Monika Andrassi-Darida

Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response

Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage‐gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2–4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N‐terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two‐hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR. 32:1398–1406, 2011. ©2011 Wiley Periodicals, Inc.

OCT-Based Macular Structure-Function Correlation in Dependence on Birth Weight and Gestational Age-the Giessen Long-Term ROP Study.

PURPOSE To compare retinal layer thicknesses in preterm and term-born children using spectral-domain optical coherence tomography (SD-OCT) and to correlate structure with retinal function. METHODS We performed SD-OCT single and volume scans in the foveal region of premature children aged 6 to 13 years without ROP (no-ROP, n = 100) and with spontaneously regressed ROP (sr-ROP, n = 50) documented with wide-angle digital imaging during routine screening for acute ROP, and 30 age-matched term-born children. Retinal layer segmentation and analysis was performed with custom-made software in single and volume-scans using an Early Treatment of Diabetic Retinopathy Study grid-based method, and compared to light increment sensitivity (LIS) data obtained with a microperimeter at eccentricity points of 0°, 2.8°, and 8°, as previously described. RESULTS Overall, seven children had to be excluded due to poor image quality (n = 1 no-ROP; n = 2 sr-ROP; n = 4 term). Total retina, ganglion cell + inner plexiform layer (GCL+) and outer nuclear layer + external limiting membrane (ONL+) thickness at the foveal center in no-ROP and sr-ROP were significantly higher compared with term children. Gestational age (GA) and birth weight (BW) were inversely correlated with these layer thicknesses. Rod and cone outer segment length did not differ in either group. The ratio of ONL+ to the whole retina at 0° correlated significantly with reduced LIS. CONCLUSIONS Increased thicknesses of the entire retina or specific layers at the fovea did not correlate with functional loss; but a thinner ONL in retinae without foveal pit did. This reduced ONL+ ratio is potentially caused by a reduced foveal cone density and may be the first morphologic functional correlate in prematurity and ROP.

Autosomal-rezessive Bestrophinopathie (ARB): klinische und molekulare Beschreibung zweier Patienten im Kindesalter

BACKGROUND Autosomal recessive bestrophinopathy (ARB) is associated with mutations in BEST1. ARB is rarely diagnosed compared to BEST1-associated autosomal dominant (a. d.) juvenile vitelliform macular degeneration (Morbus Best, VMD). This is not only due to its low prevalence, but also to the phenotypic appearance. This paper describes typical features in two patients and discusses novel findings using improved ophthalmological diagnostic tools. MATERIAL AND METHODS Two unrelated boys with reduced visual acuity as well as five further relatives underwent a comprehensive ophthalmological examination including electroretinography (ERG) and electrooculography (EOG) according to ISCEV standard, fundus autofluorescence (FAF) and spectral-domain optic coherence tomography (SD‑OCT). BEST1 was screened for mutations based on the clinical diagnosis. RESULTS Visual acuity ranged between 0.2 and 0.5 in the patients. Multifocal yellowish paramacular and peripheral lesions were visible in the fundus correlating with spots of increased FAF. The lesions correlated with thickening of the RPE layer. Especially in the inner nuclear layer hyporeflective areas were visible, reminiscent of retinoschisis but without changes of FAF. In both patients the ganzfeld ERG was within the normal range and the mfERG presented obvious reductions of amplitudes in the central area. The EOG did not show a light peak. Goldmann perimetry was normal for isopters III/4e and I/4e. The fundus controlled perimetry revealed a central sensitivity loss. Molecular genetic analysis identified four (two novel) mutations in BEST1, in the compound heterozygous state in both patients. The screened relatives carried one of the mutations in the heterozygous state and were ophthalmologically unremarkable apart from age-related changes. CONCLUSION ARB is a rare disease, presenting with obvious differences to a.d. Mobus Best. The phenotype can easily be identified by the extramacular multifocal yellowish lesions with increased FAF and accompanied by early loss of visual acuity. Specific diagnostic tests like OCT, FAF recordings and electrophysiology support the diagnosis. Molecular genetic screening confirms the diagnosis and the autosomal recessive inheritance.

Correlation of central visual function and ROP risk factors in prematures with and without acute ROP at the age of 6–13 years: the Giessen long-term ROP study

Aim To correlate light increment sensitivity (LIS) and visual acuity (VA) with birth weight (BW), gestational age (GA) and stage of acute retinopathy of prematurity (ROP) (STG) in premature children at school age. Methods 180 children (150 former prematures and 30 age-matched term-born children) were enrolled at age 6–13 years. Former prematures were categorised by the results of the initial ROP screening based on digital wide-field fundus imaging: absence of ROP (n=100) and spontaneously resolved ROP (n=50). The latter group was further subdivided according to their STG (Stg 1; Stg 2; Stg 3). Both groups were categorised into sectors by BW (<1000 g; 1000–1500 g; >1500 g), and GA (≤28 weeks; >28<32 weeks; ≥32 weeks). VA was assessed with Early Treatment of Diabetic Retinopathy Study letters, LIS was measured at 0°, 2.8° and 8° in the visual field (Microperimeter MP1, Nidek Technologies), and spherical equivalent refraction assessed with a Nidek autorefractor (Nidek, Italy). Results Central and pericentral LIS (0° and 2.8°) and VA were significantly lower in all groups and sectors compared with term-born controls except for BW >1500 g for LIS and GA >28 to <32 W for VA. No significant differences were found for LIS at 8° in all groups. No correlation was found between LIS and VA on an individual basis. Conclusions Low BW, GA and increasing severity of spontaneously resolving ROP were associated with significantly decreased central visual function. In addition to VA, LIS measurement further describes foveal function and is a unique parameter to assess parafoveal function.