Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline.

We evaluated a multiple consanguineous Turkish family with two children, a boy and a girl, affected by severe encephalopathy, hypotonia, microcephaly and retinal dystrophy by a combination of linkage analysis and Whole Exome Sequencing (WES). We analyzed the sequence data by two different bioinformatics pipelines which did not differ in overall processing strategy but involved differences in software used, minor allele frequency (MAF) thresholds and reference data sets, the usage of in-house control exomes and filter settings to prioritize called variants. Assuming autosomal recessive mode of inheritance, only homozygous variants present in both children were considered. The resulting variant lists differed partially (nine variants identified by both pipelines, ten variants by only one pipeline). Major reasons for this discrepancy were different filters for MAF and different variant prioritizations. Combining the variant lists with the results of linkage analysis and further prioritization by expression data and prediction tools, an intronic homozygous splice variant (c.1090-2A>G; IVS9-2A>G; p.?) in PGAP1 (Post-GPI Attachment To Proteins 1) was identified and validated by cDNA analysis. PGAP1 ensures the first step of maturation of GPI (glycosylphosphatidylinositol)-anchor proteins. Recently, a homozygous loss-of-function mutation in PGAP1 has been reported in one family with two children affected by a similar phenotype. The present report not only illustrates the possible influence of specific filtering settings on the results of WES but also confirms PGAP1 as a cause of severe encephalopathy.

[Fitness to drive with glaucoma]. / Verkehrstauglichkeit beim Glaukom.

Glaucoma is one of the eye diseases that are particularly relevant to driving in old age. The ophthalmologist often has to take on the task of traffic medical consultation or medical appraisal. It is essential to distinguish between fitness to drive and driving ability or driving safety and driving capability. The medical examination of fitness to drive can only be carried out over long intervals and basically requires an ophthalmological examination in compliance with all the requirements of the driving license ordinance. This is not a healthcare task. In the case of clarification of the fitness to drive in people with known glaucoma on behalf of the test persons themselves or a driving license authority, visual field testing must be performed using manual kinetic perimetry according to Goldmann, especially for all borderline case decisions by traffic experts. The ophthalmologist faces the particular difficulty of maintaining a balance between the legal duty of care and patient-centered care in order not to strain the patient-physician relationship.

[Coats' disease. Important differential diagnosis for retinoblastoma]. / Morbus Coats : Wichtige Differenzialdiagnose zum Retinoblastom.

Advanced Coats' disease is one of the most difficult differential diagnoses of retinoblastoma in early childhood. We describe the clinical and histological findings in two boys, ages 9 months and 21 months, with unilateral leucocoria. Despite comprehensive diagnostics that included examination under general anaesthesia, magnetic resonance imaging, and ultrasound, retinoblastoma could not be excluded, and the eyes were enucleated. Histological diagnosis of Coats' disease was confirmed. Because differentiation between retinoblastoma and Coats' disease may be difficult, enucleation seems to be indicated in uncertain cases due to the reduced visual prognosis and the risk of secondary complications in advanced Coats' disease.

[Edge filters : Medical indications and clinical application]. / Kantenfilter : Medizinische Indikation und klinischer Einsatz.

Edge filters are used in aphakic eyes as a substitute of the natural cut-off filter of the intact eye or in other causes of a lack of light absorption in the eye itself. Furthermore, they can remedy light adaptation disturbances, especially in hereditary retinal diseases and retinal dystrophy. They enhance contrast and reduce glare. In order to choose an adequate cut-off filter it is necessary to let the participants test various filters before prescription. Because of the (absolute) absorption of blue light, cut-off filters normally lead to a loss of ability to drive.

[Cut-off filter : Physical and physiological basics]. / Kantenfilter : Physikalische und physiologische Grundlagen.

Light filters with wavelength-dependent transmission and in particular cut-off or step filters (steep dependence of transmission on wavelength) have a broad optical application and are relevant in ophthalmology. This article describes some physical and physiological principles of cut-off filters, discusses the physiological aspects of applications, specifically the not always relevant necessity of blue-reducing filters and the lack of efficacy of color filters with color vision deficiencies.

[Electronic vision aids : New options for rehabilitation of the visually impaired]. / Elektronische Hilfsmittel : Neue Möglichkeiten zur Rehabilitation Sehbehinderter.

Due to technical advances, there has been an enormous improvement of electronic vision aids in recent years. New developments are especially small portable devices which can be easily carried. The majority of electronic vision aids serve as a reading aid. Electronic magnifiers are a portable alternative to conventional screen readers. In addition, there are mobile reading devices and special computer tools. Color recognition devices and barcode scanners are helpful in everyday life. Ultrasonic orientation systems enable the recognition of obstacles also at head height. Mechanisms incorporated in shoes even comprise a navigation system. A brand new development is OrCam (OrCam Technologies Ltd., Israel), a small, inconspicuous camera system which is attached to the spectacles. It transmits vision information as a text. Smart phones and tablet personal computers have meanwhile been developed to such an extent that they replace more expensive special vision aids. Due to the immense technical progress, electronic vision aids provide visually impaired people with many elegant functions and new possibilities for ophthalmological rehabilitation. Besides the technical, mobile and financial aspects, the social acceptance of the devices, which should be as unobtrusive as possible, plays an essential role.

[Closed-circuit television systems : Current importance and tips on adaptation and prescription]. / Bildschirmlesegeräte : Aktueller Stellenwert und Hinweise zu Anpassung und Verordnung.

Closed-circuit television systems (CCTVs) have become an indispensable tool in rehabilitating low vision patients. Compared to optical visual aids, apart from providing maximum magnification these devices have the additional advantage of improved contrast sensitivity and an enlarged field of view. They are often the only visual aid enabling patients to regain reading ability. Our data reflect a decrease in the number of prescriptions caused by improved counseling of low-vision patients. Any prescription of reading aids must be preceded by comprehensive testing and counseling. More recent developments, such as electronic magnifiers are becoming increasingly more important but they are no substitute for CCTV.

[Provision of aids to visually impaired people at the workplace]. / Hilfsmittelversorgung sehbehinderter Menschen am Arbeitsplatz.

The provision of aids for occupational use with partially sighted and blind people is not a measure for the necessary care but for an optimal work performance to secure the long-term occupational participation. This objective requires a significantly expanded consultation, which includes the occupational requirements at the specific workplace. The costs are not usually borne by the statutory health insurance but by another social insurance agency depending on the individual case. In this article several aids are presented in an occupational context, as well as the procedure for provision.

[Errors and difficulties in the assessment of severely handicapped and blind persons]. / Fehler und Schwierigkeiten der Beurteilung im Schwerbehinderten- und Blindenrecht.

The assessment of ophthalmological examination reports in social law is usually based on subjective statements by the petitioner made towards his ophthalmologist. Insufficient consideration of objective results as well as the limited experience of the officials in charge may lead to errors. An analysis of patients for consideration as legally blind in Baden, Germany, between 1980-1999, based upon 2,265 doubtful applications resulted in 33.3% false estimates by the patient's ophthalmologist. The reason, in the vast majority of cases, was misjudgment involving visual field defects or even missing manual-kinetic Goldmann perimetry. It may be assumed that this is also true for petitions in legislation for severely handicapped persons, particularly because the officials in charge are rarely ophthalmologists.

[Fundamentals for the medical evaluation of handicapped people in legislation]. / Grundlagen der Begutachtung nach dem Schwerbehindertengesetz und im sozialen Entschädigungsrecht.

In claims from social law, evaluation by the treating physician is often mandatory. He is obliged to provide information at the request of the social insurance carrier. Ophthalmologists are required to independently and objectively assess medical conditions, apart from a routine visit, and pass the data on to the consultants at the pension office in a understandable way. Functional impairment must be explained on the basis of morphology, diagnosis and examination results so that it becomes impartially comprehensible. Basically, examination results must be presented according to the standards of medical evaluation, such as DIN 58220 visual acuity testing and visual fields analogous to manual-kinetic perimetry by Goldmann perimeter or approved comparable methods of visual field testing. Results that are not compliant with the official standards need to be identified accordingly.

[Determination of visual function in legal assessment]. / Objektivierung der Sehfunktionen bei Begutachtungen.

For the determination of visual function an objective assessment is essential. Basic ophthalmologic examinations such as measurement of visual acuity and perimetry are dependent on patient statements. If the patient is not being able to provide adequate answers, as is the case for small children or mentally retarded patients, or also if the accuracy of the patient's statements is doubtful or simulation or aggravation is suspected, the denoted function in the evaluation of visual acuity has to be checked on consistency using different examination methods, and the results of objective functional tests, such as electrophysiology and morphological features, have to be taken into account.

[Central serous chorioretinopathy--retinal function and morphology: microperimetry and optical coherence tomography]. / Chorioretinopathia centralis serosa--Netzhautfunktion und -morphologie: Mikroperimetrie und optische Kohärenztomografie im Vergleich.

BACKGROUND: The purpose of this study was to evaluate and compare retinal function and morphology in patients with central serous chorioretinopathy (CSC) using fundus perimetry and optical coherence tomography (OCT). PATIENTS AND METHODS: In 14 eyes of 14 patients with unilateral and first manifestation of CSC, fundus perimetry with the Microperimeter 1 (MP1) as well as OCT were carried out. The average retinal thickness and the average differential light threshold of the corresponding visual field were analyzed. RESULTS: All patients presented a serous detachment of the central neurosensory retina with a maximal retinal thickness of 381+/-82 microm. The microperimetric examination revealed on average a mean defect of 8.3+/-3.8 dB, which showed a good correlation to retinal thickness (r=0.73). Likewise, maximal retinal thickness and mean threshold values in the corresponding visual field displayed a good correlation (r=-0.58). CONCLUSION: The MP1 enables quantification of functional defects in patients with CSC. Although visual acuity was only slightly reduced, all patients showed extensive scotomata in fundus perimetry, which correlated well with retinal thickness.

[Static fundus perimetry in normals. Microperimeter 1 versus SLO]. / Statische Fundusperimetrie bei Probanden. Microperimeter 1 versus SLO.

BACKGROUND: The Microperimeter 1 (MP-1) allows for fundus-controlled static perimetry of the central visual field. The purpose of this study was to compare MP-1 fundus perimetry with the already established scanning laser ophthalmoscope (SLO) fundus perimetry concerning detected threshold values of light increment sensitivity in normals. METHOD: In 31 eyes of 31 healthy volunteers a fundus controlled static threshold perimetry was carried out each with the MP-1 (Nidek Technologies) and the SLO (Rodenstock). In the central 21 degrees x 12 degrees visual field light increment sensitivity threshold values for 40 corresponding stimulus locations were compared in a rectangular 3 degree-grid. RESULTS: The average light increment sensitivity was 19.1+/-0.5 dB with the MP-1 and 17.2+/-0.9 dB with the SLO. On average the threshold values of the 40 corresponding test locations were 1.9+/-1.3 dB higher with the MP-1 than with the SLO. CONCLUSION: Both the MP-1 and SLO offer the possibility of a reproducible functional analysis of the central retina under simultaneous fundus control. For comparison of results of the MP-1 and SLO fundus perimetry, a correction factor of approximately 2 dB should be used.

[Influence of cutoff filters on reading behavior in age-related macular degeneration]. / Einfluss von Kantenfiltern auf die Lesefähigkeit bei altersabhängiger Makuladegeneration.

BACKGROUND: Cutoff filters may improve contrast sensitivity in different retinal dystrophies and therefore lead to improved visual function. We investigated whether cutoff filters result in improved reading ability in age-related macular degeneration (AMD). METHODS: Reading performance was examined in 22 patients with AMD aged 63-91 years (visual acuity 0.1-0.5) using the Radner reading charts. These charts were presented in random order either with or without cutoff filters (Zeiss CF 540 and CF 580) monocularly to the better eye using a defined luminance of the test charts of 105 cd/m(2). RESULTS: Using the CF 540 cutoff filter, there was no significant change in visual acuity while there was a tendency to decrease. Calculating the LogRAD score, which takes reading errors into account, three patients improved by one line, while nine deteriorated, six of them by one line or more. There was no significant improvement using the CF 580 compared to either the CF 540 or to normal reading glasses. CONCLUSIONS: Overall, we found no measurable improvement using the CF 540 cutoff filter. The cutoff filter CF 580, tested for additional comparison, did not show any advantage.

Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration.

Recently, the VMD2 gene has been identified as the causative gene in juvenile-onset vitelliform macular dystrophy (Best disease), a central retinopathy primarily characterised by an impaired function of the retinal pigment epithelium. In this study we have further characterised the spectrum of VMD2 mutations in a series of 41 unrelated Best disease patients. Furthermore we expanded our analysis to include 32 unrelated patients with adult vitelliform macular dystrophy (AVMD) and 200 patients with age-related macular degeneration (AMD). Both AVMD and AMD share some phenotypic features with Best disease such as abnormal subretinal accumulation of lipofuscin material, progressive geographic atrophy and choroidal neovascularisation, and may be the consequence of a common pathogenic mechanism. In total, we have identified 23 distinct disease-associated mutations in Best disease and four different mutations in AVMD. Two of the mutations found in the AVMD patients were also seen in Best disease suggesting a considerable overlap in the aetiology of these two disorders. There were no mutations found in the AMD group. In addition, four frequent intragenic polymorphisms did not reveal allelic association of the VMD2 locus with AMD. These data exclude a direct role of VMD2 in the predisposition to AMD.

Normal values for fundus perimetry with the scanning laser ophthalmoscope.

PURPOSE: To evaluate the normal light sensitivity values for fundus perimetry and their short time fluctuation (reliability) in normal volunteers of different ages. After the development of full-threshold static fundus perimetry, age-corrected sensitivity values for normal subjects are required to interpret results and to compare them with conventional computerized perimetry. METHOD: Full-threshold fundus perimetry of the central field (33 x 21 degrees) by means of the scanning laser ophthalmoscope was performed on 152 eyes of 99 healthy persons aged 16 to 77 years with normal vision and no eye disease. Fixation was simultaneously documented. Light sensitivity values were evaluated according to each subject's age and test point location. RESULTS: Linear regression analysis disclosed a significant (P < .0001) decrease of the mean sensitivity of 0.275 dB per decade of increasing age, starting with 16.6 dB at age 10 years. Standard deviation around the center of fixation was 0.287 degrees in the first decade, and it increased by 2.82 minutes of arc per decade (P < .0001). Variation in triple examinations of subjects did not differ from short time fluctuation. CONCLUSION: Visual fields examined with fundus perimetry show reliable measurements in a range comparable to conventional computerized perimetry. There is a significant correlation between increase of age and decrease of light sensitivity in fundus perimetry. Visual fields obtained with fundus perimetry seem to correlate well with known data from computerized static threshold perimetry. It should be recognized that even in normal subjects, the stability of fixation decreases with increasing age.

Simultaneous confocal scanning laser fluorescein and indocyanine green angiography.

PURPOSE: To evaluate clinically a recently developed confocal scanning laser ophthalmoscope for simultaneous fluorescein and indocyanine green angiography. METHODS: After comprehensive ophthalmic examination, including stereoscopic biomicroscopy, and after color fundus photographs, simultaneous confocal scanning laser fluorescein and indocyanine green angiography was performed after injection of 500 mg of fluorescein and 25 mg of indocyanine green mixed in one syringe using the Heidelberg Retina Angiograph. An argon laser beam (488 nm) and a diode laser beam (795 nm) from an external source were delivered by single-mode fibers. Emission was recorded between 500 and 700 nm and above 810 nm, respectively. Digital images were displayed simultaneously on a monitor during angiography. RESULTS: Two hundred twenty simultaneous fluorescein and indocyanine green angiograms were obtained in 193 consecutive patients with various diagnoses, including exudative age-related macular degeneration with occult and classic choroidal neovascularization. Simultaneous angiography with both dyes gave high-contrast images during all phases of the angiography, which allowed for accurate correlation of fluorescein and indocyanine green angiographic findings and correct comparison of the transit of both dyes through the retinal and choroidal circulation. Corresponding display of quasisimultaneous frames facilitated interpretation of the angiograms. CONCLUSIONS: Confocal laser scanning angiography allows for quasisimultaneous fluorescein and indocyanine green angiography. The investigation is possible at low retinal irradiance and offers high-contrast digital images. Compared with consecutive angiographic investigations using both dyes, simultaneous angiography is less time consuming, requires only one injection, and, because quasisimultaneous frames are obtained, facilitates interpretation of the angiograms.

Scanning laser ophthalmoscope fundus perimetry before and after laser photocoagulation for clinically significant diabetic macular edema.

PURPOSE: To prospectively evaluate functional and funduscopic changes after laser treatment in patients with diabetic retinopathy and clinically significant macular edema by scanning laser ophthalmoscope fundus perimetry. METHODS: Thirty eyes of 30 patients with clinically significant macular edema as a result of diabetic retinopathy were prospectively examined before and at least 3 months after focal laser treatment with automatic fundus threshold perimetry using the scanning laser ophthalmoscope. Thresholds of light sensitivity were compared with age-corrected normal values and correlated with corrected visual acuity and subjective appraisal of visual function. RESULTS: In 30 eyes, fundus perimetry lasted for 10.5+/-2.7 (mean+/-SD) minutes with 322+/-67 stimulus presentations for each eye. Whereas eight eyes remained stable (< +/-1 dB change), 15 improved concerning mean deviation (MD) (3.1+/-1.7 dB) after focal laser treatment. Stability of fixation remained the same after focal laser treatment (0.75+/-0.57 degree). Laser scars showed marked loss of function (MD > 13 dB). CONCLUSIONS: Although light sensitivity was reduced in areas of macular edema, there was no correlation between the amount of edema and visual function. Fundus perimetry allows the creation of exact maps of retinal dysfunction before and after laser treatment. It may help in making management decisions in diabetic and nondiabetic patients by offering a sensitive parameter in addition to visual acuity.

Scanning laser fundus perimetry before laser photocoagulation of well defined choroidal neovascularisation.

AIM: To assess the centre of fixation before laser photocoagulation of well defined juxtafoveal or extrafoveal choroidal neovascularisation (CNV) secondary to age related macular degeneration (AMD), and to better predict visual function after treatment using scanning laser ophthalmoscope (SLO) fundus perimetry. METHODS: 19 consecutive eyes with juxtafoveal or extrafoveal CNV were examined by fundus perimetry before and after laser treatment with documentation of the fixation point using the SLO. The stability of fixation was defined as standard deviation around the mean fixation point. Overlays of fluorescein angiographic pictures and fundus perimetry were obtained using image analysis software. RESULTS: Fundus perimetry allowed accurate determination of the centre of fixation. Overlays demonstrated the precise geographic relation of the angiographically detectable foveal margin of the CNV and the centre of fixation. Thereby, prediction of the visual outcome with regard to reading ability was facilitated. Stability of fixation did not change significantly after treatment. CONCLUSIONS: Fundus perimetry using the SLO was helpful in patients who underwent laser treatment for juxtafoveal or extrafoveal CNV secondary to AMD and may aid the pretreatment counselling of such patients.

[Fundus-controlled functional evaluation in macular diseases with the scanning laser ophthalmoscope]. / Funduskontrollierte Funktionsprüfung bei Makulaerkrankungen mit dem Scanning-Laser-Ophthalmoskop.

Exact functional testing in macular diseases still presents a challenge for the ophthalmologist in detecting both small (para)central scotomas and changes in fixation habits. The recent development of scanning laser ophthalmoscopy has enabled functional testing with simultaneous observation of the fundus. In addition to automatic static threshold fundus perimetry, kinetic fundus-controlled perimetry and special fixation tasks can be applied. This method also allows the examination of reading performance combined with the exact observation of fixation and has been increasingly integrated into clinical routine. This allows more exact observations concerning macular function for diagnostic purposes, in evaluating new treatment methods, and as expertises in simulation or aggravation in patients with macular diseases.