Tomoaki Usui

Spatial cone activity distribution in diseases of the posterior pole determined by multifocal electroretinography

Thirty patients with a reduced central vision due to diseases of the posterior pole were examined with the VERIS system developed by Sutter and Tran (Vis Res 1992;32:433-446) to characterize the topography of electroretinographic (ERG) changes in comparison to the results in 30 normal volunteers. Diagnoses included Stargardts macular dystrophy (SMD, n = 10), age-related macular degeneration (AMD, n = 5), cone dystrophy (CD, n = 5), central retinal vein occlusion (CRVO, n = 5), and autosomal dominant optic atrophy (ADOA, n = 5). The 61 local responses obtained from each subjects were grouped by eccentricity to form five concentric rings. The foveal ERG, originating from a central area of 2 degrees radius, was non-recordable or markedly diminished in all patients except those with optic atrophy, where amplitudes were found to be in the normal range. In patients with advanced stages of SMD, functional defects were larger and involved more peripheral areas than in patients with early stages of SMD or with AMD. A reduction of response amplitude even in the most peripheral ring (17-30.5 degrees eccentricity) was found in cone dystrophies and--moderately--in patients with advanced SMD and central retinal vein occlusion only. Prolonged implicit times were found in all but the patients in early stages of SMD and they were maximal in patients with CRVO. This study shows that the multifocal ERG (MFERG) can contribute to differential diagnosis of retinal diseases of the posterior pole especially in cases with a normal photopic Ganzfeld ERG.

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.

Mutations in the gene coding for guanylate cyclase-activating protein 2 (GUCA1B gene) in patients with autosomal dominant retinal dystrophies.

BackgroundWe investigated mutations in the gene coding for guanylate-cyclase activating protein 2 (GCAP2), also known as GUCA1B gene, in Japanese patients with retinitis pigmentosa (RP) and tried to identify phenotypic characteristics associated with mutations in the gene.Subjects and methodsGenomic DNA samples from 63 unrelated patients with autosomal dominant retinitis pigmentosa (ADRP) and 33 patients with autosomal recessive retinitis pigmentosa (ARRP) were screened by single-strand conformational polymorphism analysis followed by direct sequencing. Clinical features associated with a mutation were demonstrated by visual acuity, visual field testing, fundus photography, and electroretinography.ResultsA novel transitional mutation converting GGA to AGA at codon 157 (G157R) was identified. This mutation has been found in three index patients from three independent families. Phenotypic examination of seven members of the three families revealed that this mutation was associated with RP with or without macular involvement in five members, macular degeneration in one member, and asymptomatic normal phenotype in one member. In addition, previously unknown polymorphic changes including V29V, Y57Y, T87I, and L180L were identified.ConclusionsA racial difference exists in the spectrum of mutations and/or polymorphisms in the GCAP 2 gene between British and Japanese populations. Our findings suggest that the mutation in the GCAP 2 gene can cause one form of autosomal dominant retinal dystrophy, with variable phenotypic expression and incomplete penetrance.

Flicker cone electroretinogram in dichromats and trichromats

To measure cone signal strengths in the flicker electroretinogram (ERG) of dichromats and trichromats, we developed a set of flickering stimuli (30 Hz), which excite the middle-wavelength-sensitive (M-) and long-wavelength-sensitive (L-) cones independently. ERG responses to eight different ratios of L- to M-cone contrasts were recorded from each subject. The short-wavelength-sensitive (S-) cone contrast was 0% in all measurements. The recordings were Fourier analyzed to determine the amplitude of the fundamental component. ERG threshold values for each subject resulted in ellipses when plotted in an L-/M-cone contrast space. As expected, the orientations of the threshold ellipses of the protanopes (N = 2) were parallel to the L-cone axis, whereas those of the deuteranopes (N = 2) were parallel to the M-cone axis. For the trichromats (N = 5), there was considerable interindividual variation in ellipse orientation.

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.

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.

Response phase of the flicker electroretinogram (ERG) is influenced by cone excitation strength

We measured electroretinogram (ERG) response phases at different cone contrasts in trichromats and dichromats to investigate the dynamics of the long-wavelength-sensitive (L-) and middle-wavelength-sensitive (M-) cone pathways. ERG responses to stimuli, temporally modulated at 30 Hz, were recorded. The stimuli were generated on a computer controlled colour monitor. Thirty-two different combinations of L- and M-cone excitation strength, expressed as cone contrasts, were presented. The short-wavelength-sensitive (S-) cones were not stimulated (S-cone contrast = 0%). The response phase of the fundamental stimulus component was obtained from Fourier analysis. The ERG response phase lags decreased with increasing cone contrast. This was observed in all subjects with a normal appearing fundus. In dichromats and trichromats at low and intermediate contrasts, the phase lags to M-cone isolating conditions were smaller than those to L-cone isolating stimuli. In one dichromat with extreme myopia and cupping of the optic disc, the ERG phase lags increased with increasing cone contrast. The ERG response phase may be potentially useful for detecting retinal abnormalities.

Rod and cone a-waves in three cases of bietti crystalline chorioretinal dystrophy

PURPOSE To estimate retinal function in Bietti crystalline chorioretinal dystrophy using the electroretinogram. METHODS In this observational case series, the scotopic and photopic electroretinograms in three Japanese female patients (case 1, 55 years old; case 2, 56 years old; case 3, 47 years old) who showed bilateral crystalline retinal deposits but no corneal deposits were recorded. The rod and cone a-waves were analyzed by using the method described by Hood and Birch (1995, 1997). The parameters Rm(p3) (maximum a-wave amplitude) and S (sensitivity) were calculated. RESULTS In case 1, the rod Rm(p3) was decreased in both eyes. The rod S in the right eye was within the normal range, but that in the left eye was significantly reduced. Although the cone Rm(p3) was decreased, the cone S was within the normal range. In case 2, the rod and cone Rm(p3) was reduced, but the rod and cone S was within the normal range in both eyes. In case 3, the rod and cone Rm(p3) and S were within the normal range. CONCLUSIONS Electroretinograms illustrated different disease stages, however, no eye with normal Rm(p3) and decreased S was found in rods and cones. In the early stages of this disease, decreased numbers of photoreceptors and/or outer segment shortening may be present while phototransduction remains normal. As the damage to the retina progresses, phototransduction becomes severely affected. Because reduced cone S was not observed in our cases, cones may be less involved than rods in this disease.

ERG campimetry using a multi-input stimulation technique for mapping of retinal function in the central visual field.

The m-sequence stimulation technique that has previously been described allows simultaneous recording of many local electroretinograms (ERGs). For topographical mapping of cone function in the central retina ERG traces from 61 retinal areas were recorded during a 4-min period in 20 normal volunteers and 4 patients with age-related macular degeneration, Stargardts disease, choroidal atrophy, and polymyalgia associated with visual field loss. The local photopic luminance response was analyzed in each of the 61 areas. In the 2 patients with macular disease central defects were detected, in the remaining patients local defects were found outside the macular region. The method of multifocal ERG recordings provides the possibility of objective testing of visual fields when the outer retinal layers are affected.

Visual Disturbance in Patients with Melanocytoma of the Optic Disk

Visual disturbance in 11 patients with melanocytoma of the optic disk was analyzed. Goldmann visual field examination showed enlargement of Mariottes blind spot in 7 of 10 patients (70%) and visual field defect or depression in 7 patients (70%). In 6 of the 7 patients with visual field defect of depression (86%), the portion of visual field damage corresponded with the location of the tumor and retinal nerve fiber bundle defect. In 1 patient, sudden loss of visual acuity occurred, presumably due to anterior ischemic optic neuropathy induced by melanocytoma.