[Segregation Analysis in Inherited Eye Disorders: An Academic Add-on or An Essential Effort?] / Die Segregationsanalyse bei erblichen Augenerkrankungen ­ akademisches Extra oder notwendiger Aufwand?

The knowledge of the genetic basis of many eye diseases is constantly increasing. Besides retinal degeneration, developmental defects of the anterior segment, cataracts, and the development of the basic structure are often associated with genetic defects. Moreover, a lot of genetic syndromes involve eye abnormalities. The impact of genetics has become more and more evident in ophthalmological practice. Although genetic counselling is usually carried out by human geneticists, the increasing availability of therapeutic options requires ophthalmologists to have some basic knowledge of the genetic causes and how to identify them. The first step in this regard is to recognise potential genetic eye disorders and to initiate an adequate genetic analysis to confirm the diagnosis. This review discusses possible and necessary investigations within the patient's family facing ophthalmologists after the genetic cause of an eye disease has been identified.

[Genotype-Phenotype Correlations in Patients with CRB1 Mutations]. / Genotyp-Phänotyp-Korrelation bei Patienten mit CRB1-Mutationen.

Background Mutations in the CRB1 gene were identified in patients with early-onset severe retinal dystrophy (EOSRD), childhood-onset and juvenile-onset rod-cone dystrophy. This study describes the phenotypic spectrum of disease-causing CRB1-mutations in the first two decades of life. Materials and Methods Eight patients, aged three months to 20 years, underwent a full comprehensive ophthalmological examination including best corrected visual acuity testing (BCVA), color vision testing, funduscopy, spectral-domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) recording. Automated and manual retinal layer segmentation of SD-OCT recordings was performed using DIOCTA software. A full-field electroretinography (ffERG, ISCEV Standard) and visual fields were performed in cooperative patients. Results Five patients carried mutations causing a loss of the corresponding gene product (splice-mutation, nonsense-mutation, frame-shifting mutation). These patients presented with generally reduced vision in the first months of life that never exceeded 0.04 during the observational period. The sixth patient carried a homozygous missense mutation and reached maximal BCVA 0.05 at the age of 6 years. Two further patients, carrying at least one hypomorphic missense-mutation, presented with better preserved visual function with up to 0.5 at the age of 20 years. The recorded ffERG was below threshold in the majority of patients. Visual fields were severely restricted. The photoreceptor layers were significantly reduced in SD-OCT whenever stratification of retinal layers was possible. The inner nuclear layer thickness increased with progressing retinal degeneration. A-Scan analysis revealed better preservation of the retinal stratification in patients with missense mutations. Conclusions Patients with CRB1-mutations presented with a severe phenotype with severely reduced visual acuity from birth. Missense mutations with predicted residual function of the gene product were associated with moderate expression of the disease. Severe and progressive restriction of visual fields occurred in the first decade of life. The reduced retinal stratification indicates a general loss of structural integrity of the retinal layers.

[Albinism and the Range of Fundus Hypopigmentation, Macular Hypoplasia, and Nystagmus]. / Albinimus und das Spektrum der Fundushypopigmentierung, der Makulahypoplasie und des Nystagmus.

From the ophthalmological view, albinism is a disorder of reduced pigmentation of the retinal and irdial pigment epithelium and the iris and choroid stroma. The reduced pigmentation is accompanied by morphological changes in the retina and the optic nerve. The functional relationship of these morphological changes is not yet well understood. This review summarises the genetic causes of reduced pigment synthesis and impaired pigment distribution, and discusses the variability of expression of albinism symptoms, in the light of other disorders affecting retinal development.

[Recruitment of Suitable Families to Identify Causative Genes in Hereditary Strabismus]. / Zur Rekrutierung geeigneter Familien für die Identifikation ursächlicher Gene des erblichen Strabismus.

PURPOSE: The cause and origin of primary strabismus are not well understood. It is thought that there is multifactorial genetic inheritance. Only linkage analysis has been applied to study the genetic causes and correlations. The objective of this study was the compilation and statistical evaluation of a useful cohort of families for linkage analysis. METHODS: The archives of the Department of Ophthalmology of the Justus-Liebig-University Gießen were used as a database for this study. Medical records of visits between January 2001 and July 2008 were analysed. Evaluation was based on the medical history form. The data set was scanned for index families in which at least two members had any form of primary strabismus. Patients were classified according to their type of primary strabismus. Families who were most suitable for linkage analysis were approached. A disease specific questionnaire was developed to complete the data. RESULTS: Between January 2001 and July 2008, 20,813 patients affected by primary strabismus were treated. The data set contained 2380 patients with a positive family history of primary strabismus. The majority presented with esotropia (67 %), followed by exotropia (21 %). In most cases (80 %), two family members were affected and the child-parent relationship contributed the largest group, including 948 cases (40 %). Affected siblings were found in 397 families (17 %). Three affected patients were identified in 432 (18 %) families. In these, the relationship parent-child-sibling occurred most frequently, with 143 cases (6 %). A positive family history of at least four related patients was found in 46 families (2 %). Forty-two families were particularly suitable for linkage analysis. Seventeen of the 42 families answered a questionnaire aimed at improving the data set. Three families finally participated in ophthalmic examinations and agreed to blood sampling to perform linkage analysis. CONCLUSION: The fraction of families with strabismus patients in more than two consecutive generations was extremely low. If these families are included in any study, this should be coupled to treatment to improve compliance.

[Autosomal recessive bestrophinopathy (ARB): a clinical and molecular description of two patients at childhood]. / 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 (SD­OCT). 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.

Autosomal recessive bestrophinopathy: new observations on the retinal phenotype - clinical and molecular report of an Italian family.

PURPOSE: To describe the genotype and phenotype in a 9-year-old boy with bilateral retinopathy. METHODS: The patient, his healthy (by history) nonconsanguineous parents and his sister were examined by best-corrected visual acuity, matrix frequency doubling technology, monocular static field analysis, fundus autofluorescence imaging, optical coherence tomography, Ganzfeld electroretinography (ERG), pattern ERG, multifocal ERG, electro-oculography and genotyping of the BEST1 gene. RESULTS: The patient presented with an Arden ratio of 1.25, an unremarkable ERG and fluorescent yellow deposits distributed throughout the fundus suggestive of autosomal recessive bestrophinopathy (ARB). Genotyping revealed a homozygous nonsense mutation in BEST1 (p.R200X). The parents and the sister, who were heterozygous mutation carriers, presented with normal ophthalmological function. CONCLUSIONS: ARB is a rare retinal disorder. We contribute a novel patient report indicative of ARB, assessed by clinical examination and confirmed by genotyping of BEST1, to the short list of ARB cases in the literature.

Unexpected Genetic Cause in Two Female Siblings with High Myopia and Reduced Visual Acuity.

In daily life, myopia is a frequent cause of reduced visual acuity (VA) due to missing or incomplete optical correction. While the genetic cause of high myopia itself is not well understood, a significant number of cases are secondary to hereditary malfunctions or degenerations of the retina. The mechanism by which this occurs remains yet unclear. Two female siblings, 4 y and 2 y, respectively, from a consanguineous Pakistani family were referred to our department for reduced VA and strabismus. Both girls were highly myopic and hence were further examined using standard clinical tests and electroretinography (ERG). The latter confirmed confounded electrical coupling of photoreceptors and bipolar cells. Further inquiry and testing confirmed a similar condition for the father including impaired night vision, reduced VA, photophobia, and an equally characteristic ERG. Findings in the mother were unremarkable. Subsequent genetic analysis of autosomal recessive and X-linked genes for congenital stationary night blindness (CSNB) revealed a novel homozygous splice site mutation in CACNA1F in the two girls transmitted from both the father and the mother. While in males the above clinical constellation is a frequent finding, this report, to the authors' knowledge, is the first demonstrating biallelic mutations at the CACNA1F locus in females.

Genotype-phenotype correlation in a German family with a novel complex CRX mutation extending the open reading frame.

PURPOSE: To describe the genotype-phenotype correlation in a German family with a novel CRX mutation and to perform a comparative analysis of published cases. DESIGN: Retrospective observational case series, systematic review, and comparative analysis of the literature. PARTICIPANTS: Four related patients with progressive retinal degeneration. METHODS: Mutation screening by single-strand polymorphism analysis and direct sequencing. Clinical examination included kinetic visual fields (VFs), 2-color threshold perimetry (2CTP), full-field electroretinography, fundus photography, optical coherence tomography, and fundus autofluorescence (FA) recording. MAIN OUTCOME MEASURES: Visual fields, subjective and objective cone- and rod-specific function, fundus aspect, retinal stratification, and FA. RESULTS: A novel heterozygous complex mutation (c.816delCACinsAA) in CRX predicting the substitution of 27 C-terminal amino acids by 44 novel amino acids, thus abolishing the OTX tail, was identified in a 2-generation family finally diagnosed with cone-rod dystrophy (CRD), which was confirmed by 2CTP. Patients presented with variability in progression, nystagmus, and nyctalopia. Most of the patients were hyperopic. Electroretinography recordings showed residual rod and mixed cone-rod responses in 2 of the subjects. Age-dependent VF losses followed funduscopic changes of progressive atrophy of the retinal pigment epithelium and neuroretina in the macula and midperiphery marked by disturbed FA. Optical coherence tomography showed decreased central retinal thickness. Comparative analysis of the 131 published data sets revealed 2 groups: patients with early and late onset. CONCLUSIONS: We described a 2-generation family with a novel mutation in CRX. The resulting phenotype is that of CRD with variable age at onset and progression. The phenotype description of previously published cases is conclusive only for CRD.

[Genetic and clinical heterogeneity in LCA patients. The end of uniformity]. / Genetische und klinische Heterogenität bei LCA-Patienten. Das Ende der Einheitlichkeit.

BACKGROUND: Leber congenital amaurosis (LCA) usually describes patients with severely reduced vision due to a retinal dystrophy in early childhood. METHODS: In 135 families in a case series with severely reduced vision due to a retinal dystrophy in early childhood a complete ophthalmologic examination was extended by two-color threshold perimetry, fundus autofluorescence (FAF), und optical coherence tomography (OCT). Mutation screening included AIPL1, CRB1, CRX, GUCY2D, LRAT, RPE65, RPGRIP, and TULP1. RESULTS: GUCY2D mutations caused the most severe phenotype with severely reduced vision from birth but unremarkable fundus appearance. RPE65 mutations were correlated with an obvious lack of FAF. CRB1 mutations showed a significantly thickened retina on OCT. CRX mutations were associated with a progressive form of cone-rod dystrophy. CONCLUSION: A genotype-phenotype correlation for selected genes allows an optimized strategy for the molecular genetic work-up.

[Best's disease. Overview of pathology and its causes]. / Morbus Best Ein Uberblick zur Pathologie und deren Ursachen.

Best's disease is a hereditary affection with reduced penetrance and juvenile onset. The fundus may be unremarkable or present various stages up to scarring of the macula. Histopathology of advanced stages discloses deposits of lipofuscin on Bruch's membrane, the innermost layer of which is the basal membrane of the retinal pigment epithelium (RPE). The deposits correlate with lipofuscin and melanofuscin granulae in the RPE. Photoreceptors correlating with the lesions have lost their outer segments and the RPE as well as the photoreceptors appear edematous. Loss of photoreceptor function does not necessarily follow progression of fundus appearance. Loss of function usually correlates with a reduced Arden ratio of the electro-oculogram even in the absence of funduscopic changes.Best's disease is caused by mutations in VMD2 (hBEST1). Bestrophin, the gene product of hBEST1, is a regulatory part of a Ca(2+) channel or a Ca(2+)-dependent Cl(-)channel. In this paper the relevant data on clinical and genetic pathology are summarized and evaluated.

[Genetics of neuronal ceroidlipofuscinoses. Aspects of genetic counseling]. / Genetik der neuronalen Zeroidlipofuszinosen. Aspekte der humangenetischen Beratung.

Neuronal ceroid lipofuscinoses are autosomal recessive inherited disorders of neuronal cells. Neuronal ceroid lipofuscinoses belong to the lysosomal storage disorders and are characterized by accumulation of protein-lipid complexes in the lysosomal compartments of all somatic cells. This debris causes degenerative activities in the nervous system, especially in the cerebrum, the cerebellum and the afferent and efferent cranial nerves. With one exception of adult onset the disorder causes the loss of receptive, cognitive and control function in the first decade of life and an early death by the age of 20. Currently 10 loci are known which correlate to 8 genes. The genotype related phenotype and the correlated prognosis depend on the underlying gene and type of mutation. The genotype phenotype correlation is hampered by a lack of knowledge on the function of the mutant gene products. In this review we summarize the known genetic data on neuronal ceroid lipofuscinoses and comment on therapeutic approaches.

[Genetic diseases of the retinal pigment epithelium]. / Genetische Erkrankungen des retinalen Pigmentepithels.

The retinal pigment epithelium (RPE) is a cellular monolayer between the choriocapillaris and the photoreceptors which controls the uptake of nutrients by the retina and the disposal of shed photoreceptor outer segments from the retina. The RPE is responsible for a continuous supply of rhodopsin by the retinol cycle and blocking of light by its pigmentation to minimize light-induced oxidation of retinal lipids and proteins. Proteins encoded by genes in which mutations are responsible for hereditary disorders of the retina and the RPE are involved in all these functions. In this article these genes and disorders are reviewed in the context of a functional network.

Genotype-phenotype correlation and longitudinal course in ten families with Best vitelliform macular dystrophy.

AIM: Longitudinal course and genotype-phenotype correlation in patients and carriers with heterozygous mutations in hBEST1 (bestrophin). METHODS: Thirteen patients and seven possible carriers were characterised by mutation analysis with SSCPA and direct sequencing, clinical examination and fundus autofluorescence (AF). Electrophysiology (EOG and mfERG) and optical coherence tomography (OCT) were additionally performed whenever possible. RESULTS: We identified seven different heterozygous mutations in ten unrelated families with Best disease. I296del was the most frequent mutation. Five of nine individuals with I295del and two of three with N99K were asymptomatic carriers. One patient with I295del mutation had funduscopically unilateral Best disease. In three children (all with I295del), EOG initially showed a clearly present light peak that deteriorated during 5 years of follow-up in two of them. Increased AF corresponded well to funduscopically visible lesions. During 3-6 years of follow-up, the lesion area did not change significantly, but there were obvious changes in the inner structure of the lesion. CONCLUSION: In the present series I295del, the most frequent mutation in our study, and N99K showed reduced penetrance. EOG was normal in young patients even if prime signs were visible. The lesion area did not depend on the mutation and did not correlate with VA. Lower VA was associated with a more irregular AF pattern due to scarring or haemorrhage. Our results indicate a disease causing effect that is cumulative over time.