RESUMO
PURPOSE: To investigate the distribution of genotypes and natural history of ABCA4-associated retinal disease in a large cohort of patients seen at a single institution. DESIGN: Retrospective, single-institution cohort review. PARTICIPANTS: Patients seen at the University of Iowa between November 1986 and August 2022 clinically suspected to have disease caused by sequence variations in ABCA4. METHODS: DNA samples from participants were subjected to a tiered testing strategy progressing from allele-specific screening to whole genome sequencing. Charts were reviewed, and clinical data were tabulated. The pathogenic severity of the most common alleles was estimated by studying groups of patients who shared 1 allele. Groups of patients with shared genotypes were reviewed for evidence of modifying factor effects. MAIN OUTCOME MEASURES: Age at first uncorrectable vision loss, best-corrected visual acuity, and the area of the I2e isopter of the Goldmann visual field. RESULTS: A total of 460 patients from 390 families demonstrated convincing clinical features of ABCA4-associated retinal disease. Complete genotypes were identified in 399 patients, and partial genotypes were identified in 61. The median age at first vision loss was 16 years (range, 4-76 years). Two hundred sixty-five families (68%) harbored a unique genotype, and no more than 10 patients shared any single genotype. Review of the patients with shared genotypes revealed evidence of modifying factors that in several cases resulted in a > 15-year difference in age at first vision loss. Two hundred forty-one different alleles were identified among the members of this cohort, and 161 of these (67%) were found in only a single individual. CONCLUSIONS: ABCA4-associated retinal disease ranges from a very severe photoreceptor disease with an onset before 5 years of age to a late-onset retinal pigment epithelium-based condition resembling pattern dystrophy. Modifying factors frequently impact the ABCA4 disease phenotype to a degree that is similar in magnitude to the detectable ABCA4 alleles themselves. It is likely that most patients in any cohort will harbor a unique genotype. The latter observations taken together suggest that patients' clinical findings in most cases will be more useful for predicting their clinical course than their genotype. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Assuntos
Transportadores de Cassetes de Ligação de ATP , Genótipo , Doenças Retinianas , Acuidade Visual , Humanos , Estudos Retrospectivos , Pessoa de Meia-Idade , Masculino , Feminino , Idoso , Adulto , Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Criança , Acuidade Visual/fisiologia , Adulto Jovem , Pré-Escolar , Doenças Retinianas/genética , Doenças Retinianas/diagnóstico , Campos Visuais/fisiologia , Estudos Longitudinais , Mutação , Alelos , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To establish in a large healthy cohort, dendritiform cell (DC) density and morphological parameters in the central and peripheral cornea using in vivo confocal microscopy (IVCM). METHODS: A prospective, cross-sectional, observational study was conducted in 85 healthy volunteers (n = 85 eyes). IVCM images of corneal center and four peripheral zones were analyzed for DC density and morphology to compare means and assess correlations (p < 0.05 being statistically significant). RESULTS: Central corneas had lower DC density (40.83 ± 5.14 cells/mm2; mean ± SEM) as compared to peripheral corneas (75.42 ± 2.67 cells/mm2, p < 0.0001). Inferior and superior zones demonstrated higher DC density (105.01 ± 7.12 and 90.62 ± 4.62 cells/mm2) compared to the nasal and temporal zones (59.93 ± 3.42 and 51.77 ± 2.98 cells/mm2, p < 0.0001). Similarly, lower DC size, field and number of dendrites were observed in the central as compared to the average peripheral cornea (p < 0.0001), with highest values in the inferior zone (p < 0.001 for all, except p < 0.05 for number of dendrites in superior zone). DC parameters did not correlate with age or gender. Inter-observer reliability was 0.987 for DC density and 0.771-0.922 for morphology. CONCLUSION: In healthy individuals, the peripheral cornea demonstrates higher DC density and larger morphology compared to the center, with highest values in the inferior zone. We provide the largest normative cohort for sub-stratified DC density and morphology, which can be used in future clinical trials to compare differential changes in diseased states. Furthermore, as DC parameters in the peripheral zones are dissimilar, random sampling of peripheral cornea may be inaccurate.
Assuntos
Córnea , Humanos , Voluntários Saudáveis , Estudos Prospectivos , Estudos Transversais , Microscopia Confocal/métodos , Reprodutibilidade dos Testes , Córnea/diagnóstico por imagem , Contagem de CélulasAssuntos
Segmento Anterior do Olho/anormalidades , Anormalidades do Olho/diagnóstico por imagem , Oftalmopatias Hereditárias/diagnóstico por imagem , Hidroftalmia/diagnóstico por imagem , Iris/anormalidades , Adulto , Segmento Anterior do Olho/diagnóstico por imagem , Córnea/anormalidades , Anormalidades do Olho/cirurgia , Gonioscopia , Humanos , Recém-Nascido , Pressão Intraocular/fisiologia , Masculino , Tomografia de Coerência Óptica , TrabeculectomiaRESUMO
PURPOSE: To determine relationships between spectral-domain optical coherence tomography (SD-OCT) derived regional damage to the retinal ganglion cell-axonal complex (RGC-AC) and visual thresholds for each location of the Humphrey 24-2 visual field, in all stages of open-angle glaucoma. METHODS: Patients with early, moderate, and advanced glaucoma were recruited from a tertiary glaucoma clinic. Humphrey 24-2 and 9-field Spectralis SD-OCT were acquired for each subject. Individual OCT volumes were aligned, nerve fiber layer (NFL), ganglion cell and inner plexiform layers (GCL+IPL) cosegmented. These layers were then partitioned into 54 sectors corresponding to the 24-2 grid. A Support Vector Machine was trained independently for each sector to predict the sector threshold, using these structural properties. RESULTS: One hundred twenty-two consecutive subjects, 43 early, 39 moderate, and 40 advanced, glaucoma were included (122 eyes). Average correlation coefficient (R) was 0.68 (0.47-0.82), and average root mean square error (RMSE) was 6.92 dB (3.93-8.68 dB). Prediction performance averaged over the entire field, superior hemifield, and inferior hemifield had R (RMSE) values of 0.77 (3.76), 0.80 (5.05), and 0.84 (3.80) dB, respectively. CONCLUSIONS: Predicting individual 24-2 visual field thresholds from structural information derived from nine-field SD-OCT local NFL and GCL+IPL thicknesses using the RGC-AC concept is feasible, showing the potential for the predictive ability of SD-OCT structural information for visual function. Ultimately, it may be feasible to complement and reduce the burden of subjective visual field testing in glaucoma patients with predicted function derived objectively from OCT.
Assuntos
Glaucoma de Ângulo Aberto/fisiopatologia , Células Ganglionares da Retina/patologia , Testes de Campo Visual/métodos , Campos Visuais/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Glaucoma de Ângulo Aberto/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tomografia de Coerência Óptica , Adulto JovemRESUMO
PURPOSE: Best disease is a macular dystrophy caused by mutations in the BEST1 gene. Affected individuals exhibit a reduced electro-oculographic (EOG) response to changes in light exposure and have significantly longer outer segments (OS) than age-matched controls. The purpose of this study was to investigate the anatomical changes in the outer retina during dark and light adaptation in unaffected and Best disease subjects, and to compare these changes to the EOG. METHODS: Unaffected (n = 11) and Best disease patients (n = 7) were imaged at approximately 4-minute intervals during an approximately 40-minute dark-light cycle using spectral domain optical coherence tomography (SD-OCT). EOGs of two subjects were obtained under the same conditions. Automated three-dimensional (3-D) segmentation allowed measurement of light-related changes in the distances between five retinal surfaces. RESULTS: In normal subjects, there was a significant decrease in outer segment equivalent length (OSEL) of -2.14 µm (95% confidence interval [CI], -1.77 to -2.51 µm) 10 to 20 minutes after the start of light adaptation, while Best disease subjects exhibited a significant increase in OSEL of 2.07 µm (95% CI, 1.79-2.36 µm). The time course of the change in OS length corresponded to that of the EOG waveform. CONCLUSIONS: Our results strongly suggest that the light peak phase of the EOG is temporally related to a decreased OSEL in normal subjects, and the lack of a light peak phase in Best disease subjects is associated with an increase in OSEL. One potential role of Bestrophin-1 is to trigger an increase in the standing potential that approximates the OS to the apical surface of the RPE to facilitate phagocytosis.