Macular Degeneration: Heckenlively JR

Moroi SE, Heckenlively JR. · No affiliation provided · Ophthalmology. · Pubmed #18519068 No free full text.

This publication has no abstract.

Elizabeth Rakoczy P, Yu MJ, Nusinowitz S, Chang B, Heckenlively JR. · Lions Eye Institute, Centre for Ophthalmology and Visual Science, Department of Molecular Opthalmology, The University of Western Australia, 2 Verdun Street, Nedland Western Australia 6009, Australia. · Exp Eye Res. · Pubmed #16325179 No free full text.

Abstract: Recent advances in genetic technologies have greatly accelerated our ability to find disease-related genes and to generate animal models. The availability of ocular tissues with known genetic diseases are greatly contributing to our understanding of retinal disease processes including age-related macular degeneration (AMD), and panretinal and cone degenerations. While the macula is a highly specialised area of the retina not present in many mammals, the use of animal models such as mouse strains will give basic physiology and visual processing genetics relevant to human AMD. This review aims to provide a framework for better understanding some of the existing animal models and the knowledge that has been derived from their evaluations.

Ferreyra HA, Jayasundera T, Khan NW, He S, Lu Y, Heckenlively JR. · Department of Ophthalmology, Kellogg Eye Center, University of Michigan, Ann Arbor, USA. · Arch Ophthalmol. · Pubmed #19365013 No free full text.

Abstract: OBJECTIVE: To report the results of treating autoimmune retinopathy (AIR) with immunosuppression therapy. METHODS: Retrospective review of 30 consecutive patients with AIR followed for 3 to 89 months (median, 17 months) who were treated with immunosuppression (systemic or local). Subgroups were cancer-associated retinopathy (CAR), nonparaneoplastic AIR (npAIR), and npAIR with cystoid macular edema (npAIR/CME). Outcome measures were improvement of Snellen visual acuity by at least 2 lines, expansion of the visual field area by more than 25%, and resolution of CME. RESULTS: Overall, 21 of 30 patients (70%) showed improvement. All 6 CAR patients, 7 of 13 (54%) with npAIR, and 8 of 11 (73%) with npAIR/CME showed improvement. Five of 21 patients (24%) had improvement in visual acuity, 15 of 21 (71%) had expansion of visual field area, and 6 of 11 (55%) had resolution of CME. Twenty-six of 30 patients exhibited diffuse retinal atrophy without pigment deposits. An autoimmune family history was common in all the groups: npAIR, 69% (9 of 13); npAIR/CME, 64% (7 of 11); and CAR, 50% (3 of 6). CONCLUSIONS: Long-term treatment with immunosuppression resulted in clinical improvement in all subgroups of AIR. The most responsive subgroup was CAR; the least was npAIR. These results challenge the commonly held belief that AIR is untreatable.

Elner SG, Elner VM, Field MG, Park S, Heckenlively JR, Petty HR. · Department of Ophthalmology, University of Michigan, Ann Arbor, USA. · Trans Am Ophthalmol Soc. · Pubmed #19277237 links to  free full text

Abstract: PURPOSE: To establish that increased autofluorescence of mitochondrial flavoproteins, an indicator of mitochondrial oxidative stress, correlates with retinal cell dysfunction. METHODS: Retinal flavoprotein autofluorescence (FA) was imaged in humans with a fundus camera modified with 467DF8-nm excitation and 535-nm emission filters and a back-illuminated, electron-multiplying, charge-coupled device camera interfaced with a computer equipped with customized image capture software. Multiple digital images, centered on the fovea, were obtained from each eye. Histograms of pixel intensities in grayscale units were analyzed for average intensity and average curve width. Adults with diabetes mellitus, age-related macular degeneration (ARMD), central serous retinopathy, and retinal dystrophies, as well as healthy control volunteers, were imaged. Monolayers of cultured human retinal pigment epithelial (HRPE) cells, HRPE cells exposed to sublethal doses of H2O2, and HRPE cells exposed to H2O2 in the presence of antioxidants were imaged for FA using fluorescent photomicroscopy. RESULTS: Control patients demonstrated low levels of retinal FA, which increased progressively with age. Diabetics without visible retinopathy demonstrated increased FA levels compared to control volunteers (P < .001). Diabetics with retinopathy demonstrated significantly higher FA values than those without retinopathy (P < .04). Patients with ARMD, central serous retinopathy, or retinal dystrophies also demonstrated significantly increased FA. Compared to control RPE cells, cells oxidatively stressed with H2O2 had significantly elevated FA (P < .05), which was prevented by antioxidants (P < .05). CONCLUSIONS: Retinal FA is significantly increased with age and diseases known to be mediated by oxidative stress. Retinal FA imaging may provide a novel, noninvasive method of assessing retinal health and retinal dysfunction prior to retinal cell death.

Chang B, Mandal MN, Chavali VR, Hawes NL, Khan NW, Hurd RE, Smith RS, Davisson ML, Kopplin L, Klein BE, Klein R, Iyengar SK, Heckenlively JR, Ayyagari R. · The Jackson Laboratory, Bar Harbor, ME 04609, USA. · Hum Mol Genet. · Pubmed #18805803 No free full text.

Abstract: We observed that a naturally occurring mouse strain developed age-related retinal degeneration (arrd2). These mice had normal fundi, electroretinograms (ERGs) and retinal histology at 6 months of age; vessel attenuation, RPE atrophy and pigmentary abnormalities at 14 months, which progressed to complete loss of photoreceptors and extinguished ERG by 22 months. Genetic analysis revealed that the retinal degeneration in arrd2 segregates in an autosomal recessive manner and the disease gene localizes to mouse chromosome 10. A positional candidate cloning approach detected a nonsense mutation in the mouse double minute-1 gene (Mdm1), which results in the truncation of the putative protein from 718 amino acids to 398. We have identified a novel transcript of the Mdm1 gene, which is the predominant transcript in the retina. The Mdm1 transcript is localized to the nuclear layers of neural retina. Expression of Mdm1 in the retina increases steadily from post-natal day 30 to 1 year, and a high level of Mdm1 are subsequently maintained. The Mdm1 transcript was found to be significantly depleted in the retina of arrd2 mice and the transcript was observed to degrade by nonsense-mediated decay. These results indicate that the depletion of the Mdm1 transcript may underlie the mechanism leading to late-onset progressive retinal degeneration in arrd2 mice. Analysis of a cohort of patients with age-related macular degeneration (AMD) wherein the susceptibility locus maps to chromosome 12q, a region bearing the human ortholog to MDM1, did not reveal association between human MDM1 and AMD.

Ronan S, Nusinowitz S, Swaroop A, Heckenlively JR. · Department of Ophthalmology and Visual Science, Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. · Trans Am Ophthalmol Soc. · Pubmed #17471344 links to  free full text

Abstract: PURPOSE: To test if patients with age-related macular degeneration (AMD) have normal panretinal function using standardized full-field electroretinograms (ERGs). METHODS: This is a retrospective study evaluating electroretinographic studies performed in patients with AMD to assess their panretinal function. Fifty-two individuals 55 years or older had standardized ERG testing and fundus photographs. RESULTS: The study group was aged 57 to 93 years old with a mean of 75.7, and the controls ranged from 79 to 87 years with a mean of 81.4. On average, the photopic, scotopic, dark-adapted bright-flash, and flicker function response amplitudes are lower with longer implicit times in the study group than the controls. The most pronounced differences were seen with the bright-flash dark-adapted a-waves and the photopic b-wave amplitudes. Forty-three of 104 eyes had abnormal photopic b-wave ERGs of more than 2 SD compared to controls. The mean of the photopic b-wave amplitudes for the study group was 76.7 +/- 36.2 muV (1 SD) compared to 91.4 +/- 16.9 muV (1 SD) for the control group. This finding was statistically significant with P = .0269 by the Student t test and P = .0336 by the Wilcoxon test. CONCLUSIONS: There is a subgroup of AMD patients with a panretinal cone dysfunction on ERG in association with their macular degeneration. Previous studies have shown varied results when looking at ERG changes in AMD, likely reflecting the underlying complexity of this disorder. Using standardized ERG to identify a more homogeneous subgroup of AMD patients with panretinal dysfunction will aid in better characterizing subtypes clinically and is likely to be valuable in identifying new genes contributing to AMD.

Bowne SJ, Sullivan LS, Mortimer SE, Hedstrom L, Zhu J, Spellicy CJ, Gire AI, Hughbanks-Wheaton D, Birch DG, Lewis RA, Heckenlively JR, Daiger SP. · Human Genetics Center, School of Public Health, The University of Texas Health Science Center, Houston, TX 77030, USA. · Invest Ophthalmol Vis Sci. · Pubmed #16384941 links to  free full text

Abstract: PURPOSE: The purpose of this study was to determine the frequency and spectrum of inosine monophosphate dehydrogenase type I (IMPDH1) mutations associated with autosomal dominant retinitis pigmentosa (RP), to determine whether mutations in IMPDH1 cause other forms of inherited retinal degeneration, and to analyze IMPDH1 mutations for alterations in enzyme activity and nucleic acid binding. METHODS: The coding sequence and flanking intron/exon junctions of IMPDH1 were analyzed in 203 patients with autosomal dominant RP (adRP), 55 patients with autosomal recessive RP (arRP), 7 patients with isolated RP, 17 patients with macular degeneration (MD), and 24 patients with Leber congenital amaurosis (LCA). DNA samples were tested for mutations by sequencing only or by a combination of single-stranded conformational analysis and by sequencing. Production of fluorescent reduced nicotinamide adenine dinucleotide (NADH) was used to measure enzymatic activity of mutant IMPDH1 proteins. The affinity and the specificity of mutant IMPDH1 proteins for single-stranded nucleic acids were determined by filter-binding assays. RESULTS: Five different IMPDH1 variants, Thr116Met, Asp226Asn, Val268Ile, Gly324Asp, and His 372Pro, were identified in eight autosomal dominant RP families. Two additional IMPDH1 variants, Arg105Trp and Asn198Lys, were found in two patients with isolated LCA. None of the novel IMPDH1 mutants identified in this study altered the enzymatic activity of the corresponding proteins. In contrast, the affinity and/or the specificity of single-stranded nucleic acid binding were altered for each IMPDH1 mutant except the Gly324Asp variant. CONCLUSIONS: Mutations in IMPDH1 account for approximately 2% of families with adRP, and de novo IMPDH1 mutations are also rare causes of isolated LCA. This analysis of the novel IMPDH1 mutants substantiates previous reports that IMPDH1 mutations do not alter enzyme activity and demonstrates that these mutants alter the recently identified single-stranded nucleic acid binding property of IMPDH. Studies are needed to further characterize the functional significance of IMPDH1 nucleic acid binding and its potential relationship to retinal degeneration.

Fawzi AA, Vo B, Kriwanek R, Ramkumar HL, Cha C, Carts A, Heckenlively JR, Foos RY, Glasgow BJ. · Department of Ophthalmology, Jules Stein Eye Institute, The David Geffen School of Medicine, University of California at Los Angeles, USA. · Arch Ophthalmol. · Pubmed #15824221 No free full text.

Abstract: OBJECTIVES: To study the prevalence and associations of asteroid hyalosis (AH) in a series of autopsy eyes. METHODS: Retrospective review of the University of California at Los Angeles (UCLA) autopsy eye database from 1965 to 2000 yielded 10,801 patients. The patients' medical histories were reviewed for evidence of diabetes mellitus, hypertension, hyperlipidemia, alcohol abuse, hypercalcemia, hypothyroidism, and chronic renal failure. Autopsy records were searched for evidence of optic atrophy, macular degeneration, posterior vitreous detachment, atherosclerosis, and chronic renal failure. Asteroid hyalosis was diagnosed by examination of the autopsy eyes. Univariate and multivariate statistical methods were used to analyze our data. RESULTS: The prevalence of AH was 1.96% in this autopsy population. By chi(2) analysis, AH was significantly correlated with age (P<.001), male sex (P = .006), age-related macular degeneration (P = .02), hypertension (P = .03), atherosclerosis (P<.001), and posterior vitreous attachment (P<.001). After adjusting for age in a multivariate logistic regression analysis, statistical significance was found only for posterior vitreous attachment (P = .002) and male sex (P = .046). No statistically significant association was found with diabetes mellitus or alcohol abuse by univariate or multivariate analysis. Analysis of the odds ratio showed a strong age effect that increased from 5.0 (95% confidence interval, 2.2-11.3) in age group 41 to 50 years, compared with 25.4 (95% Wald confidence interval, 8.2-77.9) in the age group of patients older than 90 years. CONCLUSIONS: A unique epidemiological autopsy cohort study of AH and its systemic associations yielded a higher prevalence of AH than previous studies. Asteroid hyalosis was strongly correlated with age and inversely correlated with posterior vitreous detachment. Unlike some previous reports, we found no statistically significant correlation between AH and diabetes mellitus.

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.

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).

Heckenlively JR, Jordan BL, Aptsiauri N. · Jules Stein Eye Institute, UCLA Medical Center, Los Angeles, California, USA. · Am J Ophthalmol. · Pubmed #10334350 No free full text.

Abstract: PURPOSE: To report the association of antiretinal antibodies in patients with bilateral cystoid macular edema and retinitis pigmentosa. METHODS: In a prospective study, 30 consecutive patients with bilateral cystoid macular edema and retinitis pigmentosa were tested for antiretinal antibodies. As control subjects, 30 consecutive patients with retinitis pigmentosa who did not have cystoid macular edema and 50 normal subjects without retinitis pigmentosa or cystoid macular edema were tested for antiretinal antibodies. Laboratory personnel performing the antiretinal antibody testing were masked regarding the diagnosis of each patient. RESULTS: Twenty-seven (90%) of 30 patients with retinitis pigmentosa with cystoid macular edema had antiretinal protein antibody activity, compared with three (6%) of 50 normal controls (P < .001) and only four (13%) of 30 control patients with retinitis pigmentosa (P < .001). CONCLUSIONS: We found a significant association between cystoid macular edema and the presence of circulating antiretinal antibodies in patients who presented with retinitis pigmentosa and cystoid macular edema. This study suggests that patients with retinitis pigmentosa with cystoid macular edema may have an autoimmune process that is contributing to the formation of cystoid macular edema in retinitis pigmentosa, but to date, there is no direct evidence that the cystoid macular edema is caused by the antiretinal antibodies.