Kaoru Fujinami

A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations.

PURPOSEnWe characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease.nnnMETHODSnFull clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken.nnnRESULTSnThe mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype.nnnCONCLUSIONSnThe AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.

A Longitudinal Study of Stargardt Disease: Clinical and Electrophysiologic Assessment, Progression, and Genotype Correlations

PURPOSEnTo investigate the clinical and electrophysiologic natural history of Stargardt disease and correlate with the genotype.nnnDESIGNnCohort study of 59 patients.nnnMETHODSnClinical history, examination, and electrophysiologic assessment were undertaken in a longitudinal survey. Patients were classified into 3 groups based on electrophysiologic findings, as previously published: Group 1 had dysfunction confined to the macula; Group 2 had macular and generalized cone system dysfunction; and Group 3 had macular and both generalized cone and rod system dysfunction. At baseline, there were 27 patients in Group 1, 17 in Group 2, and 15 in Group 3. Amplitude reduction of >50% in the relevant electroretinogram (ERG) component or a peak time shift of >3xa0ms for the 30xa0Hz flicker ERG or bright flash a-wave was considered clinically significant ERG deterioration. Molecular screening of ABCA4 was undertaken.nnnRESULTSnThe mean age at baseline was 31.7 years, with the mean follow-up interval being 10.5 years. A total of 22% of patients from Group 1 showed ERG group transition during follow-up, with 11% progressing to Group 2 and 11% to Group 3. Forty-seven percent of patients in Group 2 progressed to Group 3. There was clinically significant ERG deterioration in 54% of all subjects: 22% of Group 1, 65% of Group 2, and 100% of Group 3. At least 1 disease-causing ABCA4 variant was identified in 47 patients.nnnCONCLUSIONSnAll patients with initial rod ERG involvement demonstrated clinically significant electrophysiologic deterioration; only 20% of patients with normal full-field ERGs at baseline showed clinically significant progression. Such data assist counseling by providing more accurate prognostic information and are also highly relevant in the design, patient selection, and monitoring of potential therapeutic interventions.

Clinical and Molecular Analysis of Stargardt Disease With Preserved Foveal Structure and Function

PURPOSEnTo describe a cohort of patients with Stargardt disease who show a foveal-sparing phenotype.nnnDESIGNnRetrospective case series.nnnMETHODSnThe foveal-sparing phenotype was defined as foveal preservation on autofluorescence imaging, despite a retinopathy otherwise consistent with Stargardt disease. Forty such individuals were ascertained and a full ophthalmic examination was undertaken. Following mutation screening of ABCA4, the molecular findings were compared with those of patients with Stargardt disease but no foveal sparing.nnnRESULTSnThe median age of onset and age at examination of 40 patients with the foveal-sparing phenotype were 43.5 and 46.5 years. The median logMAR visual acuity was 0.18. Twenty-two patients (22/40, 55%) had patchy parafoveal atrophy and flecks; 8 (20%) had numerous flecks at the posterior pole without atrophy; 7 (17.5%) had mottled retinal pigment epithelial changes; 2 (5%) had multiple atrophic lesions, extending beyond the arcades; and 1 (2.5%) had a bulls-eye appearance. The median central foveal thickness assessed with spectral-domain optical coherence tomographic images was 183.0 μm (n = 33), with outer retinal tubulation observed in 15 (45%). Twenty-two of 33 subjects (67%) had electrophysiological evidence of macular dysfunction without generalized retinal dysfunction. Disease-causing variants were found in 31 patients (31/40, 78%). There was a higher prevalence of the variant p.Arg2030Gln in the cohort with foveal sparing compared to the group with foveal atrophy (6.45% vs 1.07%).nnnCONCLUSIONSnThe distinct clinical and molecular characteristics of patients with the foveal-sparing phenotype are described. The presence of 2 distinct phenotypes of Stargardt disease (foveal sparing and foveal atrophy) suggests that there may be more than 1 disease mechanism in ABCA4 retinopathy.

Clinical and molecular characteristics of childhood-onset Stargardt disease.

Purpose To describe the clinical and molecular characteristics of patients with childhood-onset Stargardt disease (STGD). Design Retrospective case series. Participants Forty-two patients who were diagnosed with STGD in childhood at a single institution between January 2001 and January 2012. Methods A detailed history and a comprehensive ophthalmic examination were undertaken, including color fundus photography, autofluorescence imaging, spectral-domain optical coherence tomography (SD-OCT), and pattern and full-field electroretinograms. The entire coding region and splice sites of ABCA4 were screened using a next-generation, sequencing-based strategy. The molecular genetic findings of childhood-onset STGD patients were compared with those of adult-onset patients. Main Outcome Measures Clinical, imaging, electrophysiologic, and molecular genetic findings. Results The median ages of onset and the median age at baseline examination were 8.5 (range, 3–16) and 12.0 years (range, 7-16), respectively. The median baseline logarithm of the minimum angle of resolution visual acuity was 0.74. At baseline, 26 of 39 patients (67%) with available photographs had macular atrophy with macular/peripheral flecks; 11 (28%) had macular atrophy without flecks; 1 (2.5%) had numerous flecks without macular atrophy; and 1 (2.5%) had a normal fundus appearance. Flecks were not identified at baseline in 12 patients (31%). SD-OCT detected foveal outer retinal disruption in all 21 patients with available images. Electrophysiologic assessment demonstrated retinal dysfunction confined to the macula in 9 patients (36%), macular and generalized cone dysfunction in 1 subject (4%), and macular and generalized cone and rod dysfunction in 15 individuals (60%). At least 1 disease-causing ABCA4 variant was identified in 38 patients (90%), including 13 novel variants; ≥2 variants were identified in 34 patients (81%). Patients with childhood-onset STGD more frequently harbored 2 deleterious variants (18% vs 5%) compared with patients with adult-onset STGD. Conclusions Childhood-onset STGD is associated with severe visual loss, early morphologic changes, and often generalized retinal dysfunction, despite often having less severe fundus abnormalities on examination. One third of children do not have flecks at presentation. The relatively high proportion of deleterious ABCA4 variants supports the hypothesis that earlier onset disease is often owing to more severe variants in ABCA4 than those found in adult-onset disease.

A longitudinal study of Stargardt disease

PURPOSEnWe characterized subtypes of fundus autofluorescence (AF) and the progression of retinal atrophy, and correlated these findings with genotype in Stargardt disease.nnnMETHODSnFull clinical examination and AF imaging was undertaken in 68 patients with Stargardt disease. The baseline data were compared to those at follow-up. Patients were classified into three AF subtypes: type 1 had a localized low signal at the fovea surrounded by a homogeneous background, type 2 had a localized low signal at the macula surrounded by a heterogeneous background with numerous foci of abnormal signal, and type 3 had multiple low signal areas at the posterior pole with a heterogeneous background. At baseline, there were 19 patients with type 1, 41 with type 2, and 8 with type 3 disease. The areas of reduced AF signal were measured and rate of atrophy enlargement (RAE) was calculated as the difference of the atrophy size over time (mm²) divided by the follow-up interval (years). Molecular screening of ABCA4 was undertaken.nnnRESULTSnThe mean follow-up interval was 9.1 years. A total of 42% cases with type 1 disease progressed to type 2, and 12% with type 2 progressed to type 3. The RAE (mm²/y) based upon baseline AF subtypes was significantly different; 0.06 in type 1, 0.67 in type 2, and 4.37 in type 3. ABCA4 variants were identified in 57 patients. There was a significant association between AF subtype and genotype.nnnCONCLUSIONSnThe AF pattern at baseline influences the enlargement of atrophy over time and has genetic correlates. These data are likely to assist in the provision of counseling on prognosis in Stargardt disease and be valuable for future clinical trials.

ABCA4 Gene Screening by Next-Generation Sequencing in a British Cohort

PURPOSEnWe applied a recently reported next-generation sequencing (NGS) strategy for screening the ABCA4 gene in a British cohort with ABCA4-associated disease and report novel mutations.nnnMETHODSnWe identified 79 patients with a clinical diagnosis of ABCA4-associated disease who had a single variant identified by the ABCA4 microarray. Comprehensive phenotypic data were obtained, and the NGS strategy was applied to identify the second allele by means of sequencing the entire coding region and adjacent intronic sequences of the ABCA4 gene. Identified variants were confirmed by Sanger sequencing and assessed for pathogenicity by in silico analysis.nnnRESULTSnOf the 42 variants detected by prescreening with the microarray, in silico analysis suggested that 34, found in 66 subjects, were disease-causing and 8, found in 13 subjects, were benign variants. We detected 42 variants by NGS, of which 39 were classified as disease-causing. Of these 39 variants, 31 were novel, including 16 missense, 7 splice-site-altering, 4 nonsense, 1 in-frame deletion, and 3 frameshift variants. Two or more disease-causing variants were confirmed in 37 (47%) of 79 patients, one disease-causing variant in 36 (46%) subjects, and no disease-causing variant in 6 (7%) individuals.nnnCONCLUSIONSnApplication of the NGS platform for ABCA4 screening enabled detection of the second disease-associated allele in approximately half of the patients in a British cohort where one mutation had been detected with the arrayed primer extension (APEX) array. The time- and cost-efficient NGS strategy is useful in screening large cohorts, which will be increasingly valuable with the advent of ABCA4-directed therapies.

Clinical course of focal choroidal excavation in Vogt–Koyanagi–Harada disease

We describe focal choroidal excavation (FCE) in a case of Vogt–Koyanagi–Harada (VKH) disease and compare the findings with different chorioretinal conditions. A 55-year-old man was diagnosed with VKH based on panuveitis and exudative retinal detachments. Spectral-domain optical coherence tomography demonstrated a dome-shaped protrusion with a nonconforming pattern at the fovea, which had been detected as a conforming pattern 1 year before the onset. The FCE pattern returned into a conforming pattern following corticosteroid therapy. These findings suggest that the natively existent FCE could be affected by pathophysiological changes of VKH as well as other chorioretinal conditions.

Fundus autofluorescence imaging in a patient with the juvenile form of galactosialidosis

The authors report the characteristics of fundus autofluorescence (FAF) images in a patient with galactosialidosis who presented with a macular cherry-red spot ophthalmoscopically. The cherry-red spot in the macula was hyperreflective in the FAF images. Optical coherence tomography (OCT) revealed an abnormally hyperreflective region in the retinal ganglion cell layer; however, the boundary between hyperreflective and normal regions was not clear. The findings indicate that FAF may be a more useful method to detect macular lesions than conventional funduscopic examination and OCT imaging in patients with lysosomal storage diseases presenting with a macular cherry-red spot.

Longitudinal follow-up of siblings with a discordant Stargardt disease phenotype.

anterior segment have been reported after injection of intravitreal dexamethasone implants. Most case reports describe migration of the implant into the anterior chamber in eyes that had previous cataract surgery complicated by posterior capsule rupture. (Cronin et al. 2012; Pardo-L opez et al. 2012; Malcl es et al. 2013) Only one article reports a case similar to ours, describing cataract surgery after implant in the crystalline lens. (Koller et al. 2012) Several conclusions can be drawn from this case series. Regarding the intravitreal procedure: the 22-gauge injector has a relatively large diameter compared to 28or 30-gauge needles used for anti-VEGF treatment, and the injection technique requires a considerable pressure on the globe. In addition, the pain experienced by the patient may provoke inadvertent eye or head movements. Subconjunctival anesthesia can be used in an attempt to minimize this side-effect, even though the presence of fluid under the conjunctiva may interfere with a proper marking procedure. Secondly, when considering cataract extraction, a careful preoperative evaluation in order to identify the site and the extension of posterior capsular tear, is essential. Hydrodelineation procedures with the purpose of separating the nucleus from the epinucleus is mandatory, and when hydrodissection is planned, it must be performed very carefully. During phacoemulsification, machine parameters must be lowered and anterior vitrectomy must always be taken into consideration. Implant of a three piece IOL in the sulcus with optic plate in the bag is recommended in order to avoid stress on the already damaged capsular bag and is considered to provide the best stability in these cases. Lens damage can be a complication of dexamethasone implant. A careful cataract surgery can alleviate anatomical and functional damages.

Branch retinal artery occlusion secondary to prepapillary arterial loop.

PURPOSEnTo report a case of branch retinal artery occlusion and prepapillary loop in a 10-year-old girl.nnnMETHODSnCase report with funduscopic and fluorescein angiography imaging.nnnRESULTSnA 10-year-old girl presented with a history of the sudden onset of a superior visual field defect in her right eye. Fundus findings were consistent with thrombosis in a prepapillary arterial loop causing an inferior branch retinal artery occlusion.nnnCONCLUSIONnBilateral congenital prepapillary vascular loops are rare, and are usually asymptomatic. However, they can be complicated by vitreous hemorrhage and thrombosis. Such thrombotic events may be precipitated by hemodynamic or intravascular changes associated with exercise.