Clinical and Genetic Characteristics of Korean Congenital Stationary Night Blindness Patients.

In this study, we investigated the clinical and genetic characteristics of 19 Korean patients with congenital stationary night blindness (CSNB) at two tertiary hospitals. Clinical evaluations, including fundus photography, spectral-domain optical coherence tomography, and electroretinography, were performed. Genetic analyses were conducted using targeted panel sequencing or whole exome sequencing. The median age was 5 (3-21) years at the initial examination, 2 (1-8) years at symptom onset, and 11 (5-28) years during the final visit. Genetic mutations were identified as CNGB1 and GNAT1 for the Riggs type (n = 2), TRPM1 and NYX for the complete type (n = 3), and CACNA1F (n = 14) for the incomplete type. Ten novel variants were identified, and best-corrected visual acuity (BCVA) and spherical equivalents (SE) were related to each type of CSNB. The Riggs and TRPM1 complete types presented mild myopia and good BCVA without strabismus and nystagmus, whereas the NYX complete and incomplete types showed mixed SE and poor BCVA with strabismus and nystagmus. This is the first case series of Korean patients with CSNB, and further studies with a larger number of subjects should be conducted to correlate the clinical and genetic aspects of CSNB.

[Overview of Congenital Stationary Night Blindness with Predominantly Normal Fundus Appearance]. / Überblick über die kongenitale stationäre Nachtblindheit mit überwiegend normalem Fundus.

Congenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous group of non-progressive retinal disorder with largely normal fundus appearance. The mode of inheritance can be autosomal dominant (adCSNB), autosomal recessive (arCSNB) or X-chromosomal (XLCSNB). Additional ocular signs can be myopia, hyperopia, strabismus, nystagmus and reduced visual acuity. The Riggs and Schubert-Bornschein form of CSNB can be discriminated by electroretinography. While the Riggs form represents a dysfunction of the rods, a signal transmission defect from photoreceptors to bipolar cell is described in patients with the more frequently occurring Schubert-Bornschein form. The Schubert-Bornschein form can be further divided into incomplete (icCSNB) and complete (cCSNB) showing different electroretinograms (ERGs). While patients with cCSNB show a dysfunction of the ON-signaling pathway, patients with icCSNB show a dysfunction of the ON- and OFF-signaling pathways, affecting visual acuity as well. Using classical linkage, candidate gene analyses and more recent next-generation sequencing approaches, to date, mutations in 13 different genes have been associated with this disease. In vitro and in vivo models showed a correlation of the phenotype of patients with the expression, protein localization and function of the respective molecules: genes, mutated in patients with the Riggs form of CSNB have an important role in the rod phototransduction cascade. Genes mutated in patients with icCSNB, code for proteins important for glutamate neurotransmitter release at the synaptic cleft of the photoreceptors. Genes mutated in patients with cCSNB, code for proteins important for glutamate uptake and further signal transmission to the ON-bipolar cells. Preliminary in vivo studies showed that CSNB may be cured by gene therapy. These studies concerning CSNB are important for the precise diagnosis of patients with this disease, but are also helpful in deciphering key molecules essential for signal transmission from photoreceptors to bipolar cells. So far, it is a poorly understood field.

Multifocal oscillatory potentials in CSNB1 and CSNB2 type congenital stationary night blindness.

We evaluated the function of the inner retina in patients with congenital stationary night blindness of the complete (CSNB1) and the incomplete type (CSNB2) by recording multifocal oscillatory potentials (mf-OPs). The VERIS system was used to record mf-OPs from 61 areas of the central retina from 5 CSNB1 patients (4 with NYX gene mutation), 6 CSNB2 patients (2 with CACNA1F mutation) and 11 control subjects. For each subject group, the first- and second-order kernel responses for one eye were analysed and the amplitudes and implicit times of their major components compared to 5 concentric rings centred on the fovea. In CSNB1 patients, the mf-OP peak amplitudes of the first-order kernel responses showed a significant reduction of the first peak without significant reduction of the second, whereas in CSNB2 both peak amplitudes were barely discernable from noise for all eccentricities. In the second-order kernel, the third peak was reduced in CSNB1 patients, and again not discernable from noise in CSNB2 patients. The difference in amplitude between the control and CSNB1 groups was significant for the late components of the first- and the second-order kernel. Implicit times were not significantly altered. The difference in mf-OP amplitude between CSNB1 and CSNB2 patients reflects the different molecular mechanisms underlying the two types of disease, which differentially affect the postreceptoral pathways of cone signal processing. The well-preserved peak 2 amplitudes of first-order mf-OPs and peak 3 amplitudes of second-order mf-OPs in CSNB1 patients point to a major impact of OFF-pathway components on these responses which are not present in CSNB2 patients. In conclusion, our results show that CSNB1 and CSNB2 are two different types of disease, not only on a genetic but also on a pathophysiological level.

Coats-like lesions in Usher syndrome type II.

BACKGROUND: An unusual case of Usher syndrome type II associated with bilateral Coats-like exudative retinopathy is described. METHODS: A 14-year-old boy with congenital sensorineural deafness and normal vestibular functions presented with a recent history of night blindness. He was followed for 3 years with fundus photography, intravenous fluorescein angiography, electroretinography and audiometric testings. His parents refused any form of treatment. RESULTS: Fundoscopy showed bilateral retinitis pigmentosa and a single focus of subretinal exudation and overlying telangiectatic retinal vessels inferotemporal to the vascular arcade in the right eye. He had bilateral mild macular edema. A year later, a similar lesion developed inferotemporally in the left fundus. Electroretinography responses, particularly the rod-mediated signals, were significantly reduced. Audiometric studies documented hearing loss in high frequencies. His visual acuity declined from 20/40 to 20/80 RE and from 20/80 to 20/100 LE during follow-up. No new lesions developed. CONCLUSIONS: Coats-type exudative lesions may develop in patients with Usher syndrome type II. Although left untreated, only a minimal increase in exudation occurred over 3 years.

Usher syndrome clinical types I and II: could ocular symptoms and signs differentiate between the two types?

PURPOSE: Usher syndrome types I and II are clinical syndromes with substantial genetic and clinical heterogeneity. We undertook the current study in order to identify ocular symptoms and signs that could differentiate between the two types. METHODS: Sixty-seven patients with Usher syndrome were evaluated. Based on audiologic and vestibular findings, patients were classified as either Usher type I or II. The severity of the ocular signs and symptoms present in each type were compared. RESULTS: Visual acuity, visual field area, electroretinographic amplitude, incidence of cataract and macular lesions were not significantly different between Usher types I and II. However, the ages when night blindness was perceived and retinitis pigmentosa was diagnosed differed significantly between the two types. CONCLUSIONS: There seems to be some overlap between types I and II of Usher syndrome in regard to the ophthalmologic findings. However, night blindness appears earlier in Usher type I (although the difference in age of appearance appears to be less dramatic than previously assumed). Molecular elucidation of Usher syndrome may serve as a key to understanding these differences and, perhaps, provide a better tool for use in clinical diagnosis, prognosis and genetic counseling.

[Establishment of the concept of new clinical entities--complete and incomplete form of congenital stationary night blindness].

I summarized our long-term study to prove that the complete and incomplete types of congenital stationary night blindness (CSNB) are different clinical entities and that the latter is a newly identified disease which has never been reported in the past. CSNB with normal fundi and negative electroretinogram (ERG) showing selective reduction of the b-wave was previously known as the "Schubert-Bornschein type". For the sake of convenience, we classified the disease into two types according to the absence or the presence of rod function: complete CSNB and incomplete CSNB. The hereditary mode of the former is X-linked recessive and autosomal recessive, while that of the latter is X-linked recessive. They are never found together in a single family. We found several additional differences between the two types, including ERG oscillatory potentials, cone mediated ERG, and refractive errors, all leading us to hypothesize that the two types are not variants of a single disease but are the sum of two different clinical entities. Our hypothesis has recently been proven true by molecular genetical analysis. Namely, the mutated gene in X-linked recessive complete CSNB was found in the nyctalopin (NYX) gene, while that in incomplete CSNB was found in the calcium channel (CANCA1F) gene which encodes the retina-specific calcium channel alpha 1-subunit. These results proved that complete and incomplete CSNB are different clinical entities and that the latter is the first disease of the eye which discloses mutation of this region. We classified 90 patients to include 49 complete and 41 incomplete types. Fifteen incomplete CSNB patients underwent gene analysis and they all showed mutation of the CACNA1F gene. We also examined for gene mutation in several patients who had progressive retinal disease and negative ERG and found two siblings with CANA1F gene mutation. This finding indicates that the mutation of the CACNA1F gene can also cause progressive retinal disease in addition to incomplete CSNB. Gene analysis of 11 patients with complete CSNB was performed and 6 revealed mutation of the NYX gene. The remaining 5 patients showed neither NYX nor CACNA1F gene mutation, suggesting they are of autosomal recessive complete CSNB where gene mutation has not been identified. The comparison of our phenotype and genotype diagnosis indicated that a precise ERG analysis can provide correct differentiation between complete and incomplete types. Other clinical findings include moderately low visual acuity in both types, high or moderate myopia in complete CSNB, and wide distribution from myopia to hyperopia in incomplete CSNB. Pathophysiology studies using clinical patients and animal models suggested that complete CSNB has a complete defect of the ON-bipolar cells or their synapses in the rod and cone visual pathways, leaving the OFF pathway intact (OFF-retina). On the other hand, the incomplete CSNB has an incomplete defect of the ON and OFF bipolar cells or their synapses in the rod and cone visual pathways. The macular function is relatively well preserved in both types, which was shown by focal macular ERG. The incomplete CSNB patients seldom complain of night blindness, which causes us to overlook this disease because we then tend not to perform ERG testing. This disease is not so rare and clinicians should be more aware of its existence. The incomplete CSNB is a new hereditary retinal disease detected by Japanese investigators just like the Oguchi disease, and it has much unknown pathophysiology which needs to be identified in the future. Since the namings of complete and incomplete CSNB may be misunderstood as indicating functional classification of one disease, it has been proposed internationally to change the name "complete type" to CSNB1 and that of "incomplete type" to CSNB2.

The complete form of X-linked congenital stationary night blindness is caused by mutations in a gene encoding a leucine-rich repeat protein.

X-linked congenital stationary night blindness (XLCSNB) is characterized by impaired scotopic vision with associated ocular symptoms such as myopia, hyperopia, nystagmus and reduced visual acuity. Genetic mapping in families with XLCSNB revealed two different loci on the proximal short arm of the X chromosome. These two genetic subtypes can be distinguished on the basis of electroretinogram (ERG) responses and psychophysical testing as a complete (CSNB1) and an incomplete (CSNB2) form. The CSNB1 locus has been mapped to a 5-cM linkage interval in Xp11.4 (refs 2,5-7). Here we construct and analyse a contig between the markers DXS993 and DXS228, leading to the identification of a new gene mutated in CSNB1 patients. It is partially deleted in 3 families and mutation analysis in a further 21 families detected another 13 different mutations. This gene, designated NYX, encodes a protein of 481 amino acids (nyctalopin) and is expressed at low levels in tissues including retina, brain, testis and muscle. The predicted polypeptide is a glycosylphosphatidylinositol (GPI)-anchored extracellular protein with 11 typical and 2 cysteine-rich, leucine-rich repeats (LRRs). This motif is important for protein-protein interactions and members of the LRR superfamily are involved in cell adhesion and axon guidance. Future functional analysis of nyctalopin might therefore give insight into the fine-regulation of cell-cell contacts in the retina.

Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness.

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal pathways, causing either progressive degeneration or stationary deficits. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated. The molecular bases have been elucidated in several subtypes, providing a better understanding of the disease mechanisms and developmental retinal neurobiology. Here we have studied 22 families with 'complete' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 families from the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the visual losses seen in patients with complete CSNB.

Defects in the rhodopsin kinase gene in the Oguchi form of stationary night blindness.

Oguchi disease is a recessively inherited form of stationary night blindness due to malfunction of the rod photoreceptor mechanism. Patients with this disease show a distinctive golden-brown colour of the fundus that occurs as the retina adapts to light, called the Mizuo phenomenon. Recently a defect in arrestin, a member of the rod phototransduction pathway, was found to cause this disease in some Japanese patients. As rhodopsin kinase works with arrestin in shutting off rhodopsin after it has been activated by a photon of light, it is reasonable to propose that some cases of Oguchi disease might be caused by defects in rhodopsin kinase. This report describes an analysis of the arrestin and rhodopsin kinase genes in three unrelated cases of Oguchi disease. No defects in arrestin were detected, but all three cases had mutations in the rhodopsin kinase gene. Two cases were found to be homozygous for a deletion encompassing exon 5, predicted to lead to a nonfunctional protein. The third case was a compound heterozygote with two allelic mutations, a missense mutation (Val380Asp) affecting a residue in the catalytic domain, and a frameshift mutation (Ser536(4-bp del)) resulting in truncation of the carboxy terminus. Our results indicate that null mutations in the rhodopsin kinase gene are a cause of Oguchi disease and extend the known genetic heterogeneity in congenital stationary night blindness.

[Seeing in the dark: limited vision in the aged as a prototypical "environmentally relevant" loss in competence]. / Im Dunkeln sehen: Sehbeeinträchtigung im Alter als prototypische "umweltrelevante" Kompetenzeinbusse.

In the conceptual part of this article, the existential dimension of experiencing a dramatic visual loss in late life is highlighted. Three theoretical avenues are proposed to approach age-related vision loss: 1) a stress and burden perspective; 2) a coping perspective, 3) an environmental psychology perspective. The empirical study is based on 84 elderly subjects suffering from vision loss (42 visually impaired, 42 blind), a comparison group of 42 subjects with mobility impairments, and a control group of 42 healthy subjects (particularly not impaired in vision or mobility). In all impaired groups, the impairment appeared after the age of 55 years; identification of subjects was based on medical expertise. Mean age varies between groups from 75 to 78 years with 30 females and 12 males in each group. Data based on person (e.g., ADL-functioning, subjective well-being, depressivity) as well as person-environment-transaction measures (e.g., microecology within the house, action range outside the house) were collected. Results revealed a reduced ADL-competence, lower subjective well-being, higher depressivity, and a shrinkage of action range in subjects suffering from visual loss. However, there was also a need for a differential perspective: For example, depending on person variables (living alone/not alone, degree of visual loss, coping style, coexisting illnesses), a different "resilience" against environmental pressure was observed. These findings point to the importance of a "differential" environmental gerontology.

Heterozygous missense mutation in the rod cGMP phosphodiesterase beta-subunit gene in autosomal dominant stationary night blindness.

The locus for autosomal dominant congenital stationary night blindness (adCSNB) has recently been assigned to distal chromosome 4p by linkage analysis in a large Danish family. Within the candidate gene encoding the beta-subunit of rod photoreceptor cGMP-specific phosphodiesterase (beta PDE), we have identified a heterozygous C to A transversion in exon 4, predicting a His258Asp change in the polypeptide. We found a perfect cosegregation (Zmax = 22.6 at theta = 0.00) of this mutation with the disease phenotype suggesting that this missense mutation is responsible for the disease in this pedigree. Homozygous nonsense mutations in the beta PDE gene have been found recently in patients with autosomal recessive retinitis pigmentosa, a common hereditary photoreceptor dystrophy.

Clinical findings in patients with congenital stationary night blindness of the Schubert-Bornschein type.

We examined 23 patients (18 families) with congenital stationary night blindness (CSNB) who showed a "negative" electroretinogram of the Schubert-Bornschein type. The goal of the study was to find evidence for the classification proposed by Miyake (complete and incomplete type) based on electroretinograms (ERGs) and dark-adaptation function and to look for additional classification parameters that argue for or against heterogeneity. In all, 13 patients revealed the complete type and 10 the incomplete type. The mean age of our patients was 24.7 years (median, 21 years; SD, 14.5 years). In both groups, almost all patients were myopic (mean, -6.05 D; SD, 3.77 D; median, -6.12 D), and there was a reduction in visual acuity (mean, 0.34; SD, 0.14; median, 0.35) without significant differences between the subgroups. In all, 56.5% of the patients suffered from nystagmus and 52.2% squinted. These results confirm the Miyake classification and suggest that only ERG and dark-adaptation data allow a discrimination between the two subtypes. The ongoing molecular analysis will show whether there are correlates on the molecular level.

On- and off-responses in photopic electroretinogram in complete and incomplete types of congenital stationary night blindness.

The on- and off-responses of photopic electroretinogram (ERG) were recorded by rectangular light stimuli in 13 patients with complete type and 9 patients with incomplete type of congenital stationary night blindness. The positive on-response (b-wave) was significantly smaller in both types than in normal subjects (P less than 0.001). The rapid off-response was normal in complete type patients, but was significantly smaller in incomplete type patients than in normal subjects (P less than 0.001). Since the rapid off-response mainly reflects the decay of the late receptor potential of the cones, incomplete type patients may have a visual disturbance in the cone itself. Normal rapid off-response with abnormal on-response in complete type patients suggests the existence of a photopic visual disturbance in the middle retinal layer. These results strongly suggest that these two types of congenital stationary night blindness have a different pathogenesis in the photopic visual pathway.

Congenital stationary night blindness with negative electroretinogram. A new classification.

An analysis of 64 patients with congenital stationary night blindness showed that all had essentially normal fundi. Electroretinography (ERG) showed a normal a wave with extremely reduced b wave (negative type) when recorded with a single bright white stimulus in the dark. We classified these patients into two groups based on the evaluation of rod ERG and/or psychophysical dark adaptation measured with an 11 degree test target at 15 degrees in the upper part of the retina. One group (35 patients) lacked rod function (complete type). Nine patients could not be classified. No pedigree showed a complete and incomplete type in one family. Differences between the two groups in refractive error, photopic function, and oscillatory potentials in the ERG suggest a different pathogenesis. Our analysis may provide a new classification of congenital stationary night blindness with a negative ERG.

Vestibular and auditory function in Usher's syndrome.

Usher's syndrome is a recessive hereditary disorder in which a congenital hearing loss is combined with nyctalopia, retinal degeneration, and restriction of visual fields. The results of a comprehensive ophthalmic and neurotologic study on 70 patients are reported. Two distinct clinical and presumed genetic types were discernible on the basis of hearing impairment and vestibular sensitivity and, to a lesser extent, deterioration of retinal photoreceptor function. Such a classification has proved valuable in diagnosis, prognosis, and genetic counselling.