Dominant mutations in RP1L1 are responsible for occult macular dystrophy.

Occult macular dystrophy (OMD) is an inherited macular dystrophy characterized by progressive loss of macular function but normal ophthalmoscopic appearance. Typical OMD is characterized by a central cone dysfunction leading to a loss of vision despite normal ophthalmoscopic appearance, normal fluorescein angiography, and normal full-field electroretinogram (ERGs), but the amplitudes of the focal macular ERGs and multifocal ERGs are significantly reduced at the central retina. Linkage analysis of two OMD families was performed by the SNP High Throughput Linkage analysis system (SNP HiTLink), localizing the disease locus to chromosome 8p22-p23. Among the 128 genes in the linkage region, 22 genes were expressed in the retina, and four candidate genes were selected. No mutations were found in the first three candidate genes, methionine sulfoxide reductase A (MSRA), GATA binding 4 (GATA4), and pericentriolar material 1 (PCM1). However, amino acid substitution of p.Arg45Trp in retinitis pigmentosa 1-like 1 (RP1L1) was found in three OMD families and p.Trp960Arg in a remaining OMD family. These two mutations were detected in all affected individuals but in none of the 876 controls. Immunohistochemistry of RP1L1 in the retina section of cynomolgus monkey revealed expression in the rod and cone photoreceptor, supporting a role of RP1L1 in the photoreceptors that, when disrupted by mutation, leads to OMD. Identification of RP1L1 mutations as causative for OMD has potentially broader implications for understanding the differential cone photoreceptor functions in the fovea and the peripheral retina.

Molecular characteristics of four Japanese cases with KCNV2 retinopathy: report of novel disease-causing variants.

PURPOSE: To describe the molecular characteristics of four Japanese patients with cone dystrophy with supernormal rod responses (CDSRR). METHODS: Four individuals with a clinical and electrophysiological diagnosis of CDSRR were ascertained. The pathognomonic findings of the full-field electroretinograms (ERGs) included a decrease in the rod responses, a square-shaped a-wave, an excessive increase in the b-wave in the bright flash responses, and decreased cone-derived responses. Mutational screening of the coding regions and flanking intronic sequences of the potassium channel, subfamily V, member 2 (KCNV2) gene was performed with bidirectional sequencing. The segregation of each allele was confirmed by screening other family members. Subsequent in silico analyses of the mutational consequences for protein function were performed. RESULTS: There were two siblings from one family and one case in each of the two families. One family had a consanguineous marriage. Mutational screening revealed compound heterozygosity for the two alleles, p.C177R and p.G461R, in three patients, and homozygosity for complex alleles, p.R27H and p.R206P, in one patient from the consanguineous family. There were three putative novel variants, p.R27H, p.C177R, and p.R206P. The four variants in the families with KCNV2 were highly conserved in other species. In silico analyses predicted that all of the missense variants would alter protein function. CONCLUSIONS: Biallelic disease-causing variants were identified in four Japanese patients with CDSRR suggesting that the pathognomonic electrophysiological features are helpful in making a molecular diagnosis of KCNV2. Three novel variants were identified, and we conclude that there may be a distinct spectrum of KCNV2 alleles in the Japanese population.

[Long-term observation over ten years of four cases of cone dystrophy with supernormal rod electroretinogram].

BACKGROUND: 'Cone dystrophy with a supernormal rod electroretinogram (ERG)' is rare form of cone dystrophy, and no longitudinal description of the disease course has been reported in a Japanese population. Here, we describe long-term courses of 10 to 15 years in four Japanese patients with mutations in the KCNV2 gene. CASES: Four patients from three families were recruited. Two were siblings (Case 1, 24 y/o women; Case 2, 17 y/o man), and two were sporadic cases (Case 3, 17 y/o women; Case 4, 21 y/o women). All the patients presented with characteristic ERG findings. There were minimal abnormalities in fundus appearance: slight mottling of retinal pigment epithelium in the macula in all four cases, and granular change in the macula in Case 4. The visual acuity in Cases 1 and 2 did not change during the follow-up period, but the acuity in Cases 3 and 4 gradually decreased. Photoreceptor abnormalities in optical coherence tomography were found in all the cases, but were more severe in Cases 3 and 4. CONCLUSION: The long-term courses in Japanese patients were variable. The OCT was helpful in evaluating the disease progression.

Highly reflective foveal region in optical coherence tomography in eyes with vitreomacular traction or epiretinal membrane.

OBJECTIVE: To report the optical coherence tomography (OCT) findings in eyes with vitreomacular traction (VMT) or with an epiretinal membrane (ERM). DESIGN: Retrospective case series. PARTICIPANTS: Fifty-four eyes of 45 consecutive patients with subjective visual disturbances resulting from VMT or idiopathic ERM were studied. METHODS: The morphologic features of the photoreceptor layer at the foveal center were determined and the central foveal thickness (CFT) was measured by spectral-domain (SD) OCT. MAIN OUTCOME MEASURES: The morphologic characteristics of the foveal region observed by SD OCT. RESULTS: A roundish or diffuse highly reflective region was observed between the photoreceptor inner segment/outer segment junction line and the cone outer segment tip line at the center of the fovea. This highly reflective region was present in 7 of 7 cases of VMT and 30 of 47 cases of ERM. In the ERM cases, the mean CFT of the cases with the highly reflective region was significantly thicker than that in cases without it. The highly reflective region disappeared when the inward traction on the fovea was released surgically or spontaneously. CONCLUSIONS: The highly reflective region is a characteristic sign observed in the OCT images of eyes with VMT and ERM, and it has been termed the cotton ball sign after its appearance. The presence of the cotton ball sign indicates an inward traction on the fovea and may be a predictor of visual impairment.

Clinical characteristics of occult macular dystrophy in family with mutation of RP1l1 gene.

PURPOSE: To report the clinical characteristics of occult macular dystrophy (OMD) in members of one family with a mutation of the RP1L1 gene. METHODS: Fourteen members with a p.Arg45Trp mutation in the RP1L1 gene were examined. The visual acuity, visual fields, fundus photographs, fluorescein angiograms, full-field electroretinograms, multifocal electroretinograms, and optical coherence tomographic images were examined. The clinical symptoms and signs and course of the disease were documented. RESULTS: All the members with the RP1L1 mutation except one woman had ocular symptoms and signs of OMD. The fundus was normal in all the patients during the entire follow-up period except in one patient with diabetic retinopathy. Optical coherence tomography detected the early morphologic abnormalities both in the photoreceptor inner/outer segment line and cone outer segment tip line. However, the multifocal electroretinograms were more reliable in detecting minimal macular dysfunction at an early stage of OMD. CONCLUSION: The abnormalities in the multifocal electroretinograms and optical coherence tomography observed in the OMD patients of different durations strongly support the contribution of RP1L1 mutation to the presence of this disease.

Neuroblastoma amplified sequence gene is associated with a novel short stature syndrome characterised by optic nerve atrophy and Pelger-Huët anomaly.

BACKGROUND: Hereditary short stature syndromes are clinically and genetically heterogeneous disorders and the cause have not been fully identified. Yakuts are a population isolated in Asia; they live in the far east of the Russian Federation and have a high prevalence of hereditary short stature syndrome including 3-M syndrome. A novel short stature syndrome in Yakuts is reported here, which is characterised by autosomal recessive inheritance, severe postnatal growth retardation, facial dysmorphism with senile face, small hands and feet, normal intelligence, Pelger-Huët anomaly of leucocytes, and optic atrophy with loss of visual acuity and colour vision. This new syndrome is designated as short stature with optic atrophy and Pelger-Huët anomaly (SOPH) syndrome. AIMS: To identify a causative gene for SOPH syndrome. METHODS: Genomewide homozygosity mapping was conducted in 33 patients in 30 families. RESULTS: The disease locus was mapped to the 1.1 Mb region on chromosome 2p24.3, including the neuroblastoma amplified sequence (NBAS) gene. Subsequently, 33 of 34 patients were identified with SOPH syndrome and had a 5741G/A nucleotide substitution (resulting in the amino acid substitution R1914H) in the NBAS gene in the homozygous state. None of the 203 normal Yakuts individuals had this substitution in the homozygous state. Immunohistochemical analysis revealed that the NBAS protein is well expressed in retinal ganglion cells, epidermal skin cells, and leucocyte cytoplasm in controls as well as a patient with SOPH syndrome. CONCLUSION: These findings suggest that function of NBAS may associate with the pathogenesis of short stature syndrome as well as optic atrophy and Pelger-Huët anomaly.

Clinical Stages of Occult Macular Dystrophy Based on Optical Coherence Tomographic Findings.

Purpose: To determine the course of occult macular dystrophy (OMD, Miyake's disease) and to propose stages of OMD based on the optical coherence tomographic (OCT) findings. Methods: Sixty-one patients from 33 families with OMD who carried one of the proven variants of the RP1L1 gene were studied at seven centers in Japan. Ophthalmological examinations including the best-corrected visual acuity (BVCA) and OCT were performed. Results: The median age at the last visit was 50 years with a range of 10 to 88 years, and the median age at the symptom onset was 30 years with a range of 3 to 60 years. There were significant negative correlations between the duration of OMD and BCVA, the central retinal thickness (CRT) and the thickness between external limiting membrane and retinal pigment epithelium (ERT). The BCVA gradually decreased for 10 years after symptom onset and was stable thereafter. Kaplan-Meier survival curves of the BCVA and retinal thickness showed that all of the patients had retained a vision of 1.0 logMAR, and over 80% of the patients had retained 50% thickness of the normal CRT and ERT for at least 60 years after symptom onset. The stages of OMD based on the visual symptoms and OCT findings are proposed. Conclusions: The photoreceptors do not become completely atrophic even at the late stage, which may account for the good retinal pigment epithelium (RPE) structure and normal-appearing fundus. The proposed stages facilitate the investigation of the pathogenicity of OMD and provide information to determine the effectiveness of therapeutic procedures.

Pupillography of relative afferent pupillary defects in amblyopia associated with peripapillary myelinated nerve fibers and myopia.

Pupillary responses to light were recorded in three patients with unilateral extensive myelinated nerve fibers and amblyopia by means of binocular infrared video pupillography. All of the patients had an afferent pupillary defect in the eye with myelinated nerve fibers. This finding supports the notion that this type of amblyopia is a severe form of anisometropic amblyopia that is often resistant to treatment.

Negative scotopic ERG and photopic ERG ON response impairment in a patient with normal dark adaptation.

PURPOSE: To present ocular findings in a patient who showed negative scotopic electroretinogram (ERG) and reduced ON response, but normal dark adaptation. CASE: An 18-year-old Japanese male patient who complained of severe asthenopia. His corrected visual acuities were 1.2 in both eyes. His fundi were normal. He had normal contrast sensitivity and normal dark adaptation. METHODS: The patients underwent ERG (including the standard protocol and photopic long flash recordings). RESULTS: The amplitudes of the rod ERG b-wave were reduced. The scotopic standard combined ERG response showed negative configuration. The photopic response to long flash revealed the reduced b-wave (ON response), while the amplitude of the first peak of the d-wave (OFF response) was within the normal range. CONCLUSIONS: Postsynaptic abnormalities in both the rod and cone ON-pathways, which are often found in patients with night blindness, were suggested in the ERG findings, but the dark adaptation of our patient was normal. Neuromuscular evaluation of the patient and ophthalmological evaluation, including ERG, of his parents were normal. To our knowledge, the ophthalmological and electrophysiological findings of our patient cannot be attributed to any known clinical entity.

Pupillography of relative afferent pupillary defect contralateral to monocular mature cataract.

CASE REPORT: Few previous reports have documented a relative afferent pupillary defect (RAPD) in the eye contralateral to a dense unilateral cataract. We report pupillographic findings of a 55-year-old man with a mature cataract in the left eye and an RAPD in the right eye, whose RAPD disappeared after cataract surgery in his left eye. Using binocular infrared video pupillography, we recorded the pupillary responses of the two eyes simultaneously during an automated swinging flashlight test before and after the cataract surgery. The average contraction amplitude in both eyes was significantly larger when the unaffected left eye was stimulated before the cataract surgery, but this difference in contraction amplitude disappeared after surgery on the left eye. COMMENTS: An RAPD was shown quantitatively with a pupillographic technique in the eye contralateral to a mature cataract, confirming previous studies that indicate a dense cataract may produce a small but definite RAPD in the contralateral eye. Such an RAPD associated with a dense cataract must be taken into consideration when evaluating patients with unilateral visual loss.

Involvement of brain-derived neurotrophic factor in early retinal neuropathy of streptozotocin-induced diabetes in rats: therapeutic potential of brain-derived neurotrophic factor for dopaminergic amacrine cells.

Although neurotrophins have been assessed as candidate therapeutic agents for neural complications of diabetes, their involvement in diabetic retinopathy has not been fully characterized. We found that the protein and mRNA levels of brain-derived neurotrophic factor (BDNF) in streptozotocin-induced diabetic rat retinas were reduced to 49% (P < 0.005) and 74% (P < 0.05), respectively, of those of normal control animals. In addition, dopaminergic amacrine cells appeared to be degenerating in the diabetic rat retinas, as revealed by tyrosine hydroxylase (TH) immunoreactivity. Overall TH protein levels in the retina were decreased to one-half that of controls (P < 0.01), reflecting reductions in the density of dopaminergic amacrine cells and the intensity of TH immunoreactivity within them. To confirm the neuropathological implications of BDNF reduction, we administered BDNF protein into the vitreous cavities of diabetic rats. Intraocular administration of BDNF rescued dopaminergic amacrine cells from neurodegeneration and counteracted the downregulation of TH expression, demonstrating its therapeutic potential. These findings suggest that the early retinal neuropathy of diabetes involves the reduced expression of BDNF and can be ameliorated by an exogenous supply of this neurotrophin.

Near-infrared spectroscopy of the visual cortex in unilateral optic neuritis.

PURPOSE: To examine the occipital-lobe activation of patients with optic neuritis using near-infrared spectroscopy. DESIGN: Experimental study. METHODS: NIRS was performed on five patients with acute unilateral optic neuritis during monocular visual stimulation. As controls, six normal subjects were also tested in the same manner. RESULTS: In the patients with optic neuritis, the changes in the hemoglobin concentrations (oxyhemoglobin, deoxyhemoglobin, and total hemoglobin) in the occipital lobe were found to be markedly reduced when the clinically affected eyes were stimulated compared with the fellow eyes. The response induced by the stimulation of the affected eye was decreased, even when the patient's visual acuity improved to 20/20 in the recovery phase. There was no difference in the concentration changes between the two eyes in the control subjects. CONCLUSIONS: NIRS may be useful in detecting visual dysfunction objectively and noninvasively in patients with visual disturbance, especially when used at the bedside.

Rod and cone a-waves in central retinal vein occlusion.

PURPOSE: To evaluate rod and cone a-waves in cases with unilateral central retinal vein occlusion (CRVO). METHODS: Scotopic and photopic flash electroretinograms (ERGs) were recorded in seven patients aged 54-84 with unilateral hemorrhagic CRVO. Rod and cone a-waves were analyzed using photoreceptor models, and Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. RESULTS: Decreased rod log S was found in all seven cases, and decreased cone log S was found in five cases. In only one case, rod log S in the fellow eye was decreased. The alterations in rod and cone log Rm(p3) were smaller than those in rod and cone log S. Of three cases in which ERGs could be recorded again after a certain follow-up period, rod log S and cone logS became larger in two cases and smaller in one case. CONCLUSIONS: The change in the phototransduction cascade was confirmed not only in rods but also in cones in five of our seven cases of CRVO. The ERG findings might reflect the functional change in the photoreceptor layer after the onset of CRVO.

[Evaluation of macula in patients with branch retinal vein occlusion using multifocal electroretinogram and optical coherence tomography].

PURPOSE: To evaluate the functions of the macular area in patients with branch retinal vein occlusion (BRVO) by using multifocal electroretinograms (mERG) and optical coherence tomography(OCT). METHODS: mERGs were recorded from 18 eyes of 18 patients with BRVO. An array of 103 hexagonal elements was displayed on a monitor. The latency (ms) and response density (nV/deg2) of mERGs were measured for 7 central locations. The peak and troughs were labeled N1, P1 and N2, respectively. OCT was used to measure the foveal retinal thickness. RESULTS: Statistically significant correlation was found between visual acuity(log MAR) and P1-N1 response density (r = - 0.629, p < 0.05) and N2 latency(r = 0.619, p < 0.05). Foveal retinal thickness had the significant statistic correlations with P1-N1 response density (r = -0.750, p < 0.0001), P1-N2 response density (r = -0.520, p < 0.05) and N2 latency (r = 0.488, p < 0.05). CONCLUSIONS: In 18 BRVO patients, mERGs from the central retinal area were significantly correlated with foveal retinal thickness measured by OCT and with visual acuity. The mERG recording is sensitive to morphological changes and functional disorders induced by BRVO.

[Multifocal visually evoked responses in two children with optic neuritis].

PURPOSE: Central visual functions of two children with idiopathic optic neuritis were analyzed and followed in the course of the disease by using multifocal visually evoked potentials (mVEP) and other ophthalmological tests. SUBJECTS AND METHODS: Two girls 10 and 11 years of age with unilateral optic neuritis participated in this study. At the initial onset of the disease, visual acuity of the patients was below 20/400 and severe central visual field impairment was found in the affected eyes. There were no abnormal neurological or radiological findings suggesting multiple sclerosis in these patients. The mVEPs were recorded with a stimulus of 37 hexagons composed of black and white triangles subtending 35 degrees of visual angle. RESULTS: The amplitude of mVEPs from many stimulating locations was severely reduced in the course of the recovery of these patients. Although visual acuity and perimetric sensitivity in the affected eyes recovered to normal after steroid pulse therapy, the amplitude of mVEPs still remained 1/3 to 1/2 of that of the opposite healthy eye. The mVEPs gradually recovered to near the level of the opposite healthy eyes at the latest examination. CONCLUSIONS: Recovery from the central visual impairment due to infantile optic neuritis is more gradual than that suggested by subjective ophthalmological examinations. There is still optic nerve dysfunction after visual acuity and visual field have recovered to normal. The mVEP is one of the most sensitive tools for detecting optic nerve dysfunction in patients with optic neuritis.

Central and peripheral visual interactions in disparity-induced vergence eye movements: I. Spatial interaction.

PURPOSE: To evaluate the interaction between central and peripheral disparities in the initiation of vergence eye movements. METHODS: Eye movements were recorded in eight normal subjects using an infrared limbus tracker. Three-dimensional visual stimuli were back projected onto a tangent screen by using two liquid crystal display (LCD) projectors through crossed polarizers. The central target was a vertical bar, which always jumped from 2 to 1 m. The peripheral target was a random-dot pattern that jumped from 2 to 0.75, 1, or 1.5 m (near planes), 2 m (no change), or 3 m (far plane) simultaneously with the central target jump. Latency, amplitude at 150 ms, and average amplitude over 1 to 2 seconds after vergence onset; peak velocity; and the main-sequence relationship of the initial vergence response were calculated. How far the central target appeared to jump was scored subjectively. RESULTS: In half of the subjects, there was a clear effect of the peripheral disparity on the dynamics of the vergence response to the central disparity. The amplitude of vergence at 150 ms, as an index of open-loop gain, was significantly greater when the peripheral target moved closer, but steady state amplitude (average during 1-2 seconds) did not change, and the vergence latency was significantly greater when the peripheral target jumped away. There was no obvious relationship between the perceived amount of movement of the central target and the parameters of the dynamic properties of the vergence response. CONCLUSIONS: Peripheral disparity can modulate the dynamics of the initial vergence response to a central disparity and is probably independent of the perception of motion in depth.

ERG rod a-wave in Oguchi disease.

We analyzed the change in the ERG rod a-wave waveform during the course of dark adaptation in two patients with Oguchi disease. Two Japanese patients showed a homozygous arrestin 1147delA mutation. Scotopic flash ERGs were recorded after different periods of dark adaptation. ERG rod a-waves were obtained after subtraction of the cone ERG contribution. The rod a-waves were fitted with a model of the rod receptor signal. The parameters, Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. Longer periods in the dark produced larger rod a-wave but only to the first flash presented. The amplitude of the response to subsequent flashes was essentially independent of the period of dark adaptation. Rm(p3) increased with advance of dark adaptation. However, S was nearly constant. Our results suggest that the cause of delayed dark adaptation is not to be sought in the activation of phototransduction process or the regeneration of rhodopsin per se but rather in the deactivation process of the phototransduction cascade.

Pupillary and cardiovascular responses to a video movie in senior human subjects.

The effects of watching video movies on autonomic functions were estimated by measuring changes in pupillary and cardiovascular parameters in 10 senior subjects. The subjects looked at a series of video images (with accompanied sounds) taken during the execution of motor vehicles. The images were rear-projected on a large screen for 15 min. Pupil diameter and parameters of the light reflex were measured by an infrared pupillometer before and after the video presentation. Their electrocardiograms (ECG) and blood pressure were measured continuously. Subjects were divided into two groups depending on their values of blood pressure and fasting plasma glucose level. Subjects in Group A had blood pressures of less than 140 mm Hg and a fasting plasma glucose level of less than 7 mmol/dl (normal group). Other subjects were included in Group B (mild hypertension or diabetes mellitus group). While changes in pupillary light reflex after video viewing were minimal in the members of Group A, amplitudes of the pupillary reflex in the members of Group B varied over a significantly wide range. By the spectral analysis of cardiovascular rhythm, %LF and %HF components of blood pressure rhythm were significantly different between the two groups before video viewing. However, the ratios of frequency components before and after video viewing were not significantly different between the two groups. Our findings suggest that pupillary light reflex was less precisely controlled in subjects with mild autonomic dysfunction after prolonged audiovisual stimulation.

Electroretinographic findings in three family members with X-linked juvenile retinoschisis associated with a novel Pro192Thr mutation of the XLRS1 gene.

PURPOSE: To present ocular findings in three family members with X-linked juvenile retinoschisis (XLRS) associated with a novel Pro192Thr mutation. CASES: We examined 21- (Case 1), 17- (Case 2), and 10-year-old (Case 3) male patients who showed wheel-like cystic lesions in the macula and a silver-gray reflex in the peripheral retina. Case 2 was a cousin of Case 1. Case 3 was a brother of Case 2. METHODS: Scotopic electroretinogram (ERG) (dim and bright flash), oscillatory potentials, photopic ERG, and 30-Hz flicker responses were recorded in each patient. The XLRS1 gene was analyzed in patient blood samples by a direct sequencing method. RESULTS: A novel missense mutation (Pro192Thr) was identified in the XLRS1 gene in each patient. Variable b/a ratios upon scotopic bright flash stimulation were evident (Case 1: right 1.16, left 1.20; Case 2: right 0.98, left 1.01; Case 3: right 0.81, left 0.83). Only Case 3 showed the typical "negative" waveform. The amplitude of rod b-waves was significantly decreased in all patients. CONCLUSIONS: Three cases with a novel Pro192Thr mutation showed the phenotypic variation in ERG, especially in b/a ratio, which has been considered an important diagnostic parameter.