Cone-rod dystrophy can be a manifestation of Danon disease

Background Danon disease is a neuromuscular disorder with variable expression in the eye. We describe a family with Danon disease and cone-rod dystrophy (CRD). Methods Affected males of one family with Danon were invited for an extensive ophthalmologic examination, including color vision testing, fundus photography, Goldmann perimetry, full-field electroretinogram (ERG), and SD-OCT. Previous ophthalmologic data were retrieved from medical charts. The LAMP2 and RPGR gene were analyzed by direct sequencing. Results Two siblings had no ocular phenotype. The third sibling and a cousin developed CRD leading to legal blindness. Visual acuity deteriorated progressively over time, color vision was severely disturbed, and ERG showed reduced photopic and scotopic responses. SD-OCT revealed thinning of the photoreceptor and RPE layer. Visual fieldsdemonstrated central scotoma. The causal mutation was p. Gly384Arg in LAMP2; no mutations were found in RPGR. Conclusions This is the first description of CRD in Danon disease. The retinal phenotype was a late onset but severe dystrophy characterized by loss of photoreceptors and RPE cells. With this report, we highlight the importance of a comprehensive ophthalmologic examination in the clinical work-up of Danon disease

Assessment of Night Vision Problems in Patients with Congenital Stationary Night Blindness

Congenital Stationary Night Blindness (CSNB) is a retinal disorder caused by a signal transmission defect between photoreceptors and bipolar cells. CSNB can be subdivided in CSNB2 (rod signal transmission reduced) and CSNB1 (rod signal transmission absent). The present study is the first in which night vision problems are assessed in CSNB patients in a systematic way, with the purpose of improving rehabilitation for these patients. We assessed the night vision problems of 13 CSNB2 patients and 9 CSNB1 patients by means of a questionnaire on low luminance situations. We furthermore investigated their dark adapted visual functions by the Goldmann Weekers dark adaptation curve, a dark adapted static visual field, and a two-dimensional version of the ‘‘Light Lab’’. In the latter test, a digital image of a living room with objects was projected on a screen. While increasing the luminance of the image, we asked the patients to report on detection and recognition of objects. The questionnaire showed that the CSNB2 patients hardly experienced any night vision problems, while all CSNB1 patients experienced some problems although they generally did not describe them as severe. The three scotopic tests showed minimally to moderately decreased dark adapted visual functions in the CSNB2 patients, with differences between patients. In contrast, the dark adapted visual functions of the CSNB1 patients were more severely affected, but showed almost no differences between patients. The results from the ‘‘2D Light Lab’’ showed that all CSNB1 patients were blind at low intensities (equal to starlight), but quickly regained vision at higher intensities (full moonlight). Just above their dark adapted thresholds both CSNB1 and CSNB2 patients had normal visual fields. From the results we conclude that night vision problems in CSNB, in contrast to what the name suggests, are not conspicuous and generally not disabling

Clinical course of cone dystrophy caused by mutations in the RPGR gene

Contains fulltext : 97720.pdf (publisher's version ) (Closed access)BACKGROUND: Mutations in the RPGR gene predominantly cause rod photoreceptor disorders with a large variability in clinical course. In this report, we describe two families with mutations in this gene and cone involvement. METHODS: We investigated an X-linked cone dystrophy family (1) with 25 affected males, 25 female carriers, and 21 non-carriers, as well as a small family (2) with one affected and one unaffected male. The RPGR gene was analyzed by direct sequencing. All medical records were evaluated, and all available data on visual acuity, color vision testing, ophthalmoscopy, fundus photography, fundus autofluorescence, Goldmann perimetry, SD-OCT, dark adaptation, and full-field electroretinography (ERG) were registered. Cumulative risks of visual loss were studied with Kaplan-Meier product-limit survival analysis. RESULTS: Both families had a frameshift mutation in ORF15 of the RPGR gene; family 1 had p.Ser1107ValfsX4, and family 2 had p.His1100GlnfsX10. Mean follow up was 13 years (SD 10). Virtually all affected males showed reduced photopic and normal scotopic responses on ERG. Fifty percent of the patients had a visual acuity of <0.5 at age 35 years (SE 2.2), and 75% of the patients was legally blind at age 60 years (SE 2.3). Female carriers showed no signs of ocular involvement. CONCLUSIONS: This report describes the clinical course and visual prognosis in two families with cone dystrophy due to RPGR mutations in the 3' terminal region of ORF15. Remarkable features were the consistent, late-onset phenotype, the severe visual outcome, and the non-expression in female carriers. Expression of RPGR mutations in this particular region appears to be relatively homogeneous and predisposed to cones

Functionele visusklachten : tijdig onderzoek loont

Patients with functional vision disorder (FVD) may present with poor visual acuity, visual field loss, or a combination of the two. This paper illustrates the utility of objective tests in diagnosing FVD. We use sweep visual evoked potentials and eye tracking as objective tests for visual acuity and visual field, respectively. These measurements should be made early in the diagnostic process because appropriate treatment becomes more difficult the longer the patient has been undergoing medical workups and referrals. Additionally, objective proof of better visual functions can be used as confirmation of the absence of a serious organic disorder. The results are used to convince patients and parents that vision is potentially much better than the patient experiences and to explain FVD. Consultation should preferably take place in a multidisciplinary setting with trained ophthalmologists and psychologists

Assessment of night vision problems in patients with congenital stationary night blindness

Congenital Stationary Night Blindness (CSNB) is a retinal disorder caused by a signal transmission defect between photoreceptors and bipolar cells. CSNB can be subdivided in CSNB2 (rod signal transmission reduced) and CSNB1 (rod signal transmission absent). The present study is the first in which night vision problems are assessed in CSNB patients in a systematic way, with the purpose of improving rehabilitation for these patients. We assessed the night vision problems of 13 CSNB2 patients and 9 CSNB1 patients by means of a questionnaire on low luminance situations. We furthermore investigated their dark adapted visual functions by the Goldmann Weekers dark adaptation curve, a dark adapted static visual field, and a two-dimensional version of the Light Lab . In the latter test, a digital image of a living room with objects was projected on a screen. While increasing the luminance of the image, we asked the patients to report on detection and recognition of objects. The questionnaire showed that the CSNB2 patients hardly experienced any night vision problems, while all CSNB1 patients experienced some problems although they generally did not describe them as severe. The three scotopic tests showed minimally to moderately decreased dark adapted visual functions in the CSNB2 patients, with differences between patients. In contrast, the dark adapted visual functions of the CSNB1 patients were more severely affected, but showed almost no differences between patients. The results from the 2D Light Lab showed that all CSNB1 patients were blind at low intensities (equal to starlight), but quickly regained vision at higher intensities (full moonlight). Just above their dark adapted thresholds both CSNB1 and CSNB2 patients had normal visual fields. From the results we conclude that night vision problems in CSNB, in contrast to what the name suggests, are not conspicuous and generally not disabling. © 2013 Bijveld et al. Congenital Stationary Night Blindness (CSNB) is a retinal disorder caused by a signal transmission defect between photoreceptors and bipolar cells. CSNB can be subdivided in CSNB2 (rod signal transmission reduced) and CSNB1 (rod signal transmission absent). The present study is the first in which night vision problems are assessed in CSNB patients in a systematic way, with the purpose of improving rehabilitation for these patients. We assessed the night vision problems of 13 CSNB2 patients and 9 CSNB1 patients by means of a questionnaire on low luminance situations. We furthermore investigated their dark adapted visual functions by the Goldmann Weekers dark adaptation curve, a dark adapted static visual field, and a two-dimensional version of the “Light Lab”. In the latter test, a digital image of a living room with objects was projected on a screen. While increasing the luminance of the image, we asked the patients to report on detection and recognition of objects. The questionnaire showed that the CSNB2 patients hardly experienced any night vision problems, while all CSNB1 patients experienced some problems although they generally did not describe them as severe. The three scotopic tests showed minimally to moderately decreased dark adapted visual functions in the CSNB2 patients, with differences between patients. In contrast, the dark adapted visual functions of the CSNB1 patients were more severely affected, but showed almost no differences between patients. The results from the “2D Light Lab” showed that all CSNB1 patients were blind at low intensities (equal to starlight), but quickly regained vision at higher intensities (full moonlight). Just above their dark adapted thresholds both CSNB1 and CSNB2 patients had normal visual fields. From the results we conclude that night vision problems in CSNB, in contrast to what the name suggests, are not conspicuous and generally not disabling

A Rare Form of Retinal Dystrophy Caused by Hypomorphic Nonsense Mutations in CEP290

Purpose: To identify the gene defect and to study the clinical characteristics and natural course of disease in a family originally diagnosed with oligocone trichromacy (OT), a rare congenital cone dysfunction syndrome. Methods: Extensive clinical and ophthalmologic assessment was performed on two siblings with OT and long-term follow up data were analyzed. Subsequently, whole exome sequencing (WES) and Sanger sequence analysis of CEP290 was performed in the two siblings. Additionally, the identified CEP290 mutations were analyzed in persons with achromatopsia (ACHM) (n = 23) and autosomal recessive or isolated cone dystrophy (CD; n = 145). Results: In the first decade of life, the siblings were diagnosed with OT based on low visual acuity, photophobia, nystagmus, and absent cone response on electroretinography , but with normal color discrimination. Over time, the phenotype of OT evolved to a progressive degenerative disease without any CEP290-associated non-ocular features. In both siblings, two nonsense mutations (c.451C&gt;T; p.(Arg151*) and c.4723A&gt;T; p.(Lys1575*)) in CEP290 were found. Previously, p.(Arg151*) was demonstrated to induce nonsense-mediated alternative splicing events leading to intact open reading frames of the resulting mRNA products (p.(Leu148_Glu165del) and p.(Leu148_Lys172del)). mRNA analysis for p.(Lys1575*) confirmed a suspected hypomorphic character, as exon 36 skipping was observed in a small fraction of CEP290 mRNA, resulting in a 36 aa in-frame deletion (p.(Glu1569_Trp1604del)). No additional cases carrying these variants were identified in the ACHM and CD cohorts. Conclusions: Compound heterozygous hypomorphic mutations in CEP290 may lead to a rare form of cone-dominated retinal dystrophy, a novel phenotype belonging to the CEP290-associated spectrum of ciliopathies. These findings provide insight into the effect of CEP290 mutations on the clinical phenotype

Ultrastructural localization of GPR179 and the impact of mutant forms on retinal function in CSNB1 patients and a mouse model

Complete congenital stationary night blindness (CSNB1) is characterized by loss of night vision due to a defect in the retinal ON-bipolar cells (BCs). Mutations in GPR179, encoding the G-protein-coupled receptor 179, have been found in CSNB1 patients. In the mouse, GPR179 is localized to the tips of ON-BC dendrites. In this study we determined the ultrastructural localization of GPR179 in human retina and determined the functional consequences of mutations in GPR179 in patients and mice. The localization of GRP179 was analyzed in postmortem human retinas with immunohistochemistry. The functional consequences of the loss of GPR179 were analyzed with standard and 15-Hz flicker ERG protocols. In the human retina, GPR179 is localized on the tips of ON-BC dendrites, which invaginate photoreceptors and terminate juxtaposed to the synaptic ribbon. The 15-Hz flicker ERG abnormalities found in patients with mutations in GPR179 more closely resemble those from patients with mutations in either TRPM1 or NYX than in GRM6. 15-Hz flicker ERG abnormalities of Gpr179(nob5) and Grm6(nob3) mice were comparable. GRP179 is expressed on dendrites of ON-BCs, indicating that GRP179 is involved in the ON-BCs' signaling cascade. The similarities of 15-Hz flicker ERGs noted in GPR179 patients and NYX or TRPM1 patients suggest that the loss of GPR179 leads to the loss or closure of TRPM1 channels. The difference between the 15-Hz flicker ERGs of mice and humans indicates the presence of important species differences in the retinal activity that this signal represent

Scotopic visual field results of the normal subjects, the CSNB2 patients, and the CSNB1 patients.

<p>A: The threshold found at each location of the scotopic visual field, plotted per subject. The open markers represent the average threshold found in that subject. The dashed lines indicate the measuring range, which was 28 to 75 dB in control subjects and CSNB2 patients, and 0 to 47 dB in CSNB1 patients. We found slightly elevated thresholds in CSNB2 patients compared to the thresholds of normal subjects. The thresholds were more elevated in the CSNB1 patients. B: The averaged thresholds of four locations at 7°, 45°, 60° and 75° on the horizontal axes per subject. Thresholds were slightly elevated towards the far end of the visual field in control subjects. We found an equal decline in the control subjects, the CSNB2 and the CSNB1 patients.</p

Genotype and phenotype of 101 dutch patients with congenital stationary night blindness

To investigate the relative frequency of the genetic causes of the Schubert-Bornschein type of congenital stationary night blindness (CSNB) and to determine the genotype-phenotype correlations in CSNB1 and CSNB2. Clinic-based, longitudinal, multicenter study. A total of 39 patients with CSNB1 from 29 families and 62 patients with CSNB2 from 43 families. Patients underwent full ophthalmologic and electrophysiologic examinations. On the basis of standard electroretinograms (ERGs), patients were diagnosed with CSNB1 or CSNB2. Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in NYX, TRPM1, GRM6, and GPR179 in patients with CSNB1 and CACNA1F and CABP4 in patients with CSNB2. Data included genetic cause of CSNB, refractive error, visual acuity, nystagmus, strabismus, night blindness, photophobia, color vision, dark adaptation (DA) curve, and standard ERGs. A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a "square-wave" appearance in CSNB1 and a decreased b-wave in CSNB2. Mutations causing CSNB1 were found in NYX (20 patients, 13 families), TRPM1 (10 patients, 9 families), GRM6 (4 patients, 3 families), and GPR179 (2 patients, 1 family). Congenital stationary night blindness 2 was primarily caused by mutations in CACNA1F (55 patients, 37 families). Only 3 patients had causative mutations in CABP4 (2 families). Patients with CSNB1 mainly had rod-related problems, and patients with CSNB2 had rod- and cone-related problems. The visual acuity on average was better in CSNB1 (0.30 logarithm of the minimum angle of resolution [logMAR]) than in CSNB2 (0.52 logMAR). All patients with CSNB1 and only 54% of the patients with CSNB2 reported night blindness. The dark-adapted threshold was on average more elevated in CSNB1 (3.0 log) than in CSNB2 (1.8 log). The 3 patients with CABP4 had a relative low visual acuity, were hyperopic, had severe nonspecific color vision defects, and had only 1.0 log elevated DA threshold. Congenital stationary night blindness 1, despite different causative mutations, shows 1 unique CSNB1 phenotype. Congenital stationary night blindness 2 caused by mutations in CABP4 merely shows cone-related problems and therefore appears to be distinct from CSNB2 caused by mutations in CACNA1F. The author(s) have no proprietary or commercial interest in any materials discussed in this articl