Macular Degeneration: Stone EM

Stone EM. · No affiliation provided · N Engl J Med. · Pubmed #17021326 No free full text.

This publication has no abstract.

Stone EM. · Carver Family Center for Macular Degeneration, The Howard Hughes Medical Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52245, USA. · Arch Ophthalmol. · Pubmed #17296896 No free full text.

This publication has no abstract.

Stone EM. · The Carver Family Center for Macular Degeneration, The Howard Hughes Medical Institute, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52245, USA. · Annu Rev Med. · Pubmed #16922634 No free full text.

Abstract: Macular degeneration is a term that describes a large group of conditions that are collectively the most common cause of irreversible vision loss in the developed world. Approximately one in three people will be affected to some degree by the time they reach 75 years of age. Many forms of macular degeneration have a significant genetic component, and a large amount of progress has recently been made in understanding the genes involved. In the future, genetic testing may allow specific preventive treatments to be delivered to individuals at risk, decades before the disease would ordinarily become manifest.

Stone EM, Sheffield VC, Hageman GS. · Department of Ophthalmology, The University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242, USA. · Hum Mol Genet. · Pubmed #11673412 links to  free full text

Abstract: The numerous conditions that clinicians group under the term 'age-related macular degeneration' (AMD) are collectively the most common cause of severe visual loss in the developed world. Moreover, the number of people affected by these diseases is expected to nearly double in the next 25 years. A growing body of data suggests that a large fraction of AMD is caused by genetic factors. As a result, numerous investigators have sought genes that contribute to this disorder. At least six genes have now been identified that cause heritable macular disease, but none of these seem to cause even a moderate fraction of AMD. Affected pedigree member studies suggest that some regions of the genome do harbor AMD predisposing genes, but none have yet been identified by this approach. Studies of human donor tissue have yielded important new insights into pathways associated with AMD. These studies, when combined with the power of genetic approaches, are likely to ultimately reveal a set of genes responsible for a sizeable fraction of AMD.

Donoso LA, Edwards AO, Frost A, Vrabec T, Stone EM, Hageman GS, Perski T. · Henry and Corinne Bower Laboratory for Macular Degeneration, Eye Research Institute, Wills Eye Hospital, Philadelphia, PA 19107, USA. · Surv Ophthalmol. · Pubmed #11578648 No free full text.

Abstract: Autosomal dominant Stargardt-like macular dystrophy is one of the early onset macular dystrophies. It is characterized clinically in its early stages by visual loss and by the presence of atrophic macular changes with or without the presence of yellowish flecks. It is an important retinal dystrophy to study, not only because it has implications in the care and treatment of patients with the condition, but because it also provides important information regarding retinal function. Review of the literature suggests that many of the reported families are linked to chromosome 6q. Genetic and genealogical evidence suggests that these families have descended from a common ancestor or founder. The recent identification of a disease-causing gene that is involved in fatty acid metabolism may have implications in the study of the more common age-related macular degeneration. We review the recent clinical, genetic, and genealogical aspects of autosomal dominant Stargardt-like macular dystrophy.

Zack DJ, Dean M, Molday RS, Nathans J, Redmond TM, Stone EM, Swaroop A, Valle D, Weber BH. · Departments of Ophthalmology, Molecular Biology and Genetics, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. · Mol Vis. · Pubmed #10562654 links to  free full text

Abstract: Age-related macular degeneration (AMD) is increasingly recognized as a complex genetic disorder in which one or more genes contribute to an individual's susceptibility for developing the condition. Twin and family studies as well as population-based genetic epidemiologic methods have convincingly demonstrated the importance of genetics in AMD, though the extent of heritability, the number of genes involved, and the phenotypic and genetic heterogeneity of the condition remain unresolved. The extent to which other hereditary macular dystrophies such as Stargardts disease, familial radial drusen (malattia leventinese), Best's disease, and peripherin/RDS-related dystrophy are related to AMD remains unclear. Alzheimer's disease, another late onset, heterogeneous degenerative disorder of the central nervous system, offers a valuable model for identifying the issues that confront AMD genetics.

Duncan JL, Aleman TS, Gardner LM, De Castro E, Marks DA, Emmons JM, Bieber ML, Steinberg JD, Bennett J, Stone EM, MacDonald IM, Cideciyan AV, Maguire MG, Jacobson SG. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA. · Exp Eye Res. · Pubmed #12014918 No free full text.

Abstract: Choroideremia is an incurable X-linked retinal degeneration caused by mutations in the gene encoding Rab escort protein-1. A group of clinically defined and genotyped patients were studied to determine: (1) the degree of rod and cone dysfunction and structural abnormality in the central retina and the level of macular pigment; and (2) the response of macular pigment and foveal vision to a 6 month trial of supplementation with oral lutein (at 20 mg per day). Rod and cone-mediated function was measured with dark-adapted static perimetry; in vivo retinal structure was determined with optical coherence tomography; and macular pigment optical density was measured with heterochromatic flicker photometry. In this cohort of patients (ages 15-65 years), both rod- and cone-mediated central function declined with age as did central retinal thickness. Macular pigment levels did not differ between patients and male control subjects. Supplementation of oral lutein in a subset of patients led to an increase in serum lutein and macular pigment levels; absolute foveal sensitivity did not change. It is concluded that macular pigment density can be augmented by oral intake of lutein in patients with choroideremia. There was no short-term change in the central vision of the patients on the supplement, but long-term influences of lutein supplementation on disease natural history warrant further study.

Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM, Palczewski K. · Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Hum Mol Genet. · Pubmed #19074458 No free full text.

Abstract: Autosomal recessive retinal diseases caused by mutations in the ABCA4 gene are being considered for gene replacement therapy. All individuals with ABCA4-disease show macular degeneration, but only some are thought to progress to retina-wide blindness. It is currently not predictable if or when specific ABCA4 genotypes will show extramacular disease, and how fast it will progress thereafter. Early clinical trials of focal subretinal gene therapy will aim to arrest disease progression in the extramacular retina. In 66 individuals with known disease-causing ABCA4 alleles, we defined retina-wide disease expression by measuring rod- and cone-photoreceptor-mediated vision. Serial measurements over a mean period of 8.7 years were consistent with a model wherein a normal plateau phase of variable length was followed by initiation of retina-wide disease that progressed exponentially. Once initiated, the mean rate of disease progression was 1.1 log/decade for rods and 0.45 log/decade for cones. Spatio-temporal progression of disease could be described as the sum of two components, one with a central-to-peripheral gradient and the other with a uniform retina-wide pattern. Estimates of the age of disease initiation were used as a severity metric and contributions made by each ABCA4 allele were predicted. One-third of the non-truncating alleles were found to cause more severe disease than premature truncations supporting the existence of a pathogenic component beyond simple loss of function. Genotype-based inclusion/exclusion criteria and prediction of the age of retina-wide disease initiation will be invaluable for selecting appropriate candidates for clinical trials in ABCA4 disease.

Iannaccone A, Fung KH, Eyestone ME, Stone EM. · Retinal Degeneration and Ophthalmic Genetics Service, Hamilton Eye Institute, University of Tennessee Health Science Center, Memphis, Tennessee, USA. · Am J Ophthalmol. · Pubmed #18835469 No free full text.

Abstract: PURPOSE: To report on the efficacy of the oral carbonic anhydrase inhibitor (CAI) acetazolamide in treating macular retinoschisis (RS) in the rare vitreoretinal dystrophy best known as the enhanced S-cone syndrome (ESCS). DESIGN: Interventional case report. METHODS: setting: University-based practice. patient: A 48-year old Jewish Italian male with clinically, functionally, and molecularly confirmed ESCS, attributable to homozygosity for the R311Q mutation in the NR2E3 gene, presented with sudden visual acuity (VA) loss (20/200) and metamorphopsia in the left eye resulting from acute, late-onset, asymmetric macular RS. intervention: Open-label, off-label treatment with the oral CAI acetazolamide. main outcome measure(s): Best-corrected VA, retinal thickness, and retinal microanatomy, assessed by Stratus optical coherence tomography (OCT) criteria. RESULTS: Following treatment, instituted one month after the acute-onset VA loss, retinal thickness and microanatomic profile normalized in the affected eye, with restoration of 20/20 corrected VA. The fellow eye, which had remained asymptomatic at 20/16 vision, had experienced mild paracentral macular RS evident by OCT criteria, which also resolved completely following oral CAI treatment. The outcome was maintained throughout the follow-up period at a low maintenance dose. CONCLUSIONS: Taken together with other recent reported benefits of topical and oral CAIs in the treatment of macular RS in X-linked retinoschisis, this interventional case report shows that CAIs can be used to treat effectively macular RS in general, and also specifically in ESCS.

Thompson S, Philp AR, Stone EM. · Howard Hughes Medical Institute and The Carver Family Center for Macular Degeneration, Department of Ophthalmology and Visual Sciences, 4111 MERF, 375 Newton Road, The University of Iowa, Iowa City, IA 52242, USA. · Vision Res. · Pubmed #17825348 No free full text.

Abstract: A measure of improved vision remains the most meaningful way to demonstrate the efficacy of a therapy. Animal models allow us to describe the pathology of inherited retinal degenerations and to evaluate emerging therapies in specific disorders in ways not possible in human subjects. The potential use of mice in this role has been limited by the lack of a simple, unambiguous and practical test of an innate visually guided behavior. To begin to address this need, we have developed equipment and protocols to measure a performance enhancing effect of vision on use of a running wheel; a scotopic visually guided behavior termed positive masking. This assay is objective, quantitative, automated and can be adapted for in-depth studies of visual thresholds, longitudinal studies of visual pathology or treatment efficacy, and large scale screening programs. Proof-of-principle experiments show that our equipment and protocols are able to characterize the full range of masking responses in normal mice in an informative and efficient manner. A sustained activity increase across a range of dim light irradiances was consistent with scotopic visual guidance of behavior, while at higher irradiances a dose dependent suppression of activity was apparent. This study also describes for the first time the interaction of experience and vision in performing a task. Specifically, we identified an experience dependent acclimatization to wheel use in scotopic conditions; a performance reduction in complete darkness; and a partial but not complete recovery of performance levels with experience in complete darkness. This suggests that where visual guidance is performance enhancing but not essential, loss of the contribution of visual guidance to the tasks might be compensated for by experience or training.

Fu L, Garland D, Yang Z, Shukla D, Rajendran A, Pearson E, Stone EM, Zhang K, Pierce EA. · F.M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Hum Mol Genet. · Pubmed #17666404 links to  free full text

Abstract: Age-related macular degeneration (AMD) is the most common cause of vision loss in developed countries. A defining characteristic of this disorder is the accumulation of material between Bruch's membrane and the retinal pigment epithelium (RPE), first as microscopic basal deposits and later as clinically evident drusen. The pathogenesis of these deposits remains to be defined. Biochemical and genetic studies have suggested that inflammation and complement activation may play roles in AMD. Several lines of evidence also suggest that alterations to the extracellular matrix (ECM) of the RPE and choroid contribute to the development of AMD. The inherited macular degeneration Doyne honeycomb retinal dystrophy/Malattia Leventinese is thought to be caused by an R345W mutation in the EFEMP1 gene (also called fibulin-3). The pathogenicity of this mutation has been questioned because all individuals identified to date with the R345W mutation have shared a common haplotype. We investigated the pathogenicity of this mutation in families with early-onset macular degeneration and by generating Efemp1-R345W knockin mice. Genetic studies show that one of the identified families with the R345W mutation has a novel haplotype. The mutant Efemp1-R345W mice develop deposits of material between Bruch's membrane and the RPE, which resemble basal deposits in patients with AMD. These basal deposits contain Efemp1 and Timp3, an Efemp1 interacting protein. Evidence of complement activation was detected in the RPE and Bruch's membrane of the mutant mice. These results confirm that the R345W mutation in EFEMP1 is pathogenic. Further, they suggest that alterations in the ECM may stimulate complement activation, demonstrating a potential connection between these two etiologic factors in macular degeneration.

Mullins RF, Kuehn MH, Faidley EA, Syed NA, Stone EM. · Carver Family Center for Macular Degeneration, Department of Ophthalmology and Visual Science, The University of Iowa Carver College of Medicine, Iowa City, Iowa 52242, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17591911 links to  free full text

Abstract: PURPOSE: Best disease, or vitelliform macular degeneration, is an autosomal dominant form of macular degeneration that is caused by mutations in the gene encoding bestrophin. On clinical examination, Best disease is characterized by an elevated lesion beneath the neurosensory retina, resembling an egg yolk. The lesions in Best disease are primarily restricted to the macula, a small region of the retina responsible for central vision. The nature of the vitelliform material and the reason the development of such lesions is usually restricted to the macula are two unsolved questions in the pathogenesis of this disorder. METHODS: The expression of bestrophin protein and mRNA was evaluated by immunohistochemistry, Western blot, and quantitative PCR in a series of normal human eyes. The ultrastructure of the retinal pigment epithelium and the histopathology of two donors with clinically diagnosed Best disease were also examined. RESULTS: An eye from a Best disease donor with a T6R mutation was found to have deposits containing lipid and glycoconjugates within the central retinal scar. These deposits may be remnants of the vitelliform lesion. Immunohistochemical localization of bestrophin in a series of 22 unaffected eyes revealed a pattern in which macular labeling was less robust than labeling outside the macula in most (18/22) cases. This pattern was confirmed using quantitative PCR and Western blotting. CONCLUSIONS: Topographic differences in the levels of bestrophin protein may in part explain the propensity for the macula to develop lesions in Best disease.

Bakall B, Radu RA, Stanton JB, Burke JM, McKay BS, Wadelius C, Mullins RF, Stone EM, Travis GH, Marmorstein AD. · Department of Ophthalmology and Vision Science, University of Arizona, Tucson, AZ 85724, USA. · Exp Eye Res. · Pubmed #17477921 No free full text.

Abstract: Best vitelliform macular dystrophy (BMD) is an autosomal dominant inherited macular degenerative disease caused by mutations in the gene BEST1 (formerly VMD2). Prior reports indicate that BMD is characterized histopathologically by accumulation of lipofuscin in the retinal pigment epithelium (RPE). However, this accumulation has not been quantified and the chemical composition of lipofuscin in BMD has not been examined. In this study we characterize the histopathology of a donor eye from a rare individual homozygous for a mutation (W93C) in BEST1. We find that this individual's disease was not any more severe than has been described for heterozygotes. We then used this tissue to quantify lipofuscin accumulation by enriching intracellular granules from RPE cells on sucrose gradients and counting the granules in each density fraction. Granules from the homozygous donor eye as well as a donor eye from an individual heterozygous for the mutation T6R were compared with age-matched control eyes. Interestingly, the least dense fraction, representing classical lipofuscin granules was either not present or significantly diminished in the BMD donor eyes and the autoflourescence associated with lipofuscin had shifted to denser fractions. However, a substantial enrichment for granules in fractions of higher density was also noted in the BMD samples. Inspection of granules from the homozygous donor eye by electron microscopy revealed a complex abnormal multilobular structure. Analysis of granules by HPLC indicated a approximately 1.6- and approximately fourfold overall increase in A2E in the BMD eyes versus age-matched control eyes, with a shift of A2E to more dense granules in the BMD donor eyes. Despite the increase in A2E and total intracellular granules, the RPE in the homozygous donor eyes was relatively well preserved. Based on these data we conclude that the clinical and histopathologic consequences to the homozygous donor were not any more severe than has been reported previously for individuals who are established or presumptive heterozygotes. We find that A2E is a component of the lipofuscin accumulated in BMD and that it is more abundant than in control eyes suggesting that the etiology of BMD is similar to Stargardt's disease and Stargardt-like macular dystrophy. Finally, the changes we observe in the granules suggest that the histopathology and eventual vision loss associated with BMD may be due to defects in the ability of the RPE to fully degrade phagocytosed photoreceptor outer segments.

Thomas G, Grassi MA, Lee JR, Edwards AO, Gorin MB, Klein R, Casavant TL, Scheetz TE, Stone EM, Williams AB. · Department of Computer Science, University of Iowa, Iowa City, Iowa, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17460291 links to  free full text

Abstract: PURPOSE: To use the power of knowledge acquisition and machine learning in the development of a collaborative computer classification system based on the features of age-related macular degeneration (AMD). METHODS: A vocabulary was acquired from four AMD experts who examined 100 ophthalmoscopic images. The vocabulary was analyzed, hierarchically structured, and incorporated into a collaborative computer classification system called IDOCS. Using this system, three of the experts examined images from a second set of digital images compiled from more than 1000 patients with AMD. Images were annotated, and features were identified and defined. Decision trees, a machine learning method, were trained on the data collected and used to extract patterns. Interrelationships between the data from the different clinicians were investigated. RESULTS: Six drusen classes in the structured vocabulary were largely sufficient to describe all the identified features. The decision trees classified the data with 76.86% to 88.5% accuracy and distilled patterns in the form of hierarchical trees composed of 5 to 15 nodes. Experts were largely consistent in their characterization of soft, and to a lesser extent, hard drusen, but diverge in definition of other drusen. Size and crystalline morphology were the main determinants of drusen type across all experts. CONCLUSIONS: Machine learning is a powerful tool for the characterization of disease phenotypes. The creation of a defined feature set for AMD will facilitate the development of an IDOCS-based classification system.

Guziewicz KE, Zangerl B, Lindauer SJ, Mullins RF, Sandmeyer LS, Grahn BH, Stone EM, Acland GM, Aguirre GD. · Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17460247 links to  free full text

Abstract: PURPOSE: Canine multifocal retinopathy (cmr) is an autosomal recessive disorder of multiple dog breeds. The disease shares a number of clinical and pathologic similarities with Best macular dystrophy (BMD), and cmr is proposed as a new large animal model for Best disease. METHODS: cmr was characterized by ophthalmoscopy and histopathology and compared with BMD-affected patients. BEST1 (alias VMD2), the bestrophin gene causally associated with BMD, was evaluated in the dog. Canine ortholog cDNA sequence was cloned and verified using RPE/choroid 5'- and 3'-RACE. Expression of the canine gene transcripts and protein was analyzed by Northern and Western blotting and immunocytochemistry. All exons and the flanking splice junctions were screened by direct sequencing. RESULTS: The clinical phenotype and pathology of cmr closely resemble lesions of BMD. Canine VMD2 spans 13.7 kb of genomic DNA on CFA18 and shows a high level of conservation among eukaryotes. The transcript is predominantly expressed in RPE/choroid and encodes bestrophin, a 580-amino acid protein of 66 kDa. Immunocytochemistry of normal canine retina demonstrated specific localization of protein to the RPE basolateral plasma membranes. Two disease-specific sequence alterations were identified in the canine VMD2 gene: a C(73)T stop mutation in cmr1 and a G(482)A missense mutation in cmr2. CONCLUSIONS: The authors propose these two spontaneous mutations in the canine VMD2 gene, which cause cmr, as the first naturally occurring animal model of BMD. Further development of the cmr models will permit elucidation of the complex molecular mechanism of these retinopathies and the development of potential therapies.

Cideciyan AV, Swider M, Aleman TS, Roman MI, Sumaroka A, Schwartz SB, Stone EM, Jacobson SG. · Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia 19104, and Howard Hughes Medical Institute, University of Iowa Hospitals and Clinics, Iowa City 52242, USA. · J Opt Soc Am A Opt Image Sci Vis. · Pubmed #17429493 links to  free full text

Abstract: The health of the retinal pigment epithelium (RPE) can be estimated with autofluorescence (AF) imaging of lipofuscin, which accumulates as a byproduct of retinal exposure to light. Lipofuscin may be toxic to the RPE, and its toxicity may be enhanced by short-wavelength (SW) illumination. The high-intensity and SW excitation light used in conventional AF imaging could, at least in principle, increase the rate of lipofuscin accumulation and/or increase its toxicity. We considered two reduced-illuminance AF imaging (RAFI) methods as alternatives to conventional AF imaging. RAFI methods use either near-infrared (NIR) light or reduced-radiance SW illumination for excitation of fluorophores. We quantified the distribution of RAFI signals in relation to retinal structure and function in patients with the prototypical lipofuscin accumulation disease caused by mutations in ABCA4. There was evidence for two subclinical stages of macular ABCA4 disease involving hyperautofluorescence of both SW- and NIR-RAFI with and without associated loss of visual function. Use of RAFI methods and microperimetry in future clinical trials involving lipofuscinopathies should allow quantification of subclinical disease expression and progression without subjecting the diseased retina/RPE to undue light exposure.

Aleman TS, Cideciyan AV, Windsor EA, Schwartz SB, Swider M, Chico JD, Sumaroka A, Pantelyat AY, Duncan KG, Gardner LM, Emmons JM, Steinberg JD, Stone EM, Jacobson SG. · Scheie Eye Institute, Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17325179 links to  free full text

Abstract: PURPOSE: To determine macular pigment (MP) optical density (OD) in patients with ABCA4-associated retinal degenerations (ABCA4-RD) and the response of MP and vision to supplementation with lutein. METHODS: Patients with Stargardt disease or cone-rod dystrophy and known or suspected disease-causing mutations in the ABCA4 gene were included. All patients had foveal fixation. MPOD profiles were measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity, and retinal thickness were quantified. Changes in MPOD and central vision were determined in a subset of patients receiving oral supplementation with lutein for 6 months. RESULTS: MPOD in patients ranged from normal to markedly abnormal. As a group, patients with ABCA4-RD had reduced foveal MPOD, and there was a strong correlation with retinal thickness. Average foveal tissue concentration of MP, estimated by dividing MPOD by retinal thickness, was normal in patients, whereas serum concentration of lutein and zeaxanthin was significantly lower than normal. After oral lutein supplementation for 6 months, 91% of the patients showed significant increases in serum lutein, and 63% of the patients' eyes showed a significant augmentation in MPOD. The retinal responders tended to be female and to have lower serum lutein and zeaxanthin, lower MPOD, and greater retinal thickness at baseline. Responding eyes had significantly lower baseline MP concentration than did nonresponding eyes. Central vision was unchanged after the period of supplementation. CONCLUSIONS: MP is strongly affected by the stage of ABCA4 disease leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in some patients. There was no change in central vision after 6 months of lutein supplementation. Long-term influences of this supplement on the natural history of these macular degenerations require further study.

Grassi MA, Folk JC, Scheetz TE, Taylor CM, Sheffield VC, Stone EM. · Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, USA. · Arch Ophthalmol. · Pubmed #17210858 links to  free full text

Abstract: 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.

Grassi MA, Fingert JH, Scheetz TE, Roos BR, Ritch R, West SK, Kawase K, Shire AM, Mullins RF, Stone EM. · Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City 52242, USA. · Hum Mutat. · Pubmed #16865697 No free full text.

Abstract: Age-related macular degeneration (AMD) is the most common cause of irreversible visual loss in the developed world. Previous studies have demonstrated that the c.1204T>C, p.Tyr402His allelic variant in the complement factor H (CFH) gene is associated with an approximately three-fold increased risk for AMD in Caucasians of predominantly European descent. Both the prevalence as well as the phenotypic spectrum of AMD varies widely among persons of different ethnicities. We hypothesized that populations with a lower prevalence of AMD might also have a lower prevalence of the CFH risk allele. In this study we sought to determine the frequency of this sequence variant in control populations of Caucasians, African Americans, Hispanics, Somalis, and Japanese. Normal control populations were assembled for each ethnic group: Caucasian (n=148), Somali (n=128), African American (n=75), Hispanic (n=81), and Japanese (n=82). Individuals were genotyped using a restriction digest assay and the frequency of the C allele at nucleotide position 1204 of the CFH gene was determined. A bioinformatic approach was used to identify SNPs in linkage disequilibrium with rs1061170 (c.1204T>C, p.Tyr402His) from the human haplotype map project database (HapMap) in order to validate the findings. We found widely discordant frequencies of the risk allele between some of the different ethnic groups: Japanese 0.07+/-0.02, Hispanics 0.17+/-0.03, African-Americans 0.35+/-0.04, Caucasians 0.34+/-0.03, and Somalis 0.34+/-0.03. Allele frequencies generated by analysis of the HapMap database were consistent with these findings. This study suggests that there are other yet unidentified genetic factors important in the pathogenesis of AMD that may mitigate the effects of c.1204T>C, p.Tyr402His variant.

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.

Fingert JH, Eliason DA, Phillips NC, Lotery AJ, Sheffield VC, Stone EM. · Dept. of Ophthalmology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Arch Ophthalmol. · Pubmed #16682602 No free full text.

This publication has no abstract.

Mullins RF, Oh KT, Heffron E, Hageman GS, Stone EM. · Center for Macular Degeneration, Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City 52242, USA. · Arch Ophthalmol. · Pubmed #16286623 links to  free full text

Abstract: 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.

Allen RC, Russell SR, Streb LM, Alsheikheh A, Stone EM. · Molecular Ophthalmology Laboratory, Center for Macular Degeneration, The University of Iowa Carver School of Medicine, Iowa City, IA 52242, USA. · Eye. · Pubmed #15776010 No free full text.

Abstract: PURPOSE: To determine the molecular pathology and clinical severity of two pedigrees with a history of early retinal detachment and peripheral retinal vascular abnormalities. DESIGN: Longitudinal cohort study. METHODS: A longitudinal clinical study and DNA analysis was performed on 49 family members of two pedigrees. RESULTS: Nine individuals were found to be hemizygous for a mutation at codon 112 (Gly112Glu) of the Norrie disease protein (NDP) in one pedigree. Significant phenotypic heterogeneity was found. The proband presented with a unilateral subtotal retinal detachment at the age of 3 years, and subsequently developed a slowly progressive tractional retinal detachment involving the macula in the contralateral eye at the age of 4 years. One individual had only mild peripheral retinal pigmentary changes with normal vision at the age of 79 years. The remaining seven individuals had varying degrees of peripheral retinal vascular abnormalities and anterior segment findings. Seven affected members of a second pedigree affected by a previously reported mutation, Arg74Cys, also demonstrated wide ocular phenotypic variation. CONCLUSION: A novel mutation (Gly112Glu), which represents the most carboxy located, NDP mutation reported, results in significant phenotypic heterogeneity. These data support the contention that the spectrum of ocular disease severity associated with these NDP mutations is broad. Use of terms that characterize this entity by phenotypic appearance, such as familial exudative vitreoretinopathy, do not adequately communicate the potential spectrum of severity of this disorder to affected or carrier family members.

Schwartz SB, Aleman TS, Cideciyan AV, Windsor EA, Sumaroka A, Roman AJ, Rane T, Smilko EE, Bennett J, Stone EM, Kimberling WJ, Liu XZ, Jacobson SG. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. · Invest Ophthalmol Vis Sci. · Pubmed #15671307 links to  free full text

Abstract: PURPOSE: To investigate the retinal disease expression in USH2C, the subtype of Usher syndrome type 2 recently shown to be caused by mutation in the VLGR1 gene, and compare results with those from USH2A, a more common cause of Usher syndrome. METHODS: Three siblings with USH2C and 14 patients with USH2A were studied. Visual function was measured by kinetic perimetry, static chromatic perimetry, and electroretinography (ERG). Central retinal microstructure was studied with optical coherence tomography (OCT). RESULTS: The siblings with VLGR1 mutation showed abnormal photoreceptor-mediated function in all retinal regions, and there was greater rod than cone dysfunction. USH2A had a wider spectrum of disease expression and included patients with normal function in some retinal regions. When abnormalities were detected, there was more rod than cone dysfunction. Retinal microstructure in both USH2C and USH2A shared the abnormality of loss of outer nuclear layer thickness. Central retinal structure in both genotypes was complicated by cystic macular lesions. A coincidental finding in an USH2C patient was that oral intake of antihistamines was associated with temporary resolution of the macular cystic change. CONCLUSIONS: USH2C and USH2A manifest photoreceptor disease with rod- and cone-mediated visual losses and thinning of the outer nuclear layer. An orderly progression through disease stages was estimated from cross-sectional and limited longitudinal data. Intrafamilial and interfamilial variation in retinal severity in USH2A, however, suggests that genetic or nongenetic modifiers may be involved in the disease expression.

Oh KT, Weleber RG, Stone EM, Oh DM, Rosenow J, Billingslea AM. · Department of Ophthalmology, University of North Carolina, Chapel Hill, North Carolina, USA. · Retina. · Pubmed #15579991 No free full text.

Abstract: PURPOSE: To characterize the clinical and electroretinogram (ERG) features of our cohort of patients with Stargardt disease (STGD) exhibiting coding sequence variations in the ABCA4 gene. METHODS: Review of 76 patients with the clinical diagnosis of Stargardt disease/fundus flavimaculatus (STGD/FF) from the University of Iowa Department of Ophthalmology and Visual Sciences (41 patients) and the Casey Eye Institute (35 patients). Clinical examination, Goldmann perimetry, and electroretinography were performed on all 76 patients. Patients were divided into three groups on the basis of their funduscopic and electroretinographic features: (1) a normal ERG by the standards of the laboratory; (2) minimal rod or cone abnormalities; (3) severe ERG dysfunction. The latter category was further subdivided on the basis of a cone-dominated loss of function (C > R or "cone-rod dystrophy") or diffuse depression of rods and cones (C = R). Mutational analysis of the coding sequence of the ABCA4 gene was performed by single strand conformation polymorphism analysis followed by automated DNA sequencing. Each electroretinographic group was analyzed for the presence of disease causing changes using exact tests of binomial proportions corrected for multiple comparisons by Bonferroni method. Quantitative polymerase chain reaction (QPCR) was performed on patients who were homozygous for disease causing changes in the ABCA4 gene to rule out the possibility of deletions. RESULTS: Overall, 56 of 76 patients (and 77 of 152 alleles) exhibited coding sequence variations that were compatible with high-penetrance disease-causing mutations. The most common of these were His423Arg (9), frameshift mutations (7), Ala1038Val (7), and Pro1380Leu (6). Although no patients with His423Arg presented with normal ERGs, no significant correlation was observed between specific sequence variations and the electroretinographic characteristics or fundus appearance. However, a significantly greater fraction of patients with normal ERG studies failed to exhibit detectable disease-causing coding sequence variations in the ABCA4 gene identified on either allele (P = 0.0006). CONCLUSION: STGD/FF patients in our cohort exhibit a wide range of electroretinographic abnormalities, some of which are more prevalent than previously suspected. No direct correlation between clinical appearance, electrophysiologic characteristics and specific ABCA4 alleles could be identified, although a significantly lower number of our cohort with a normal ERG exhibited detectable coding sequence variations in the ABCA4 gene. However, four patients with ERG dysfunction were homozygous for a His423Arg change proven by QPCR not to be an artifact of a deletion. The presence of electrophysiologic dysfunction is not uncommon in our cohort of patients with STGD. Thus, the ERG provides clinically important information of retinal function for STGD/FF and, as such, is still indicated as part of the evaluation of these patients.