Hyperautofluorescent Dots are Characteristic in Ceramide Kinase Like-associated Retinal Degeneration.

There is a lack of studies which seek to discern disease expression in patients with mutations that alter retinal ceramide metabolism, specifically in the ceramide kinase like (CERKL) gene. This cross-sectional case series reports a novel phenotypic manifestation of CERKL-associated retinopathy. Four unrelated patients with homozygous CERKL mutations underwent a complete ocular exam, spectral-domain optical coherence tomography, short-wavelength fundus autofluorescence (SW-AF), quantitative autofluorescence (qAF), and full-field electroretinogram (ffERG). Decreased visual acuity and early-onset maculopathy were present in all patients. All four patients had extensive hyperautofluorescent foci surrounding an area of central atrophy on SW-AF imaging, which has not been previously characterized. An abnormal spatial distribution of qAF signal was seen in one patient, and abnormally elevated qA

Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder

Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p < 5 × 10−8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR = 3.9 × 10−47) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p = 0.009). This represents the largest genetic study on MacTel to date and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health

Quantifying Fundus Autofluorescence in Patients With Retinitis Pigmentosa

Purpose Using quantitative fundus autofluorescence (qAF), we analyzed short-wavelength autofluorescent (SW-AF) rings in RP. Methods: Short-wavelength autofluorescent images (486 nm excitation) of 40 patients with RP (69 eyes) were acquired with a confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference. Mean qAF was measured in eight preset segments (qAF8) and in region of interest (ROI)-qAF (200–700 μm) within and external to the borders of the rings at superior, temporal, and inferior sites relative to the ring. For both groups, qAF in patients with RP was compared to age-similar and race/ethnicity-matched healthy eyes at equivalent retinal locations. Results: In 71% of eyes of RP patients, qAF8 acquired internal to the inner border of the ring, was within the 95% confidence interval (CI) for healthy eyes, while in the remaining RP eyes qAF8 was either higher or lower than the CI. Measured external to the ring, qAF8 values were within the CI in 47% of RP eyes with the other eyes being higher or lower. In 28% of sites measured by ROI-qAF within the SW-AF ring, values were above the 95% CI of healthy controls. Region of interest-qAF measured just external to the ring was within the CI of healthy eyes in 74% of locations. The average local elevation in qAF within the ring was approximately 15%. In SD-OCT scans, photoreceptor-attributable reflectivity bands were thinned within and external to the ring. Conclusions: Increased fluorophore production may be a factor in the formation of the SW-AF rings in RP

Clinical and Molecular Characteristics of Childhood-Onset Stargardt Disease.

To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD)

Genetic Variations Strongly Influence Phenotypic Outcome in the Mouse Retina

Variation in genetic background can significantly influence the phenotypic outcome of both disease and non-disease associated traits. Additionally, differences in temporal and strain specific gene expression can also contribute to phenotypes in the mammalian retina. This is the first report of microarray based cross-strain analysis of gene expression in the retina investigating genetic background effects. Microarray analyses were performed on retinas from the following mouse strains: C57BL6/J, AKR/J, CAST/EiJ, and NOD.NON-H2-nb1 at embryonic day 18.5 (E18.5) and postnatal day 30.5 (P30.5). Over 3000 differentially expressed genes were identified between strains and developmental stages. Differential gene expression was confirmed by qRT-PCR, Western blot, and immunohistochemistry. Three major gene networks were identified that function to regulate retinal or photoreceptor development, visual perception, cellular transport, and signal transduction. Many of the genes in these networks are implicated in retinal diseases such as bradyopsia, night-blindness, and cone-rod dystrophy. Our analysis revealed strain specific variations in cone photoreceptor cell patterning and retinal function. This study highlights the substantial impact of genetic background on both development and function of the retina and the level of gene expression differences tolerated for normal retinal function. These strain specific genetic variations may also be present in other tissues. In addition, this study will provide valuable insight for the development of more accurate models for human retinal diseases

ATM Gene Variants in Patients with Idiopathic Perifoveal Telangiectasia

PURPOSE. To investigate the prevalence of sequence variants in the ATM gene and to determine the frequency of major agerelated macular degeneration (AMD)-associated variants in CFH, CFB, and 10q26 loci in patients with idiopathic perifoveal telangiectasia (IPT). METHODS. Thirty patients with diagnoses of IPT underwent standard ophthalmologic evaluation that included visual acuity testing, fundus photography, and fluorescein angiography. DNA was screened for variations in the ATM gene by a combination of denaturing high-performance liquid chromatography and direct sequencing. Major AMD-associated alleles in CFH, CFB, and 10q loci were screened by PCR-restriction fragment-length polymorphism. RESULTS. Nineteen female and 11 male patients (average age, 59 years) with a median visual acuity of 20/50 were evaluated. Six patients were of Asian-Indian origin, one was Hispanic, and 23 were of European-American ancestry. Nine of 30 (30%) patients had diabetes mellitus, 18 of 30 (60%) patients had hypertension, and 12 of 30 (40%) patients had a history of smoking. Screening of the ATM gene revealed a null allele in 2 of 23 (8.7%) patients of European ancestry, previously disease-associated missense alleles in 4 of 23 (17.4%) patients, and common missense alleles in 7 of 23 (30.4%) patients. No variants were identified in the ATM gene in patients of Asian or Hispanic origin. Frequencies of major AMD-associated alleles in CFH, CFB, and 10q loci in the IPT cohort were similar to those in the ethnically matched general population. CONCLUSIONS. At least 26%, and maybe up to 57%, of IPT patients of European-American descent carried possibly diseaseassociated ATM alleles. Vascular risk factors such as hypertension, diabetes, and smoking may be associated with the pathogenesis of the disease. (Invest Ophthalmol Vis Sci. 2008; 49:3806 -3811