Macular Degeneration: Jacobson SG

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.

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.

Shu X, Tulloch B, Lennon A, Hayward C, O'Connell M, Cideciyan AV, Jacobson SG, Wright AF. · MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK · Adv Exp Med Biol. · Pubmed #17249553 No free full text.

This publication has no abstract.

Lebherz C, Maguire AM, Auricchio A, Tang W, Aleman TS, Wei Z, Grant R, Cideciyan AV, Jacobson SG, Wilson JM, Bennett J. · Department of Medical Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 190104-6069, USA. · Diabetes. · Pubmed #15793254 links to  free full text

Abstract: Neovascularization leads to blindness in numerous ocular diseases, including diabetic retinopathy, age-related macular degeneration, retinopathy of prematurity, and sickle cell disease. More effective and stable treatments for ocular neovascularization are needed, yet there are major limitations in the present animal models. To develop primate models of diabetic retinopathy and choroidal neovascularization, rhesus monkeys were injected subretinally or intravitreally with an adeno-associated virus (AAV)-2 vector carrying the cDNA encoding human vascular endothelial growth factor (VEGF). Overexpression of VEGF was measured by intraocular fluid sampling over time. Neovascularization was evaluated by ophthalmoscopy through angiography, optical coherence tomography, and ultimately histopathology. Overexpression of VEGF through AAV2 results in rapid development of features of diabetic retinopathy or macular edema, depending on the targeted cell type/mode of production of VEGF and diffusion of VEGF. Nonhuman primate models will be useful in testing long-term safety and efficacy of novel therapeutic agents for blinding neovascular diseases.

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.

Abecasis GR, Yashar BM, Zhao Y, Ghiasvand NM, Zareparsi S, Branham KE, Reddick AC, Trager EH, Yoshida S, Bahling J, Filippova E, Elner S, Johnson MW, Vine AK, Sieving PA, Jacobson SG, Richards JE, Swaroop A. · Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105, USA. · Am J Hum Genet. · Pubmed #14968411 links to  free full text

Abstract: Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.

Hayward C, Shu X, Cideciyan AV, Lennon A, Barran P, Zareparsi S, Sawyer L, Hendry G, Dhillon B, Milam AH, Luthert PJ, Swaroop A, Hastie ND, Jacobson SG, Wright AF. · MRC Human Genetics Unit, Western General Hospital, Edinburgh, UK. · Hum Mol Genet. · Pubmed #12944416 links to  free full text

Abstract: A primary feature of age-related macular degeneration (AMD) is the presence of extracellular deposits between the retinal pigment epithelium (RPE) and underlying Bruch's membrane, leading to RPE dysfunction, photoreceptor death and severe visual loss. AMD accounts for about 50% of blind registrations in Western countries and is a common, genetically complex disorder. Very little is known regarding its molecular basis. Late-onset retinal degeneration (L-ORD) is an autosomal dominant disorder with striking clinical and pathological similarity to AMD. Here we show that L-ORD is genetically heterogeneous and that a proposed founder mutation in the CTRP5 (C1QTNF5) gene, which encodes a novel short-chain collagen, changes a highly conserved serine to arginine (Ser163Arg) in 7/14 L-ORD families and 0/1000 control individuals. The mutation occurs in the gC1q domain of CTRP5 and results in abnormal high molecular weight aggregate formation which may alter its higher-order structure and interactions. These results indicate a novel disease mechanism involving abnormal adhesion between RPE and Bruch's membrane.

Pianta MJ, Aleman TS, Cideciyan AV, Sunness JS, Li Y, Campochiaro BA, Campochiaro PA, Zack DJ, Stone EM, Jacobson SG. · Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, 51 N, 39th Street, Philadelphia, PA 19104, USA. · Exp Eye Res. · Pubmed #12565808 No free full text.

Abstract: Best macular dystrophy (BMD) is an autosomal dominant retinopathy caused by mutations in the VMD2 gene that encodes a chloride channel in the basolateral membrane of the retinal pigment epithelium (RPE). BMD patients were studied using optical coherence tomography (OCT) to understand the disease process in the macula leading to vision loss. BMD patients (ages 5-61), representing four families with known VMD2 mutations, were included. OCT scans were recorded in the central retina and longitudinal reflectivity profiles were analysed. The central retina in BMD showed different OCT abnormalities at or near the level of the highly reflective deep retinal band termed the outer retina-choroid complex (ORCC). Two types of ORCC change were noted to occur either separately or together: (1) splitting with or without intervening hyporeflective areas; and (2) elevation. Longitudinal study of a BMD patient indicated that such abnormalities were dynamic and changed in type and degree with time. The pathogenetic sequence in BMD may begin with defective fluid transport across the RPE secondary to the channelopathy in the basolateral membrane. In the macula, this leads to an abnormal interface with adjacent structures at both apical and basal surfaces of the RPE. The disease process results in detachments of the neurosensory retina, such as in central serous chorioretinopathy, and sub-RPE pathology resembling some stages of age-related macular degeneration, with eventual loss of photoreceptors, inner retina and central vision.

Scilley K, Jackson GR, Cideciyan AV, Maguire MG, Jacobson SG, Owsley C. · Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, 700 S 18th Street, Birmingham, AL 35294-0009, USA. · Ophthalmology. · Pubmed #12093644 No free full text.

Abstract: PURPOSE: To determine whether early age-related maculopathy (ARM) is associated with visual difficulty in daily activities beyond the difficulty that would be expected based on normal retinal aging; to determine whether scotopic sensitivity and visual acuity are associated with visual difficulties in these older adults. STUDY DESIGN: Comparative, cross-sectional questionnaire study. SUBJECTS: Ninety-two older adults with early ARM in at least one eye as defined by one or more large (>63 microm) drusen and/or focal hyperpigmentation but no choroidal neovascularization or geographic atrophy, acuity of 20/60 or better, and a reference group of 55 older adults in the same age range without these fundus features and acuity of 20/35 or better in each eye. METHOD: Tests of visual acuity and scotopic sensitivity and a general health questionnaire were carried out. The Activities of Daily Vision Scale (ADVS) was administered to assess self-reported visual difficulties in everyday tasks and expressed on a scale of 0 (extreme difficulty) to 100 (no difficulty). Fundus photographs were taken and graded to characterize the presence and severity of ARM to determine eligibility. RESULTS: For purposes of analysis, the early ARM group was divided into those whose fellow eye (FE) was 20/60 or better and those whose FE was worse than 20/60. ADVS subscale scores were substantially lower in the early ARM group with FE worse than 20/60 (medians, 58-83) compared with the normal retinal health group (medians, 97-100). Even for those with early ARM with FE 20/60 or better, four of five subscale scores were lower (medians, 81-97), albeit slightly in some cases, than those of the reference group. For both ARM subgroups, the night driving subscale had the lowest scores of all subscales. Persons with early ARM with FE 20/60 or better were more likely to report difficulty on the night driving (odds ratio [OR], 4.3; 95% confidence interval [CI], 1.6-11.4), near vision (OR, 5.0; 95% CI, 1.9-12.9), and glare disability (OR, 2.7; 95% CI, 1.1-6.3) subscales compared with those in normal retinal health, adjusting for age, gender, medical comorbidities, and lens density. For early ARM patients with FE worse than 20/60, there was widespread reporting of difficulty on all subscales (ORs ranging from 4.7-52.9). Poor scotopic sensitivity was highly associated with difficulty on the night driving subscale (OR, 6.6; 95% CI, 1.2-35.5) but not with any other subscale. Acuity worse than 20/25 in both eyes was significantly associated with difficulty on all ADVS subscales; when this acuity impairment was present in one eye only, associations were still significantly present on some subscales, although they were weaker. CONCLUSIONS: Persons in the early phases of ARM, even when their fellow eye has relatively good acuity, are more likely to experience difficulty in night driving, near vision tasks, and glare disability compared with those in good retinal health. Scotopic dysfunction, a functional marker of early ARM, is linked to reported night driving problems. Even when acuity impairment occurs in one eye only, patients report difficulties with day driving and near and far vision tasks.

Jacobson SG, Cideciyan AV, Bennett J, Kingsley RM, Sheffield VC, Stone EM. · Scheie Eye Institute, 51 N 39th St, Philadelphia, PA 19104, USA. · Arch Ophthalmol. · Pubmed #11879143 links to  free full text

Abstract: 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.

Aleman TS, Duncan JL, Bieber ML, de Castro E, Marks DA, Gardner LM, Steinberg JD, Cideciyan AV, Maguire MG, Jacobson SG. · Department of Ophthalmology, Scheie Eye Institute, 51 N. 39th Street, University of Pennsylvania, Philadelphia, PA 19104, USA. · Invest Ophthalmol Vis Sci. · Pubmed #11431456 links to  free full text

Abstract: PURPOSE. To determine macular pigment (MP) in patients with inherited retinal degeneration and the response of MP and vision to supplementation of lutein. METHODS. Patients with retinitis pigmentosa (RP) or Usher syndrome and normal subjects had MP optical density profiles measured with heterochromatic flicker photometry. Serum carotenoids, visual acuity, foveal sensitivity, and retinal thickness (by optical coherence tomography [OCT]) were quantified. The effects on MP and central vision of 6 months of lutein supplementation at 20 mg/d were determined. RESULTS. MP density in the patients as a group did not differ from normal. Among patients with lower MP, there was a higher percentage of females, smokers, and light-colored irides. Disease expression tended to be more severe in patients with lower MP. Inner retinal thickness by OCT correlated positively with MP density in the patients. After supplementation, all participants showed an increase in serum lutein. Only approximately half the patients showed a statistically significant increase in MP. Retinal nonresponders had slightly greater disease severity but were otherwise not distinguishable from responders. Central vision was unchanged after supplementation. CONCLUSIONS. Factors previously associated with lower or higher MP density in normal subjects showed similar associations in RP and Usher syndrome. In addition, MP in patients may be affected by stage of retinal disease, especially that leading to abnormal foveal architecture. MP could be augmented by supplemental lutein in many but not all patients. There was no change in central vision after 6 months of lutein supplementation, but long-term influences on the natural history of these retinal degenerations require further study.

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).

Milam AH, Curcio CA, Cideciyan AV, Saxena S, John SK, Kruth HS, Malek G, Heckenlively JR, Weleber RG, Jacobson SG. · Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Ophthalmology. · Pubmed #11097607 No free full text.

Abstract: PURPOSE: To clarify the pathogenesis of late-onset retinal degeneration (L-ORD), an autosomal dominant disorder characterized by thick deposits of lipid-rich material between the retinal pigment epithelium (RPE) and Bruch's membrane. STUDY DESIGN: Comparative clinicopathologic case report and case series. TISSUES: Eyes of an 82-year-old L-ORD eye donor and an age-matched control. SUBJECTS: Five descendants of the eye donor and his affected sister. METHODS: The eyes were processed for histopathologic examination, including electron microscopy and immunohistochemistry. Family members were examined clinically and with retinal function tests. RESULTS: The L-ORD eye had sub-RPE deposits that were positive for lipid, including esterified and unesterified cholesterol. The deposits were thinnest in the macula, which retained the highest percentage of photoreceptors. In the periphery, RPE thinning and photoreceptor loss correlated with thickness of the sub-RPE deposits. The eye donor was asymptomatic until his late 50s, when he developed problems with adapting to darkness. At age 68, the eye donor had normal acuity but a midperipheral scotoma and subnormal electroretinograms (ERGs); visual loss was progressive. The five descendants (at the time of examination ages 44-58) of the eye donor and his affected sister, who were at 50/50 risk of inheriting L-ORD, had normal ERGs, but four showed defects in dark adaptation. The dark adaptation abnormalities had a distribution similar to the thickness of the sub-RPE deposits in the eye donor, with slow kinetics in the midperiphery and normal kinetics centrally. CONCLUSIONS: The L-ORD donor eye differed from a previous case in the regional distribution of sub-RPE deposits and photoreceptors. In the next generation of this L-ORD family, the first expression of disease, abnormal dark adaptation, mirrored the regional distribution of the deposits in the donor eye. The fine structure and staining characteristics of the sub-RPE deposits in L-ORD resemble those in age-related macular degeneration and Sorsby fundus dystrophy.

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.

Owsley C, Jackson GR, Cideciyan AV, Huang Y, Fine SL, Ho AC, Maguire MG, Lolley V, Jacobson SG. · Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10634630 links to  free full text

Abstract: PURPOSE: To determine whether there is rod system dysfunction in the central retina of patients with age-related macular degeneration (AMD). METHODS: Dark-adapted sensitivity (500-nm stimulus) and light-adapted sensitivity (600 nm) were measured psychophysically at 52 loci in the central 38 degrees (diameter) of retina in 80 patients with AMD, and results were compared with those from older adult normal controls. All dark-adapted data were corrected for preretinal absorption. RESULTS: Mean field dark-adapted sensitivity was significantly lower in AMD patients as a group than in normal subjects. Within the AMD group were subsets of patients with normal mean dark- and light-adapted sensitivities; reduced dark-adapted sensitivities without detectable light-adapted losses; both types of losses; and, least commonly, only light-adapted losses. Regional retinal analyses of the dark-adapted deficit indicated the greatest severity was 2 degrees to 4 degrees or approximately 1 mm from the fovea, and the deficit decreased with increasing eccentricity. CONCLUSIONS: These psychophysical results are consistent with histopathologic findings of a selective vulnerability for parafoveal rod photoreceptors in AMD. The different patterns of rod and cone system losses among patients at similar clinical stages reinforces the notion that AMD is a group of disorders with underlying heterogeneity of mechanism of visual loss. Dark-adapted macula-wide testing may be a useful complement to the more traditional outcome measures of fundus pathology and foveal cone-based psychophysics in future AMD trials.

Lewis CA, Batlle IR, Batlle KG, Banerjee P, Cideciyan AV, Huang J, Alemán TS, Huang Y, Ott J, Gilliam TC, Knowles JA, Jacobson SG. · Riverview Medical Center, Carrabelle, Florida, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10440267 links to  free full text

Abstract: PURPOSE: To characterize the disease expression of an autosomal recessive human retinal degeneration associated with a mutation in TULP1 (tubby-like protein 1), a gene with currently unknown function. METHODS: Homozygotes and heterozygotes from an extended Dominican kindred with a TULP1 splice-site gene mutation (IVS14+1,G-->A) were studied clinically and with visual function tests. Sequence analysis of TULP1 was also performed in unrelated patients with severe retinal degeneration from a North American clinic population. RESULTS: Homozygotes had nystagmus, visual acuity of 20/200 or worse, color vision disturbances, bull's eye maculopathy, and peripheral pigmentary retinopathy. Younger patients had a relatively wide extent of kinetic visual fields; older patients had only peripheral islands. No rod function was measurable by psychophysics in any of the patients; markedly reduced cone function was detectable across the visual field of younger patients and in the remaining peripheral islands of older patients. Rod and cone electroretinograms (ERGs) were not detectable using standard methods; microvolt-level cone ERGs were present in some patients. Heterozygotes had normal visual function. No putative pathogenic sequence changes in TULP1 were observed in North American patients with comparably severe retinal phenotypes, mainly in the diagnostic category of Leber congenital amaurosis. CONCLUSIONS: This TULP1 splice-site mutation in homozygotes causes early-onset, severe retinal degeneration involving macular and peripheral cones and rods. The constellation of phenotypic findings suggests that the TULP1 gene product is critically important for normal photoreceptor function and may play a role in retinal development.

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).