Macular Degeneration: Fishman GA

Jampol LM, Fishman GA. · No affiliation provided · Arch Ophthalmol. · Pubmed #19365043 No free full text.

This publication has no abstract.

Walia S, Fishman GA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612-7234, USA. · Ophthalmic Genet. · Pubmed #19373676 No free full text.

Abstract: Stargardt macular dystrophy is the most common form of juvenile onset macular degeneration. This article reviews the four stages through which this dystrophy may progress. Also, reviewed here are the variations that may be observed in the visual acuity of patients with Stargardt disease.

Fishman GA, Apushkin MA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL 60612, USA. · Br J Ophthalmol. · Pubmed #17215269 No free full text.

Abstract: AIM: To determine the value of a topical carbonic anhydrase inhibitor for extended treatment of cystoid macular oedema (CME) in patients with retinitis pigmentosa (RP). METHOD: Eight patients with RP and foveal cystic-appearing lesions observed on fundus examination and by optical coherence tomography (OCT) testing were treated with a topical form of carbonic anhydrase inhibitor. RESULTS: Foveal cystic-like spaces were documented by OCT testing in all eight patients before treatment. All patients had a significant reduction in their foveal thickness (FT) and foveal zone thickness (FZT) in at least one eye after using 2% dorzolamide three times a day for 1 or 2 months. Six patients had an improvement in both eyes. After an additional 6-13 months of the same treatment regimen, out of six patients who had a sustained reduction in FT and FZT in at least one eye, four had this reduction in both eyes. While they were still taking Trusopt, a recurrence (rebound) of CME in both eyes was observed in two patients, whereas one patient had a sustained improvement in one eye and rebound of CME in the other eye. Out of 8 patients, 3 showed an improvement in their visual acuity by > or =7 letters, in at least one eye, on Snellen acuity charts, which was determined as clinically significant. CONCLUSION: Results from this study suggest that patients with RP could potentially sustain a beneficial effect from continued treatment with a topical form of carbonic anhydrase inhibitor.

Grover S, Apushkin MA, Fishman GA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 1855 West Taylor Street, Chicago, IL 60612, USA. · Am J Ophthalmol. · Pubmed #16546110 No free full text.

Abstract: PURPOSE: To determine if topical dorzolamide, as observed with the use of systemic acetazolamide and methazolamide, would be effective in treating cystoid macular edema (CME) in patients with retinitis pigmentosa (RP). DESIGN: Prospective, nonrandomized clinical trial. METHODS: setting: Institutional. patients: Fifteen patients with CME and RP. intervention: A baseline visual acuity and optical coherence tomography (OCT) measurements were obtained in all patients. Each one of them was then treated with topical dorzolamide, three times a day, for at least four weeks in both eyes. main outcome measures: Significant decrease in "foveal thickness" (more than 16%) and "foveal zone thickness" (more than 11%), as measured by OCT. RESULTS: Thirteen (87%) of 15 patients showed a significant decrease in retinal thickness in at least one eye after use of topical dorzolamide for at least four weeks. Five patients (33%) demonstrated improvement in both eyes. All patients, except one, who responded showed the effect within four weeks, but were monitored for a period of two to nine months (average 4.5 months). Four patients (31%) who showed an initial improvement in macular edema showed worsening with continued treatment. CONCLUSIONS: The present study documents the potential efficacy of topical dorzolamide for treating CME in patients with RP. We observed that some patients may show a "rebound phenomenon" with continued use of the medication; hence, there is a need for careful follow-up in patients being treated.

Hajali M, Fishman GA, Anderson RJ, McAnany JJ. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA. · Invest Ophthalmol Vis Sci. · Pubmed #19234345 No free full text.

Abstract: PURPOSE: To determine the extent of interocular difference in visual acuity (VA) and the time to at least double the minimal angle of resolution (MAR) in a cohort of patients with Stargardt disease. METHODS: One hundred fifty patients with Stargardt disease who were examined at least four times over a minimum period of 3 years were identified and their VA and age at each visit recorded. The maximum interocular difference of VA was determined by whether the MAR between the two eyes differed by less than a factor of 2 or by a factor of 2 or greater. Differences in maximum VA between the two eyes were also examined according to a Bland-Altman-type approach. One hundred thirty-one eyes from 76 patients were subjected to survival analysis to determine whether the time to at least double the MAR was dependent on age at baseline or starting VA. RESULTS: Of the 150 patients, 48% had interocular MAR that differed maximally by a factor of less than 2. Thirty-five percent showed a maximum interocular difference in their Snellen VA of less than one line. The Bland-Altman- type analysis showed that maximum interocular acuity difference was dependent on the mean acuity of the two eyes. The hazard for at least doubling the MAR was related to baseline vision and patient age. CONCLUSIONS: This information has clinical significance for patient counseling and for monitoring possible benefits and patient selection in future treatment trials.

Hajali M, Fishman GA, Anderson RJ. · Department of Ophthalmology and Visual Sciences (MC 648), Room 3.85, Eye and Ear Infirmary, 1855 W Taylor Street, Chicago, IL 60612-7234, USA. · Br J Ophthalmol. · Pubmed #18653601 No free full text.

Abstract: AIMS: To determine the prevalence of cystoid macular oedema (CMO) in retinitis pigmentosa (RP) patients of various genetic subtypes using optical coherence tomography (OCT). METHODS: We performed a complete ocular examination on 124 RP patients including best corrected visual acuity, intraocular pressure measurement, anterior segment and a detailed fundus exam. OCT images were then acquired using two different units. The presence of hypo-reflective lacunae was used to diagnose CMO. RESULTS: Of the 124 patients, 47 showed CMO in at least one eye (38%), while 34 showed CMO in both eyes (27%). The prevalence of CMO in at least one eye for autosomal dominant (AD) patients was 52%, for autosomal recessive (AR) 39%, isolated 39%, Usher II 35% and none in the X linked recessive (XL) group. Using a chi-square analysis, no statistical significant difference was found for the prevalence of "bilateral CMO" (p = 0.60) or "CMO in at least one eye" (p = 0.59) among the AD, AR, isolated and Usher II genetic subtypes. CONCLUSION: Because of its notable prevalence, it would seem prudent to screen RP patients by OCT for the possible presence of CMO, to identify those amenable to treatment and also for future treatment trials when monitoring visual acuity.

Walia S, Fishman GA. · Department of Ophthalmology and Visual Sciences, Eye and Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois 60612-7234, USA. · Invest Ophthalmol Vis Sci. · Pubmed #18421083 links to  free full text

Abstract: PURPOSE: To determine peripapillary retinal nerve fiber layer thickness (RNFL) abnormalities in patients with retinitis pigmentosa (RP) using Fourier-domain optical coherence tomography (Fd-OCT) and to evaluate the potential effect of cystoid macular edema (CME) or axial length on RNFL measurements in such patients. METHODS: Ninety-seven eyes of 52 patients with diagnoses of retinitis pigmentosa or Usher syndrome type II underwent complete ocular examination. Peripapillary RNFL thickness was measured using Fd-OCT in 16 segments from 4 quadrants--temporal (316 degrees -45 degrees ), superior (46 degrees -135 degrees ), nasal (136 degrees -225 degrees ), and inferior (226 degrees -315 degrees ). These measurements were compared with age- and disc size-adjusted control values. Further analyses were performed to determine the correlation of axial length or CME with RNFL thickness. RESULTS: Thinning of the RNFL was observed in 37 eyes (38.14%) of 23 patients (44.23%). A maximum number of eyes had thinning in the nasal quadrant followed by the inferior quadrant; the superior and temporal quadrants were abnormally thin in fewer eyes. No correlation was found between axial length and RNFL thickness in the total cohort (correlation coefficient, 0.039). An abnormal increase in RNFL thickness was observed in 21.65% eyes, but no association was found between the presence of CME and increased RNFL thickness. CONCLUSIONS: RP eyes may show abnormal thinning or increased thickness of RNFL measurements on testing with Fd-OCT. RNFL defects observed by OCT testing document the presence of anatomic defects in more anterior structures within the retina in a notable number of patients with RP.

Apushkin MA, Fishman GA, Grover S, Janowicz MJ. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA. · Retina. · Pubmed #18040255 No free full text.

Abstract: PURPOSE: To demonstrate the presence of a rebound effect with the use of acetazolamide for the treatment of cystoid macular edema (CME) in patients with retinitis pigmentosa (RP). METHODS: Six patients with RP and cystic-appearing lesions in the macula demonstrated by fluorescein angiography and/or optical coherence tomography (OCT) were treated with an oral form of carbonic anhydrase inhibitor (acetazolamide [500 mg]) as a single daily dose. RESULTS: All patients, treated with acetazolamide for a period of 3 weeks to 5 weeks, had initial improvement of macular edema demonstrated by OCT. However, extended use of acetazolamide, for at least 8 weeks to 12 weeks, resulted in recurrence (rebound) of CME in 3 of the 6 patients. CONCLUSIONS: Results from our study suggest that rebound of CME with the continued use of acetazolamide observed by OCT may occur more frequently than previously appreciated.

Yzer S, Fishman GA, Racine J, Al-Zuhaibi S, Chakor H, Dorfman A, Szlyk J, Lachapelle P, van den Born LI, Allikmets R, Lopez I, Cremers FP, Koenekoop RK. · McGill Ocular Genetics Centre, Division of Ophthalmology, Montreal, Quebec, Canada. · Invest Ophthalmol Vis Sci. · Pubmed #16936081 links to  free full text

Abstract: PURPOSE: To test human CRB1 heterozygotes for possible clinical or functional retinal changes and to evaluate whether a patient with Leber congenital amaurosis (LCA) with CRB1 mutations not consistent with previously described CRB1 phenotypes carried a modifier allele in another LCA gene. METHODS: Seven unrelated heterozygous carriers of CRB1 mutations underwent phenotyping by full eye examinations (indirect ophthalmoscopy and slit lamp biomicroscopy) and functional testing (standard full-field electroretinography [ERG] and multifocal ERG). For genotyping of the LCA patients and their parents, denaturing high-performance liquid chromatography (dHPLC) analyses were performed, followed by sequence analysis of CRB1, followed by sequence analysis of the AIPL1 and CRX genes to identify a putative modifier effect in a patient with an atypical CRB1 phenotype. RESULTS: Reduced full-field ERG b-wave amplitudes were observed with scotopic -2 dB flash (140 microV; P < 0.05), normal full-field cone ERGs, and significant regional retinal dysfunction on mfERG in five of seven carriers of CRB1 mutations. A known AIPL1 mutation (p. R302L) was identified as a potential modifier allele in a patient with LCA carrying two CRB1 mutations and with a prominent maculopathy. CONCLUSIONS: In human heterozygotes of CRB1 mutations (parents of offspring with LCA), distinctive regional retinal dysfunctions were found by multifocal ERG measurements that were consistent with the focal histologic abnormalities reported for the two CRB1 knockout mice models. This phenotypic finding may identify CRB1 carriers and point to the causal gene defect in affected LCA offspring, significantly facilitating the molecular diagnostic process. Evidence suggests a modifier allele in AIPL1 in a patient with LCA with prominent atrophic macular lesions and homozygous defects in CRB1.

Kim LS, Fishman GA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA. · Ophthalmology. · Pubmed #16872677 No free full text.

Abstract: PURPOSE: To investigate a previously reported observation that the presence of diffuse, as compared with localized, fundus flecks is an indicator of a more severe course for visual acuity (VA) loss beyond 20/200 in patients with Stargardt's disease. DESIGN: Retrospective clinic-based cross-sectional study. PARTICIPANTS: Four hundred five patients with Stargardt's disease. METHODS: Visual acuity in 405 patients with Stargardt's disease was analyzed at their initial and most recent visits. The stage of Stargardt's disease and appearance of the macula were recorded. The diagnosis and stage of Stargardt's disease were based on the extent and appearance of fundus flecks. MAIN OUTCOME MEASURES: Best-corrected VA, stage of Stargardt's disease, and appearance of the macula at the initial and most recent visits were used in the cross-sectional analysis. RESULTS: At their initial visit, 199 patients were identified as having stage 1 Stargardt's disease, of whom 97.5% maintained 20/200 or better VA in at least one eye. One hundred eighty-five were identified as having stage 2 or stage 2-3 Stargardt's disease combined, of whom 83.2% maintained 20/200 VA or better. Patients with stage 1 were more likely to maintain 20/200 or better VA in at least one eye when compared with patients with stage 2/stage 2-3 Stargardt's disease (chi2(1) = 21.25, P<0.001). Ninety-nine percent of stage 1 patients and 94.1% of stage 2/stage 2-3 patients maintained 20/400 or better VA in at least one eye (chi2(1) = 5.72, P = 0.017). CONCLUSIONS: Patients with stage 1 Stargardt's disease exhibiting fundus flecks limited to the posterior pole are more likely to maintain a level of VA at 20/200 or better when compared with patients with stage 2/stage 2-3 disease who have diffuse fundus flecks. Nevertheless, over 80% of the patients with stage 2/stage 2-3 Stargardt's disease still maintained VA of 20/200 or better. Only 5.9% of patients with stage 2/stage 2-3 had VA levels worse than 20/400. In our cohort of patients with Stargardt's disease and diffuse fundus flecks, the majority of patients did not lose VA to a greater extent than those with localized flecks.

Apushkin MA, Fishman GA, Taylor CM, Stone EM. · Department of Ophthalmology and Visual Science, University of Illinois at Chicago, USA. · Arch Ophthalmol. · Pubmed #16769844 links to  free full text

Abstract: 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.

Seiple W, Szlyk JP, McMahon T, Pulido J, Fishman GA. · Department of Ophthalmology, New York University School of Medicine, New York, NY 10016, USA. · Invest Ophthalmol Vis Sci. · Pubmed #16043863 links to  free full text

Abstract: PURPOSE: To determine whether training oculomotor control, without direct practice in reading sentences, could increase reading speed in patients with age-related macular degeneration (AMD). METHODS: Sixteen patients with AMD participated in the study (age range, 65-87 years; mean, 77). The training program consisted of a series of exercises that were designed to allow the patients to practice eye movements. At the beginning of training, the subjects practiced small horizontal saccades in response to cognitively easy stimuli (e.g., dots). The training then progressed to practicing larger eye movements and then to practicing saccades with single letters, pairs of letters, and three-letter words. Reading of sentences was practiced in only one exercise, during the last session of the 8-week training. RESULTS: The difference between average reading speeds before and after training was 24.7 wpm (difference between medians, 17.9 wpm). The increase in speed was statistically significant (Wilcoxon signed rank test = 124.0, P < 0.001). There was no significant relationship between change in maximum reading speed and ETDRS (Early Treatment Diabetic Retinopathy Study) acuity (r = -0.14, P = 0.76) or between change in maximum reading speed and age (r = 0.25, P = 0.45). CONCLUSIONS: The results indicate that a training curriculum that concentrates on eye-movement control can increase reading speed in patients with AMD. This finding is especially interesting, because the training involved little direct practice in reading sentences but instead concentrated on having subjects practice control of eye positions and eye movements.

Bonilha VL, Hollyfield JG, Grover S, Fishman GA. · Cole Eye Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue i31, Cleveland, OH 44195, USA. · Ophthalmic Genet. · Pubmed #16020309 No free full text.

Abstract: PURPOSE: To define the distribution of the red/green and blue opsins in cones from donor eyes from an affected member of a clinically well-characterized family with an autosomal dominant form of cone dystrophy. METHODS: Tissue was fixed and processed for immunohistochemistry. Cryosections were studied by indirect immunofluorescence, using well-characterized antibodies to cone cytoplasm, rhodopsin, and cone opsins. The cone-associated matrix was also labeled with the lectin PNA. The affected donor eyes were compared to a postmortem matched normal eye. RESULTS: Electroretinogram (ERG) testing three years prior to the affected member's death showed normal rod function, while the cone b-wave amplitude was reduced 40% below the lower limit of normal. Fundus exam showed only isolated drusen within the macula. Either a normal-appearing or only nonspecific macular findings were noted in the other affected family members who were examined. Immunofluorescence studies showed that blue cone opsin was restricted to the outer segments of blue cones in the affected retina. Red/green opsins were distributed along the entire plasma membrane of these cone types, from the tip of the outer segment to the synaptic base. Cone-associated matrix displayed a heterogeneous distribution. These patterns were observed both in the macula and in the periphery of the affected retina. Cone pedicles appeared larger than normal. In contrast, rhodopsin staining appeared normal. CONCLUSIONS: The immunocytochemical data obtained suggest that the clinical manifestation of this dystrophy is associated with an abnormal distribution of cone red/green opsins. Additionally, changes in the cone pedicles could have contributed to the abnormal cone ERG in this patient.

Alexander KR, Barnes CS, Fishman GA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 60612, USA. · Vision Res. · Pubmed #15845241 No free full text.

Abstract: Contrast sensitivity and contrast discrimination were evaluated in six males with X-linked retinoschisis (XLRS), a form of early-onset macular degeneration, using testing paradigms designed to favor either the magnocellular (MC) or parvocellular (PC) pathway. Compared to a group of age-similar control observers, the patients with XLRS showed a pronounced loss of contrast sensitivity at high spatial frequencies, consistent with their reduced visual acuities. At low spatial frequencies, the patients' deficits were greater under conditions favoring the MC pathway, for both contrast sensitivity and contrast discrimination. The pattern of contrast sensitivity loss shown by the patients with XLRS could be simulated in control observers by testing at a parafoveal locus, although by optical coherence tomography, none of the patients with XLRS had eccentric fixation. The pattern of findings indicates that the foveas of patients with XLRS functionally resemble the normal parafoveal retina.

Piri N, Gao YQ, Danciger M, Mendoza E, Fishman GA, Farber DB. · Department of Ophthalmology, Jules Stein Eye Institute, UCLA, Los Angeles, California 90095, USA. · Ophthalmology. · Pubmed #15629837 No free full text.

Abstract: OBJECTIVE: To identify genes responsible for cone dystrophies and determine the functional consequences of their underlying mutations. DESIGN: Case-control study. PARTICIPANTS: Two hundred forty unrelated patients diagnosed with cone dystrophy, cone-rod dystrophy, macular dystrophy, macular degeneration, or Stargardt disease, 95 control individuals, and 2 unrelated families with a distinctive type of cone dystrophy. METHODS: The DNAs of the 240 probands were screened for sequence variants in the PDE6H gene (that encodes the inhibitory gamma-subunit of cone cyclic guanosine monophosphate [cGMP]-phosphodiesterase [PDE]) by single-strand conformation polymorphism electrophoresis. The effect of a nucleotide substitution in the DNA of a patient on gene expression efficiency was analyzed by in vitro transcription/translation. MAIN OUTCOME MEASURES: Cone-specific gene variants, fundus, visual field and electroretinogram (ERG) findings, and protein synthesis efficiency. RESULTS: We found a heterozygous G to C substitution in the 5' untranslated region (UTR) of the PDE6H gene in the DNA of a patient with a distinctive form of cone dystrophy, her sibling, and their father. This rare form of disease is very different in manifestation from other cone dystrophies and has been described as "cone dystrophy with nyctalopia and supernormal rod responses," "cone dystrophy with supernormal scotopic ERGs" and "supernormal and delayed rod ERG syndrome." Among the 240 patients that we studied, only 1 proband had the G to C variant. Furthermore, none of the 95 controls used in this study had this nucleotide change. We also determined that the PDE6H variant was not present in another family affected with this particular type of cone dystrophy. Because the 5' UTR of mRNAs plays a critical role in the regulation of protein synthesis, we determined the effect of the G to C change in this process. By use of in vitro transcription/translation experiments, we demonstrated that this substitution could lead to an increase in PDE6H gene expression. CONCLUSIONS: Our results indicate that mutations in the PDE6H gene are not common, because only 1 of 240 patients with cone dystrophy showed a single nucleotide substitution in the 5' UTR of PDE6H mRNA that could be associated with the disease. If the effect of the G to C substitution we observed in vitro also occurs in vivo, it will lead to PDE6H overexpression in the photoreceptors. Excess of PDEgamma may affect normal cone cGMP-PDE function by inhibiting the catalytic PDEalpha,beta activity and lead to pathogenic elevation of cGMP and eventual degeneration of cone photoreceptors.

Sharma MC, Fishman GA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago Eye and Ear Infirmary, Chicago, Illinois 60612, USA. · Retina. · Pubmed #15492638 No free full text.

This publication has no abstract.

Apushkin MA, Fishman GA, Janowicz MJ. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois 60612, USA. · Ophthalmology. · Pubmed #15465554 No free full text.

Abstract: PURPOSE: To determine the value of optical coherence tomography (OCT) imaging in the diagnosis and monitoring of cystoid macular edema (CME) in patients with retinitis pigmentosa (RP). DESIGN: Prospective, noncomparative, small case series. PARTICIPANTS: Three patients with RP and cystic-appearing spaces in the macula on OCT images. INTERVENTION: All 3 patients were treated with a carbonic anhydrase inhibitor, and 1 also received topical and systemic steroids. MAIN OUTCOME MEASURES: Changes in OCT images, fluorescein angiography, and best-corrected visual acuity (VA). RESULTS: Although foveal cysticlike spaces were evident on OCT images in all 3 patients, only 1 patient showed CME on fluorescein angiography at baseline. Two of the 3 patients showed funduscopic evidence of macular cystic lesions, whereas a third showed no clinically evident fundus changes in the macula. Optical coherence tomography images documented improvement in the cystic-appearing spaces after treatment with the carbonic anhydrase inhibitor. Changes on fluorescein angiography were either not apparent or considerably less apparent. An improvement of > or =1 line on a Snellen acuity chart was recorded in 2 patients, whereas a third showed no change of VA in either eye. CONCLUSIONS: Optical coherence tomography is a potential method for the diagnosis and monitoring of CME in patients with RP. It was more sensitive in this regard than either fluorescein angiography or funduscopic examination.

Rotenstreich Y, Fishman GA, Anderson RJ. · Department of Ophthalmology and Visual Science, University of Illinois at Chicago, 60612, USA. · Ophthalmology. · Pubmed #12799240 No free full text.

Abstract: PURPOSE: To assess visual acuity impairment in Stargardt disease. DESIGN: Retrospective clinic-based cross-sectional study. PARTICIPANTS: Three-hundred sixty-one patients with Stargardt disease. METHODS: Clinical findings in 361 patients were analyzed as part of a cross-sectional evaluation. Visual acuity at their most recent visit, fundus photographs, and electroretinographic findings were reviewed, and patients were categorized into four clinical phenotypes. Seventy-three patients with 20/40 or better vision and 38 patients with 20/50 to 20/100 vision in the better seeing eye at their initial visit who were followed for at least 1 year were included in a survival analysis. For analysis purposes, these latter patients were categorized into four 20-year age groups according to their age at initial visit. MAIN OUTCOME MEASURES: Best-corrected visual acuity from the eye with better vision on the most recent visit was used in the cross-sectional analysis. For the survival analysis, best-corrected visual acuity was used from the eye with better vision on the initial visit. RESULTS: Eighty-two of the 361 patients (23%) had 20/40 or better acuity in at least one eye, 64 (18%) 20/50 to 20/100, and 199 (55%) 20/200 to 20/400, whereas 16 (4%) had worse than 20/400 in each eye at their most recent visit. In the patients with visual acuity of 20/40 or better, 59 (72%) had foveal sparing visible on ophthalmoscopic examination. The median time to develop visual acuity of 20/200 or worse was 22 years for the patients with 20/40 or better visual acuity at their initial visit. Those seen initially in the first two decades of life with this level of acuity showed a median time of 7 years to reach a visual acuity of 20/200 or worse compared with 22 years and 29 years for those who were initially seen at ages 21 to 40 or 41 to 60, respectively. Analyzing by the four 20-year age groups, the log rank statistic indicated significant differences in the survival experience among the four groups (P = 0.004). The median time to develop 20/200 vision or worse was 6 years for the patients with 20/50 to 20/100 visual acuity at their initial visit, and this result, based on the log rank statistic, was independent of age group at initial visit (P = 0.852). CONCLUSIONS: In a large cohort of Stargardt patients, a cross-sectional analysis showed that almost a quarter had vision of 20/40 or better, whereas 4% had acuity of worse than 20/400. The presence of foveal sparing ophthalmoscopically was associated with a higher prevalence of 20/40 or better visual acuity. Survival analysis showed that the prognosis of patients who initially were seen with visual acuity of 20/40 or better is related to age at initial visit.

Grover S, Fishman GA, Stone EM. · Department of Ophthalmology & Visual Sciences, Eye & Ear Infirmary, University of Illinois at Chicago, Chicago, Illinois 60612, USA. · Ophthalmology. · Pubmed #12045052 No free full text.

Abstract: PURPOSE: To describe the atypical clinical presentations of pattern dystrophy (PD) in two unrelated families with novel peripherin/RDS mutations. DESIGN: Observational case reports and family genetic study with review of peripherin/RDS mutations. PARTICIPANTS: Affected and unaffected members of two families with PD. METHODS: The probands of two families, as well as other family members, underwent an ophthalmologic assessment including slit-lamp biomicroscopy, applanation tonometry, and a dilated fundus examination. Goldmann visual fields and fluorescein angiography were performed, wherever appropriate. Blood samples were obtained from affected and selected unaffected members of the families for DNA analysis. RESULTS: The proband of family 1 had an acute onset of decreased vision and a yellowish lesion in both maculae that appeared inflammatory. However, resolution of the acute lesion ultimately resulted in fundus changes more typical for PD. Moreover, the proband's sister showed more classic-appearing PD lesions. Screening of the peripherin/RDS gene for sequence variations showed a 2-bp deletion, resulting in a translational frameshift at codon 290 in affected members of the family. The proband's father, who showed this sequence variation, did not have a macular lesion. The proband of family 2 was asymptomatic and showed a fundus phenotype similar to fundus flavimaculatus. The patient had normal visual acuity and did not demonstrate a "dark choroid" on fluorescein angiography. Molecular screening showed a Gln331stop variation in the peripherin/RDS gene. CONCLUSIONS: We describe two novel mutations in the peripherin/RDS gene in two unrelated families with PD. Clinicians should recognize the atypical features that may occur in patients with PD. A suspected diagnosis of PD may be confirmed by the identification of a mutation in the peripherin/RDS gene. In isolated family members with PD, a mutation in this gene may occur even in the absence of a clinically discernible macular lesion.

Webster AR, Héon E, Lotery AJ, Vandenburgh K, Casavant TL, Oh KT, Beck G, Fishman GA, Lam BL, Levin A, Heckenlively JR, Jacobson SG, Weleber RG, Sheffield VC, Stone EM. · Department of Ophthalmology, The University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. · Invest Ophthalmol Vis Sci. · Pubmed #11328725 links to  free full text

Abstract: PURPOSE. To assess the allelic variation of the ATP-binding transporter protein (ABCA4). METHODS. A combination of single-strand conformation polymorphism (SSCP) and automated DNA sequencing was used to systematically screen this gene for sequence variations in 374 unrelated probands with a clinical diagnosis of Stargardt disease, 182 patients with age-related macular degeneration (AMD), and 96 normal subjects. RESULTS. There was no significant difference in the proportion of any single variant or class of variant between the control and AMD groups. In contrast, truncating variants, amino acid substitutions, synonymous codon changes, and intronic variants were significantly enriched in patients with Stargardt disease when compared with their presence in subjects without Stargardt disease (Kruskal-Wallis P < 0.0001 for each variant group). Overall, there were 2480 instances of 213 different variants in the ABCA4 gene, including 589 instances of 97 amino acid substitutions, and 45 instances of 33 truncating variants. CONCLUSIONS. Of the 97 amino acid substitutions, 11 occurred at a frequency that made them unlikely to be high-penetrance recessive disease-causing variants (HPRDCV). After accounting for variants in cis, one or more changes that were compatible with HPRDCV were found on 35% of all Stargardt-associated alleles overall. The nucleotide diversity of the ABCA4 coding region, a collective measure of the number and prevalence of polymorphic sites in a region of DNA, was found to be 1.28, a value that is 9 to 400 times greater than that of two other macular disease genes that were examined in a similar fashion (VMD2 and EFEMP1).

Alexander KR, Barnes CS, Fishman GA. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 60612, USA. · J Opt Soc Am A Opt Image Sci Vis. · Pubmed #11318324 No free full text.

Abstract: The aim of this study was to identify the origin of a high-frequency attenuation in the flicker electroretinogram (ERG) of patients with X-linked retinoschisis (XLRS) through an analysis of nonlinearities in the ERG response. The ERGs of six patients with XLRS and six age-similar control subjects were recorded in response to stimuli that consisted of pairs of sinusoids that had varying temporal frequencies and that differed by either 8 or 16 Hz. Compared with the control subjects, the patients with XLRS showed a significant reduction in the amplitude of the difference frequency to high-frequency stimuli that paralleled the high-frequency attenuation of their ERG response fundamental. This result indicates that a response attenuation at an initial linear filter, most likely photoreceptoral, was a major determinant of the reduced ERG amplitude of the XLRS patients at high temporal frequencies. Additional analyses of nonlinearities in the ERG responses provided evidence of a postreceptoral component to the flicker ERG deficits of the XLRS patients, as well.

Lotery AJ, Munier FL, Fishman GA, Weleber RG, Jacobson SG, Affatigato LM, Nichols BE, Schorderet DF, Sheffield VC, Stone EM. · Department of Ophthalmology, The University of Iowa College of Medicine, Iowa City 52242, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10798642 links to  free full text

Abstract: PURPOSE: To assess the allelic variation of the VMD2 gene in patients with Best disease and age-related macular degeneration (AMD). METHODS: Three hundred twenty-one AMD patients, 192 ethnically similar control subjects, 39 unrelated probands with familial Best disease, and 57 unrelated probands with the ophthalmoscopic findings of Best disease but no family history were screened for sequence variations in the VMD2 gene by single-strand conformation polymorphism (SSCP) analysis. Amplimers showing a bandshift were reamplified and sequenced bidirectionally. In addition, the coding regions of the VMD2 gene were completely sequenced in six probands with familial Best disease who showed no SSCP shift. RESULTS: Forty different probable or possible disease-causing mutations were found in one or more Best disease or AMD patients. Twenty-nine of these variations are novel. Of the 39 probands with familial Best disease, mutations were detected in all 39 (33 by SSCP and 6 by DNA sequencing). SSCP screening of the 57 probands with a clinical diagnosis of Best disease but no family history revealed 16 with mutations. Mutations were found in 5 of 321 AMD patients (1.5%), a fraction that was not significantly greater than in control individuals (0/192, 0%). CONCLUSIONS: Patients with the clinical diagnosis of Best disease are significantly more likely to have a mutation in the VMD2 gene if they also have a positive family history. These findings suggest that a small fraction of patients with the clinical diagnosis of AMD may actually have a late-onset variant of Best disease, whereas at the same time, a considerable fraction of isolated patients with the ophthalmoscopic features of Best disease are probably affected with some other macular disease.

Gao YQ, Danciger M, Longmuir R, Piriev NI, Zhao DY, Heckenlively JR, Fishman GA, Weleber RG, Jacobson SG, Stone EM, Farber DB. · Jules Stein Eye Institute, University of California Los Angeles School of Medicine, CA 90095-7008, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10393054 links to  free full text

Abstract: PURPOSE: To screen the exons of the gene encoding the alpha'-subunit of cone cyclic guanosine monophosphate (cGMP>phosphodiesterase (PDE6C) for mutations in a group of 456 unrelated patients with various forms of inherited retinal disease, including cone dystrophy, cone-rod dystrophy, macular dystrophy, and simplex/multiplex and autosomal recessive retinitis pigmentosa. METHODS: The 22 exons of the PDE6C gene were screened for mutations either by denaturing gradient gel electrophoresis and single-strand conformation polymorphism electrophoresis (SSCP) or by SSCP alone; variants were sequenced directly. RESULTS: Although many sequence variants were found, none could be associated with disease. CONCLUSIONS: The results show that PDE6C was not the site of the amutations responsible for the types of inherited retinal degenerations analyzed in the large population of patients 'in the present study. The types of degeneration included those that predominantly affect cone-mediated function (cone and cone-rod dystrophies) or rod-mediated function (retinitis pigmentosa) or that have a predilection for disease in the macula (macular dystrophies).

Fishman GA, Stone EM, Grover S, Derlacki DJ, Haines HL, Hockey RR. · Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, 60612, USA. · Arch Ophthalmol. · Pubmed #10206579 links to  free full text

Abstract: 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.