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

Multimodal imaging documentation of rapid evolution of retinal changes in handheld laser-induced maculopathy

Purpose To use multimodal imaging to document the relatively rapid clinical evolution of handheld laser-induced maculopathy (HLIM). To demonstrate that inadvertent ocular injury can result from devices mislabeled with respect to their power specifications. Methods The clinical course of a 17-year-old male who sustained self-inflicted, central macular damage from a 20–25 s direct stare at a red-spectrum, handheld laser pointer ordered from an internet retailer is provided. Retrospective review of multimodal imaging that includes fundus photography, fluorescein angiography, MultiColor reflectance, eye-tracked spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence, and microperimetry is used to describe the evolving clinical manifestations of HLIM in the first 3 months. Results Curvilinear bands of dense hyperreflectivity extending from the outer retina and following the Henle fibers were seen on SD-OCT immediately after injury. This characteristic appearance had largely resolved by 2 weeks. There was significant non-uniformity in the morphological characteristics of HLIM lesions between autofluorescence and reflectance images. The pattern of lesion evolution was also significantly different between imaging modalities. Analysis of the laser device showed its wavelength to be correctly listed, but the power was found to be 102.5–105 mW, as opposed to the <5 mW described on the label. Conclusion While the immediate SD-OCT characteristics are highly specific for handheld laser -induced maculopathy, this finding can undergo rapid resolution in the span of several days. In the absence of this finding, other multimodal imaging clues and a careful history may aid in recognizing this diagnosis. A greater awareness regarding inaccurate labeling on some of these devices could help reduce the frequency of this preventable entity

Gene therapy in patient-specific stem cell lines and a preclinical model of retinitis pigmentosa with membrane frizzled-related protein defects

Defects in Membrane Frizzled-related Protein (MFRP) cause autosomal recessive retinitis pigmentosa (RP). MFRP codes for a retinal pigment epithelium (RPE)-specific membrane receptor of unknown function. In patient-specific induced pluripotent stem (iPS)-derived RPE cells, precise levels of MFRP, and its dicistronic partner CTRP5, are critical to the regulation of actin organization. Overexpression of CTRP5 in naive human RPE cells phenocopied behavior of MFRP-deficient patient RPE (iPS-RPE) cells. AAV8 (Y733F) vector expressing human MFRP rescued the actin disorganization phenotype and restored apical microvilli in patient-specific iPS-RPE cell lines. As a result, AAV-treated MFRP mutant iPS-RPE recovered pigmentation and transepithelial resistance. The efficacy of AAV-mediated gene therapy was also evaluated in Mfrp(rd6)/Mfrp(rd6) mice--an established preclinical model of RP--and long-term improvement in visual function was observed in AAV-Mfrp-treated mice. This report is the first to indicate the successful use of human iPS-RPE cells as a recipient for gene therapy. The observed favorable response to gene therapy in both patient-specific cell lines, and the Mfrp(rd6)/Mfrp(rd6) preclinical model suggests that this form of degeneration caused by MFRP mutations is a potential target for interventional trials

Clinical course of acute zonal occult outer retinopathy complicated by choroidal neovascularization

Purpose To report the clinical course and multimodal imaging features of acute zonal occult outer retinopathy (AZOOR) complicated by choroidal neovascularization (CNV) treated with anti-vascular endothelial growth factor (VEGF) treatment or photodynamic therapy (PDT). Methods Observational case series. Retrospective analysis of patients presenting to different institutions with evidence of AZOOR and neovascular lesions. Diagnosis of AZOOR was made on the basis of clinical presentation and multimodal imaging. All patients underwent a comprehensive ophthalmic evaluation and multimodal retinal imaging, including color fundus photos, fundus autofluorescence, fundus fluorescein angiography and spectral-domain optical coherence tomography. Results Four patients (three males, mean age 53.5 years) were included in the study. Mean follow-up was 5.1 years. Presentation of AZOOR was unilateral in two patients and bilateral in the remainder two patients. One of the patients presenting with unilateral AZOOR developed zonal lesions in the fellow eye during follow-up. All patients presented with unilateral type 2 (subretinal) CNV. Three patients underwent intravitreal anti-VEGF injections and one patient underwent a single PDT. Multimodal retinal imaging showed zonal or multizonal progression during treatment. After treatment, visual acuity and CNV stabilization was observed in all patients. Conclusions The presence of CNV expands the clinical spectrum of AZOOR. CNV complicating AZOOR may be effectively treated with intravitreal injections of anti-VEGF, despite progression of the zonal lesions. Further studies are required to define the role of treatment in the progression of the zonal lesions

New best1 mutations in autosomal recessive bestrophinopathy

PURPOSE: To report the ocular phenotype in patients with autosomal recessive bestrophinopathy and carriers, and to describe novel BEST1 mutations. METHODS: Patients with clinically suspected and subsequently genetically proven autosomal recessive bestrophinopathy underwent full ophthalmic examination and investigation with fundus autofluorescence imaging, spectral domain optical coherence tomography, electroretinography, and electrooculography. Mutation analysis of the BEST1 gene was performed through direct Sanger sequencing. RESULTS: Five affected patients from four families were identified. Mean age was 16 years (range, 6-42 years). All affected patients presented with reduced visual acuity and bilateral, hyperautofluorescent subretinal yellowish deposits within the posterior pole. Spectral domain optical coherence tomography demonstrated submacular fluid and subretinal vitelliform material in all patients. A cystoid maculopathy was seen in all but one patient. In 1 patient, the location of the vitelliform material was seen to change over a follow-up period of 3 years despite relatively stable vision. Visual acuity and fundus changes were unresponsive to topical and systemic carbonic anhydrase inhibitors and systemic steroids. Carriers had normal ocular examinations including normal fundus autofluorescence. Three novel mutations were detected. CONCLUSION: Three novel BEST1 mutations are described, suggesting that many deleterious variants in BEST1 resulting in haploinsufficiency are still unknown. Mutations causing autosomal recessive bestrophinopathy are mostly located outside of the exons that usually harbor vitelliform macular dystrophy-associated dominant mutations

Genome-wide analyses identify common variants associated with macular telangiectasia type 2

Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2; MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10−8) were identified at three independent loci (rs73171800 at 5q14.3, P = 7.74 × 10−17; rs715 at 2q34, P = 9.97 × 10−14; rs477992 at 1p12, P = 2.60 × 10−12) and then replicated (P < 0.01) in an independent cohort of 172 cases and 1,134 controls. The 5q14.3 locus is known to associate with variation in retinal vascular diameter, and the 2q34 and 1p12 loci have been implicated in the glycine/serine metabolic pathway. We subsequently found significant differences in blood serum levels of glycine (P = 4.04 × 10−6) and serine (P = 2.48 × 10−4) between MacTel cases and controls

Idiopathic multifocal choroiditis

Idiopathic multifocal choroiditis (MFC) and/or punctate inner choroidopathy (PIC) describe a chronic progressive bilateral inflammatory chorioretinopathy that predominantly affect healthy myopic white women with no known associated systemic or ocular diseases. The principal sites of involvement are the retinal pigment epithelium (RPE) and outer retinal spaces; the choroid is not affected during the active phase of the disease. Idiopathic MFC with atrophy is a recently described variant. Although there is no generally accepted standard treatment, anti-inflammatory and anti-VEGF (vascular endothelial growth factor) agents are necessary in the acute stage to control the inflammation and choroidal neovascularization (CNV)

Retinal Vascular Disease in Limb-Girdle Muscular Dystrophy

PURPOSETo report bilateral retinal vascular occlusive disease in limb-girdle muscular dystrophy. METHODSCase report. RESULTSA 34-year-old Asian woman was referred for evaluation and management of central retinal vein occlusion. Ultra-wide-field fluorescein angiography showed resolving initial peripheral retinal vein occlusion in one eye and peripheral venular segmental staining in the fellow asymmetric eye. Genetic testing established the diagnosis of limb-girdle muscular dystrophy (LGMD). CONCLUSIONSimilar to other forms of muscular dystrophy, LGMD is caused by genetic abnormalities in sarcolemma proteins, a key structural component that connects the intracellular cytoskeleton of a myofiber to the extracellular matrix. Like other muscular dystrophies, LGMD may be associated with retinal vascular abnormalities noted. In this case, retinal vascular smooth muscle dysfunction was seen in LGMD, analogous to reported vascular abnormalities in other muscular dystrophies such as facioscapulohumeral dystrophy and Duchenne muscular dystrophy

Pseudo-vitelliform macular detachment and cuticular drusen: Exclusion of 6 candidate genes

Purpose: The etiology and genetic cause of pseudo-vitelliform macular detachment with cuticular drusen (PVMD/CD) are unknown; nor is it clear if this phenotype represents a separate disease entity, or is a sub-phenotype of disorders with overlapping clinical presentation. To answer this question, we screened a cohort of patients affected with PVMD/CD for variation in six plausible candidate genes (ABCA4, VMD2, TIMP-3, peripherin/RDS, fibulin 5 (FIBL5) and complement factor H (CFH)) associated with diseases of overlapping phenotypes. Methods: Twenty-eight patients, diagnosed with pseudo-vitelliform macular detachment and cuticular drusen, were evaluated by clinical examination, fundus photography, fluorescein angiography and autofluorescence imaging. DNA from all study subjects were screened for variants in the ABCA4, VMD2, TIMP-3, peripherin/RDS, FIBL5 and CFH genes by a combination of DHPLC, array screening and direct sequencing. Results: All patients presented with cuticular drusen; pseudo-vitelliform detachment was seen in 21 cases, while atrophic changes following regression of the detachment were seen in the remaining 7 subjects. Visual acuity ranged from 20/20 to CF. The screening revealed an 132V mutation in peripherin/RDS in one patient and 2 ABCA4 variants, T8971 and G1961E, in 2 more patients. No amino acid-altering variants were detected in VMD2, TIMP-3, and FIBL5 genes. The frequency of the CFH Y402H variant in this cohort corresponded to that detected in the general population. Conclusions: Screening of 6 candidate genes detected possibly disease-associated mutations in only 3/28 (10.7%) of patients presenting with PVMD/CD, eliminating these genes as causal for this phenotype