. Electro-oculographic light-rise was subnormal in all probands and carriers. Carriers had normal findings from fundus examination, multifocal electroretinography, and visual acuity, and were emmetropic or myopic. Only probands had hyperopia and fundus findings typical of Best macular dystrophy. Optical coherence tomography of vitelliform lesions demonstrated retinal pigment epithelium elevation without subretinal fluid; atrophic lesions exhibited disruption of the hyperreflective outer retina-retinal pigment epithelium complex. Intense hyperautofluorescence correlated with the vitelliform lesion., Conclusions: Patients with the Glu292Lys variation in BEST1 exhibit intrafamilial and interfamilial phenotypic variability. A disproportionate fraction (26%) of Best disease-causing mutations occurs in exon 8, suggesting that the portion of protein encoded by this exon (amino acids 290-316) may be especially important to bestrophin's function. Relatively good visual acuity with vitelliform lesions can be explained by preservation of the outer retina, demonstrated by optical coherence tomography. Clinical Relevance A novel mutation in this region of BEST1 carries implications for disease pathogenesis.

Objective: To identify the gene causing retinitis pigmentosa (RP) in an autosomal dominant pedigree., Methods: Family members with RP were studied with linkage analysis using single-nucleotide polymorphism and short tandem repeat polymorphic markers. Candidate genes in the linked region were evaluated with DNA sequencing., Results: Nineteen family members had a mild form of RP. Multipoint linkage analysis of single-nucleotide polymorphism genotypes yielded a maximum nonparametric linkage score of 19.97 with markers located on chromosome 14q. LOD scores higher than 3.0 were obtained with 20 short tandem repeat polymorphic markers, and recombinants defined a 21.7-centimorgan locus on chromosome 14q. The retinol dehydrogenase 12 (RDH12) gene lies within this locus and was evaluated as a candidate gene. A frameshift mutation (776delG) was detected in all affected family members and was not detected in 158 control subjects., Conclusions: Heterozygous mutations in RDH12 can cause autosomal dominant RP with a late onset and relatively mild severity. This phenotype is dramatically different from the other disease associated with mutation in this gene, autosomal recessive Leber congenital amaurosis., Clinical Relevance: The demonstration that mutations in a gene previously associated with recessive Leber congenital amaurosis can also cause dominant RP illustrates the wide phenotypic variability of retinal degeneration genes.

Objective: To determine the histidine frequency in patients with the cuticular drusen phenotype of age-related macular degeneration (AMD)., Methods: Fifty individuals were identified who met the criteria for the cuticular drusen phenotype using a standard threshold photograph. We genotyped DNA samples using a polymerase chain reaction-based restriction digest assay. Seven hundred individuals with typical AMD and 252 controls were also genotyped. Fisher exact test was used to analyze the significance of allele frequency differences., Results: The histidine variant was present in 70% (frequency +/- SE, 0.70 +/- 0.05) of the cuticular cohort, 55% (frequency +/- SE, 0.55 +/- 0.01) of the more typical AMD cases, and 34% (frequency +/- SE, 0.34 +/- 0.02) of controls. The association between the cuticular drusen phenotype and the histidine allele was highly significant (P = .003; odds ratio, 2.0; 95% confidence interval, 1.21-3.07; vs AMD cases P<.001; odds ratio 4.54; 95% confidence interval, 2.79-7.50; vs controls). Genotype distribution between the 3 groups was similarly significant (P<.001)., Conclusion: The cuticular drusen phenotype is highly associated with the Tyr402His variant of the complement factor H (CFH) gene. The significantly higher histidine allele frequency in this group compared with the typical AMD cohort suggests that the complement cascade may play a greater role in the pathogenesis of the cuticular drusen subtype than in AMD as a whole., Clinical Relevance: The c.1204T>C, p.Tyr402His allelic variant in the CFH gene is associated with a 3-fold increased risk for AMD. A high frequency of the histidine allele has also been noted in patients with membranoproliferative glomerulonephritis type II.

Objective: To report a novel de novo vitelliform macular dystrophy (VMD2) mutation in a patient with Best macular dystrophy., Methods: Best-corrected visual acuity, dilated fundus examination, and electro-oculography were performed in a patient with Best macular dystrophy and his parents. Both the patient and his parents also had blood samples drawn, and their DNA was analyzed by direct genomic sequencing., Results: A heterozygous VMD2 gene missense mutation in exon 2 (Thr6Ala [ACA>GCA]) was identified in the proband. This mutation was not present in his clinically unaffected parents., Conclusions: A novel de novo mutation in the VMD2 gene was found in a patient whose phenotype and electro-oculographic findings were characteristic of Best macular dystrophy, whereas both parents were phenotypically and genetically unaffected. The findings in this family document that a de novo mutation needs to be considered when an isolated family member is found to have a Best disease phenotype.

Objective: To provide the clinicopathologic findings of a patient who developed the clinical characteristics of Best disease (typically considered a juvenile macular degeneration) at the age of 75 years after being documented to be ophthalmoscopically normal at the age of 51 years., Design: A member of a large family with Best disease, possessing a Y227N mutation in the VMD2 gene (the gene responsible for the disease, which encodes the bestrophin protein), developed small vitelliform lesions in both eyes at the age of 75 years and later developed yellow flecklike depositions at the level of the retinal pigment epithelium (RPE), which were also identified in fundus photographs of family members. The patient died at the age of 93 years, and the histological features of the macular lesion and peripheral flecks were examined., Results: Histopathologically, the retinal outer nuclear layer was attenuated, particularly in the macula. This attenuation was frequently associated with normal RPE. A large area of photoreceptor degeneration was present in the central macula, with loss of the underlying RPE cells. Outside of this region, the RPE density was within normal limits. The peripheral flecks were clusters of basal laminar deposits and drusen. Bestrophin immunohistochemistry revealed labeling along both the basolateral and apical membranes of the RPE., Conclusions: Findings characteristic of Best disease may not manifest in a molecularly affected individual until late in life. Mutations in bestrophin appear to lead to extracellular deposit formation outside the macula in some families. The distribution of bestrophin in the RPE suggests that the protein may be mistargeted in those with Best disease who have the Y227N mutation, and that this may be a cause of the associated RPE and photoreceptor dysfunction.

Objective: To investigate the phenotype and age-related penetrance of primary open-angle glaucoma (POAG) in Australian families with the myocilin mutation Thr377Met., Method and Design: Cross-sectional genetic study. Four unrelated pedigrees carrying the Thr377Met mutation were ascertained from more than 2000 consecutive cases of POAG in the Glaucoma Inheritance Study in Tasmania and from families with glaucoma referred to the study from throughout Australia. Index cases and available family members were examined for signs of glaucoma, and the presence of the GLC1A Thr377Met mutation was ascertained by single-strand conformation polymorphism analysis and subsequent direct sequencing., Results: From the 4 pedigrees carrying the Thr377Met mutation, 23 individuals with either ocular hypertension (OHT) or POAG were found, with a mean +/- SD age at diagnosis of 41.2 +/- 11.5 years, and a mean peak intraocular pressure of 31.7 +/- 9.9 mm Hg. A further 9 mutation carriers older than 18 years were studied who as yet showed no signs of OHT or POAG (6 of these 9 were younger than 30 years). A single individual with POAG was identified who did not carry the Thr377Met mutation. For Thr377Met carriers, age-related penetrance for OHT or POAG was 88% at age 30 years. A positive family history of POAG was present for 3 of the 4 index cases. Thirteen (57%) of the 23 Thr377Met carriers with OHT or POAG had undergone glaucoma drainage surgery. Although the glaucoma in these families appears to be pressure dependent, 2 individuals showed optic disc cupping before detected elevation in intraocular pressure. One family was of British origin, with a different background haplotype from the other 3 families from Greece or Macedonia, who shared a common haplotype., Conclusions: The GLC1A Thr377Met mutation is associated with POAG that, in the pedigrees studied, had a younger age at onset and higher peak intraocular pressure than in pedigrees with the more common Gln368STOP mutation. In addition, patients with glaucoma with the Thr377Met mutation were more likely to have undergone glaucoma drainage surgery.

Objective: To identify sequence variations in the ABCA4 gene in a cohort of patients with autosomal recessive cone-rod dystrophy., Methods: The coding sequences of the ABCA4 gene were analyzed in 30 unrelated probands. In those patients with plausible disease-causing variations, correlations were made between genotype and fundus phenotype as well as with electrophysiological and visual field findings., Results: Sixteen (53%) of 30 probands were found to harbor plausible disease-causing variations in the ABCA4 gene. Two distinctly different fundus phenotypes were observed in our cohort of patients. Twelve patients showed diffuse pigmentary degenerative changes, whereas 4 showed either no pigmentary changes or only a mild degree of peripheral pigment degeneration. An associa-tion between certain sequence variations and each of these 2 different phenotypes was observed., Conclusions: Our findings confirm that a substantial percentage of patients with autosomal recessive cone-rod dystrophy are likely to harbor a mutation in the ABCA4 gene as the cause of their disease. The fundus phenotype observed in such patients is quite variable, and certain fundus phenotypes may be more associated with certain genotypes. Clinical Relevance Identification of the molecular genetic basis for various inherited human retinal dystrophies, such as cone-rod dystrophy, facilitates a potentially better understanding of the mechanisms by which photoreceptor cells degenerate. This in turn provides guidance as to how to better proceed in identifying the most optimal future therapeutic strategies.

Objective: To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects., Methods: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism., Results: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele., Conclusions: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity., Clinical Relevance: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma.

Objective: To determine the molecular basis of a retinopathy previously described as dominant macular subretinal neovascularization with peripheral retinal degeneration., Methods: The TIMP3 gene was analyzed in family members, and 4 mutation-positive patients were studied using psychophysics and electroretinography., Results: Cosegregating with disease in the family was a single base pair change in the TIMP3 gene, altering a conserved tyrosine to cysteine at amino acid position 172 (Y172C). There was psychophysical and electroretinographic evidence of rod dysfunction greater than cone dysfunction. Dark adaptometry showed abnormalities with regional retinal variation in degree., Conclusions: The Y172C mutation in the TIMP3 gene is another cause of Sorsby fundus dystrophy. The expression of this form of the disease, as in other C-terminal TIMP3 mutations, is speculated to be secondary to mutant TIMP-3, causing a decreased turnover of the extracellular matrix., Clinical Relevance: The molecular clarification of inherited retinal degeneration involving abnormal extracellular matrix turnover in and around Bruch's membrane should provide clues to the pathogenesis of not only these particular diseases but also forms of age-related macular degeneration.

Background: Von Hippel-Lindau (VHL) disease is a dominantly inherited cancer syndrome. Since the identification of the VHL gene, at least 3 clinical-genetic subtypes of the disease have been recognized., Objectives: To identify the specific abnormality in the VHL gene and to correlate it with the prevalence and severity of ocular involvement in a large family with VHL disease., Methods: A longitudinal clinical study and DNA analysis of 24 family members., Results: All 14 affected family members exhibited a thymine-to-cysteine change at nucleotide 505 (T505C) in exon 1 of the VHL gene, consistent with the clinical diagnosis of VHL disease subtype 2A. Two asymptomatic gene carriers were also identified. Seventy-five percent (12/16) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angioma. Five gene carriers (31%) had lost vision because of angiomatosis. Cerebellar hemangioblastomas were present in 4 patients (25%) and pheochromocytomas in 11 (69%). No patient was found to have a renal cell carcinoma., Conclusions: The family shows a low susceptibility to renal carcinoma consistent with the clinical diagnosis of VHL disease type 2A. The prevalence and severity of ocular angiomatosis in this subtype do not significantly differ from those of the other more common subtypes of VHL. Recognition of the VHL disease 2A phenotype suggests the presence of a specific mutation (T505C) in the VHL gene. Confirmation of this genotype increases the clinician's ability to provide favorable prognostic information to affected family members.

Objectives: To investigate the role of 2 specific alleles of the Stargardt disease gene (ABCA4) in the pathogenesis of age-related macular degeneration (AMD). Secondary objectives were to investigate differences in frequency of the G1961E allele in selected ethnic groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families with AMD., Methods: Five hundred forty-four patients with AMD and 689 controls were ascertained from 3 continents. Blood samples from 62 normal individuals of Somalian ancestry were also obtained. Participants were screened for the presence of these ABCA4 alleles with a combination of restriction digestion and single-strand conformation polymorphism analysis of polymerase chain reaction amplification products. Detected alleles were confirmed by DNA sequencing. The number of subjects exhibiting the G1961E or D2177N variants were compared between AMD and control groups using a 2-tailed Fisher exact test., Results: There was no significant difference (P >.1) in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). In contrast, there was a significant difference (P< .001) in the frequency of the G1961E alleles between normal individuals of Somali ancestry (11.3%) and normal individuals from other populations (0.4%). There was no evidence of cosegregation of these alleles and the AMD phenotype in the 5 multiplex families with AMD examined. These two ABCA4 alleles were slightly more frequent in patients with AMD with choroidal neovascularization (2.7%) than those without this complication (2.5%)., Conclusions: Somali ancestry is more than 100 times more strongly associated with presence of the G1961E allele than the AMD phenotype. This study did not find any statistically significant evidence for involvement of the G1961E or D2177N alleles of the ABCA4 gene in AMD., Clinical Relevance: The ABCA4 gene is definitively involved in the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration. However, it does not seem to be involved in a statistically significant fraction of AMD cases.

Objectives: To characterize a disease-associated haplotype in 7 families with autosomal dominant Stargardt-like macular dystrophy and to determine whether these families share a common ancestor., Methods: Twenty-five polymorphic DNA markers spanning known dominant Stargardt-like gene loci were used to determine the haplotype associated with disease. In addition, an extensive genealogical investigation searching for a common ancestor shared by all of the 7 families was performed., Results: We clinically evaluated 171 patients and genotyped 145 samples. The same DNA haplotype on chromosome 6q16 was shared by all evaluated affected members within the 7 families. In addition, we were able to genealogically join all of the families into one larger family consisting of 31 branches and 2314 individuals. Twenty-seven branches have known living descendants, with 7 branches having affected family members. In addition, we refined the critical region for the gene to approximately 1000 kilobases (kb) and eliminated part or all of 9 candidate disease-causing genes., Conclusions: Our study indicates that most reported cases of autosomal dominant Stargardt-like macular dystrophy in North America are part of a single larger family associated with a gene locus on chromosome 6q16. Furthermore, the DNA haplotype associated with disease is useful in excluding individuals with phenotypically similar retinal conditions., Clinical Relevance: The disease-associated haplotype allows for more accurate genetic counseling to be given to individuals with a Stargardt-like phenotype inherited in an autosomal dominant pattern.

Objectives: To test the hypothesis that mutations in the CRB1 gene cause Leber congenital amaurosis (LCA) and, if so, to describe the ocular phenotype of patients with LCA who harbor CRB1 sequence variations., Patients: One hundred ninety probands with a clinical diagnosis of LCA were selected from a cohort of 233 probands ascertained in 5 different countries. The remaining 43 probands (18%) were excluded because they harbored sequence variations in previously identified LCA genes., Methods: One hundred ninety unrelated individuals with LCA were screened for coding sequence mutations in the CRB1 gene with single-strand conformation polymorphism analysis followed by automated DNA sequencing., Results: Twenty-one of the 190 probands (9% of the total cohort of 233) and 2 (1.4%) of 140 controls harbored amino acid-altering sequence variations in the CRB1 gene (P =.003)., Conclusions: In our cohort of patients with LCA, coding sequence variations were observed in the CRB1 gene more frequently than in any of the other 5 known LCA-associated genes. Likely disease-causing sequence variations have now been identified in 64 (28%) of 233 subjects in this cohort., Clinical Relevance: Molecular diagnosis can confirm and clarify the diagnosis in an increasing fraction of patients with LCA. As genotype data accumulate, clinical phenotypes associated with specific mutations may be established. This will facilitate the counseling of patients regarding their visual prognosis and the likelihood of associated systemic anomalies.

Objectives: To report the clinical characteristics of a family with autosomal dominant retinitis pigmentosa caused by a proline-to-alanine mutation at codon 23 (Pro23Ala) of the rhodopsin gene and to compare this phenotype with that associated with the more common proline-to-histidine mutation at codon 23 (Pro23His)., Methods: We examined 6 patients within a single pedigree. The electroretinograms (ERGs) of 35 patients with known Pro23His mutations and of 22 healthy individuals were reviewed. Scotopic dim flash-response amplitudes, maximum combined-response amplitudes, and photopic-response amplitudes from the ERGs of these patients were plotted against age. The ERG indices of 5 individuals in the Pro23Ala family were compared with those of the patients with Pro23His mutations and of healthy individuals. Multiple linear regression was performed to evaluate the effect of age and mutation type on amplitudes. Mutation detection was performed using single-strand conformation polymorphism analysis, followed by automated DNA sequencing., Results: Patients with the Pro23Ala mutation have a clinical phenotype characterized by onset of symptoms in the second to fourth decades of life, loss of superior visual field with relatively well-preserved inferior fields, and mild nyctalopia. Comparison with patients with the Pro23His mutation demonstrates statistically significant differences (P<.001) in responses to dim flash, maximum combined, and photopic responses between patients with these mutations after controlling for the effects of age. Patients with Pro23Ala mutations were less affected by ERG criteria than patients with Pro23His mutations. Patients with Pro23Ala mutations also differed significantly from healthy patients in all ERG indices examined (P<.001), after controlling for age., Conclusion: We describe a rare mutation in codon 23 of rhodopsin causing autosomal dominant retinitis pigmentosa. The retinal dystrophy associated with the Pro23Ala mutation is characteristically mild in presentation and course, with greater preservation of ERG amplitudes than the more prevalent Pro23His mutation. Arch Ophthalmol. 2000;118:1269-1276

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.

Objectives: To identify a congenital nystagmus locus on the X chromosome and to characterize the phenotype of a 4-generation family affected with congenital nystagmus and color deficiency., Methods: Sixty-five patients underwent an eye examination, including evaluation for the presence of nystagmus and color vision abnormalities. Affected patients and obligate carriers of the congenital nystagmus mutation were genotyped with short tandem repeat polymorphisms located on the X chromosome, and these data were subjected to linkage analysis., Results: Fourteen patients were affected with a horizontal, conjugate, congenital nystagmus. All examined patients had a visual acuity of 20/60 or better. There were no associated ocular or systemic findings except that 18 of the family members had deficient red-green color vision, which was classified as deuteranomaly (the most common form of anomalous trichromacy). Five patients exhibited nystagmus and deuteranomaly. Significant linkage was demonstrated between the nystagmus phenotype and 11 markers from Xq. The maximum lod score was 4.84 (theta = 0) and was obtained with marker DXS8041. Analysis of recombinants defined the disease interval to lie between markers ATA59C05 and DXS1192 (a 5.4-centimorgan region). The proximity of this locus to the red-green opsin gene cluster (11 centimorgans more telomeric) explains the frequent coexistence of nystagmus and color vision deficiency in this family., Conclusions: We have identified the genetic locus of the X-linked congenital nystagmus gene in this family. The critical interval in this report is less than half the size of the previously described nystagmus locus. These findings will aid in identifying the gene responsible for this condition.

Objective: To report the spectrum of ophthalmic findings in patients with Stargardt dystrophy or fundus flavimaculatus who have a specific sequence variation in the ABCR gene., Patients: Twenty-nine patients with Stargardt dystrophy or fundus flavimaculatus from different pedigrees were identified with possible disease-causing sequence variations in the ABCR gene from a group of 66 patients who were screened for sequence variations in this gene., Methods: Patients underwent a routine ocular examination, including slitlamp biomicroscopy and a dilated fundus examination. Fluorescein angiography was performed on 22 patients, and electroretinographic measurements were obtained on 24 of 29 patients. Kinetic visual fields were measured with a Goldmann perimeter in 26 patients. Single-strand conformation polymorphism analysis and DNA sequencing were used to identify variations in coding sequences of the ABCR gene., Results: Three clinical phenotypes were observed among these 29 patients. In phenotype I, 9 of 12 patients had a sequence change in exon 42 of the ABCR gene in which the amino acid glutamic acid was substituted for glycine (Gly1961Glu). In only 4 of these 9 patients was a second possible disease-causing mutation found on the other ABCR allele. In addition to an atrophic-appearing macular lesion, phenotype I was characterized by localized perifoveal yellowish white flecks, the absence of a dark choroid, and normal electroretinographic amplitudes. Phenotype II consisted of 10 patients who showed a dark choroid and more diffuse yellowish white flecks in the fundus. None exhibited the Gly1961Glu change. Phenotype III consisted of 7 patients who showed extensive atrophic-appearing changes of the retinal pigment epithelium. Electroretinographic cone and rod amplitudes were reduced. One patient showed the Gly1961Glu change., Conclusions: A wide variation in clinical phenotype can occur in patients with sequence changes in the ABCR gene. In individual patients, a certain phenotype seems to be associated with the presence of a Gly1961Glu change in exon 42 of the ABCR gene., Clinical Relevance: The identification of correlations between specific mutations in the ABCR gene and clinical phenotypes will better facilitate the counseling of patients on their visual prognosis. This information will also likely be important for future therapeutic trials in patients with Stargardt dystrophy.

Background: Mutations in the RPGR gene at the RP3 locus have been found to cause x-linked retinitis pigmentosa in some families., Objectives: To identify a previously undescribed 2-base pair insertion in codon 99 of the RPGR gene and to describe the phenotype in a well-characterized family with X-linked retinitis pigmentosa., Design: Case reports with clinical features, fluorescein angiography, kinetic perimetry, electrophysiological studies, and molecular genetics., Setting: University medical centers., Patients: Eight members of the family were screened for the codon 99 insertion in the RPGR gene., Results: Three affected males were found to be hemizygous for the 2-base pair insertion; 2 carriers were heterozygous. This insertion creates a frameshift that would be expected to cause a premature arrest of translation after only 132 amino acids (683 amino acids less than the normal protein). The affected males had typical retinitis pigmentosa with visual field contraction and abnormal findings on electroretinograms with little to no rod activity, profoundly subnormal residual cone responses to single flash and 30-Hz flicker stimuli, and prolonged b-wave implicit times. The electroretinogram of a 49-year-old carrier showed amplitudes that were roughly half of normal. Carrier women did not show a tapetallike fundus reflex but showed asymmetrical patchy pigmentary disturbances consistent with lyonization., Conclusion: A frameshifting 2-base pair insertion at codon 99 of the RPGR gene produced typical retinitis pigmentosa and carrier findings (but no tapetallike reflex) in this family.

Objectives: To refine the dominant optic atrophy locus, OPA1, on chromosome 3q and to characterize the phenotype of a 6-generation family pedigree affected with this disease., Methods: Fifty-six family members had a complete eye examination. Clinical records of an additional 3 patients were reviewed. Goldmann perimetry and a 21-chip subtest of the Farnsworth-Munsell 100-Hue test were performed on selected patients. Affected patients, unaffected siblings, and potentially informative spouses were genotyped with short tandem repeat polymorphisms located on chromosome 3. The genotypic data were subjected to linkage analysis., Results: Thirty-four family members were found to be clinically affected. Most experienced vision loss (20/40 or poorer) in the first decade of life. Most (9 of the 16 eyes) progressed to 20/800 or poorer visual acuity by age 60 years, while 2 patients maintained visual acuities of 20/40 at that age. Affected patients had a 2- to 10-fold increase in the error score of a 21-chip subtest of the Farnsworth-Munsell 100-Hue test compared with age-matched unaffected family members. The optic nerve examination revealed temporal pallor and excavation in all affected individuals. Linkage analysis revealed significant lod scores with 9 markers. The highest lod score, 10.1 (theta = 0) [corrected], was obtained with marker D3S2305. Analysis of recombinants narrowed the disease interval to approximately 3.8 centimorgans, flanked by D3S3669 (centromeric) and D3S1305 (telomeric)., Conclusions: Most patients affected with dominant optic atrophy in this family progressed to legal blindness by middle age. Color vision testing is a sensitive method for detection of affected patients. The dominant optic atrophy locus, OPA1, has been refined by the identification of new flanking markers: D3S3669 (centromeric) and D3S1305 (telomeric).

Objective: To identify the chromosomal location of the gene involved in the pathogenesis of autosomal dominant radial drusen (malattia leventinese)., Patients: Eighty-six members of four families affected with radial drusen; one family of American origin and three families of Swiss origin., Methods: Family members were clinically examined for the presence of radial drusen. Affected patients and potentially informative spouses were genotyped with short tandem repeat polymorphisms distributed across the autosomal genome. The clinical and genotypic data were subjected to linkage analysis., Results: Fifty-six patients were found to be clinically affected. Significant linkage was observed between the disease phenotype and markers known to lie on the short arm of chromosome 2. The maximum two-point lod score (Zmax) observed for all four families combined was 10.5 and was obtained with marker D2S378. Multipoint analysis yielded a Zmax of 12, centered on marker D2S378. The lod-1 confidence interval was 8 cM, while the disease interval defined by observed recombinants was 14 cM., Conclusions: The gene responsible for autosomal dominant radial drusen has been mapped to the short arm of chromosome 2. This is an important step toward actually isolating the disease-causing gene. In addition, this information can be used to evaluate other familial drusen phenotypes such as Doyne's macular dystrophy for a possible allelic relationship.

Objective: To diagnose the carriers and noncarriers in a family affected with Norrie disease based on molecular analysis., Design: Family members from three generations, including one affected patient, two obligate carriers, one carrier identified with linkage analysis, one noncarrier identified with linkage analysis, and one female family member with indeterminate carrier status, were examined clinically and electrophysiologically. Linkage analysis had previously failed to determine the carrier status of one female family member in the third generation. Blood samples were screened for mutations in the Norrie disease gene with single-strand conformation polymorphism analysis. The mutation was characterized by dideoxy-termination sequencing., Results: Ophthalmoscopy and electroretinographic examination failed to detect the carrier state. The affected individuals and carriers in this family were found to have a transition from thymidine to cytosine in the first nucleotide of codon 39 of the Norrie disease gene, causing a cysteine-to-arginine mutation. Single-strand conformation polymorphism analysis identified a patient of indeterminate status (by linkage) to be a noncarrier of Norrie disease., Conclusion: Ophthalmoscopy and electroretinography could not identify carriers of this Norrie disease mutation. Single-strand conformation polymorphism analysis was more sensitive and specific than linkage analysis in identifying carriers in this family.