Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo.

Rod tetrameric arrestin 1 (tet-ARR1), stored in the outer nuclear layer/inner segments in the dark, modulates photoreceptor synaptic activity; light exposure stimulates a reduction via translocation to the outer segments for terminating G-protein coupled phototransduction signaling. Here, we test the hypothesis that intraretinal spin-lattice relaxation rate in the rotating frame (1/T1ρ), an endogenous MRI contrast mechanism, has high potential for evaluating rod tet-ARR1 and its reduction via translocation. Dark- and light-exposed mice (null for the ARR1 gene, overexpressing ARR1, diabetic, or wild type with or without treatment with Mn2+, a calcium channel probe) were studied using 1/T1ρ MRI. Immunohistochemistry and single-cell recordings of the retinas were also performed. In wild-type mice with or without treatment with Mn2+, 1/T1ρ of avascular outer retina (64% to 72% depth) was significantly (P < 0.05) greater in the dark than in the light; a significant (P < 0.05) but opposite pattern was noted in the inner retina (<50% depth). Light-evoked outer retina Δ1/T1ρ was absent in ARR1-null mice and supernormal in overexpressing mice. In diabetic mice, the outer retinal Δ1/T1ρ pattern suggested normal dark-to-light tet-ARR1 translocation and chromophore content, conclusions confirmed ex vivo. Light-stimulated Δ1/T1ρ in inner retina was linked to changes in blood volume. Our data support 1/T1ρ MRI for noninvasively assessing rod tet-ARR1 and its reduction via protein translocation, which can be combined with other metrics of retinal function in vivo.

Primate short-wavelength cones share molecular markers with rods.

Macaca, Callithrix jacchus marmoset monkey, Pan troglodytes chimpanzee and human retinas were examined to define if short wavelength (S) cones share molecular markers with L&M cone or rod photoreceptors. S cones showed consistent differences in their immunohistochemical staining and expression levels compared to L&M cones for "rod" Arrestin1 (S-Antigen), "cone" Arrestin4, cone alpha transducin, and Calbindin. Our data verify a similar pattern of expression in these primate retinas and provide clues to the structural divergence of rods and S cones versus L&M cones, suggesting S cone retinal function is "intermediate" between them.

Combined rod and cone transduction by adeno-associated virus 2/8.

Gene transfer to both cone and rod photoreceptors (PRs) is essential for gene therapy of inherited retinal degenerations that are caused by mutations in genes expressed in both PR types. Vectors based on the adeno-associated virus (AAV) efficiently transduce PRs of different species. However, these are predominantly rods and little is known about the ability of the AAV to transduce cones in combination with rods. Here we show that AAV2/8 transduces pig cones to levels that are similar to AAV2/9, and the outer nuclear layer (mainly rods) to levels that are on average higher, although not statistically significant, than both AAV2/5 and AAV2/9. We additionally found that the ubiquitous cytomegalovirus (CMV), but not the PR-specific GRK1 promoter, transduced pig cones efficiently, presumably because GRK1 is not expressed in pig cones as observed in mice and humans. Indeed, the GRK1 and CMV promoters transduce a similar percentage of murine cones with the CMV reaching the highest expression levels. Consistent with this, the AAV2/8 vectors with either the CMV or the GRK1 promoter restore cone function in a mouse model of Leber congenital amaurosis type 1 (LCA1), supporting the use of AAV2/8 for gene therapy of LCA1 as well as of other retinal diseases requiring gene transfer to both PR types.

CNG-modulin: a novel Ca-dependent modulator of ligand sensitivity in cone photoreceptor cGMP-gated ion channels.

The transduction current in several different types of sensory neurons arises from the activity of cyclic nucleotide-gated (CNG) ion channels. The channels in these sensory neurons vary in structure and function, yet each one demonstrates calcium-dependent modulation of ligand sensitivity mediated by the interaction of the channel with a soluble modulator protein. In cone photoreceptors, the molecular identity of the modulator protein was previously unknown. We report the discovery and characterization of CNG-modulin, a novel 301 aa protein that interacts with the N terminus of the ß subunit of the cGMP-gated channel and modulates the cGMP sensitivity of the channels in cone photoreceptors of striped bass (Morone saxatilis). Immunohistochemistry and single-cell PCR demonstrate that CNG-modulin is expressed in cone but not rod photoreceptors. Adding purified recombinant CNG-modulin to cone membrane patches containing the native CNG channels shifts the midpoint of cGMP dependence from ∼91 µM in the absence of Ca(2+) to ∼332 µM in the presence of 20 µM Ca(2+). At a fixed cGMP concentration, the midpoint of the Ca(2+) dependence is ∼857 nM Ca(2+). These restored physiological features are statistically indistinguishable from the effects of the endogenous modulator. CNG-modulin binds Ca(2+) with a concentration dependence that matches the calcium dependence of channel modulation. We conclude that CNG-modulin is the authentic Ca(2+)-dependent modulator of cone CNG channel ligand sensitivity. CNG-modulin is expressed in other tissues, such as brain, olfactory epithelium, and the inner ear, and may modulate the function of ion channels in those tissues as well.

Potential cellular functions of N-ethylmaleimide sensitive factor in the photoreceptor.

Recent work has established potential new functional roles for NSF in the photoreceptor. First, the interaction of Arr1 and NSF is ATP-dependent, and the N-terminal domain of Arr1 interacts with the N and D1 junctional domains of NSF. The Arr1-NSF interactions are greater in the photoreceptor synaptic terminal in the dark. Furthermore, Arr1 enhances the NSF ATPase activity and increases the NSF disassembly activities, which are critical for NSF functions in sustaining a higher rate of exocytosis in the photoreceptor synapses and the compensatory endocytosis to retrieve vesicle membrane and vesicle proteins for vesicle recycling. These data demonstrate the Arr1 and NSF interaction are necessary for both maintenance and modulation of normal photoreceptor synaptic regulation. Second, NSF colocalizes and specifically binds to RP2, especially in the ciliary and synaptic region of the photoreceptor, and NSF-RP2 interaction may play an important role in membrane protein trafficking in the photoreceptor. Inherited retinal degeneration affects about 1 in 2,000-3,000 individuals in the world and is the leading cause of visual loss in young people and accounts for a large proportion of blindness in adult life. These studies accelerate our ability to gain insight into the diverse roles of the NSF in the photoreceptor cells and enable us to understand more precisely the molecular mechanisms underlying night blindness associated with clinically diagnosed Oguchi disease or other forms of retinitis pigmentosa.

(1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent γ-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction.

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at (1)/(300) to (1)/(600) the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose (1)/(300) that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, 1 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.

TMEM237 is mutated in individuals with a Joubert syndrome related disorder and expands the role of the TMEM family at the ciliary transition zone.

Joubert syndrome related disorders (JSRDs) have broad but variable phenotypic overlap with other ciliopathies. The molecular etiology of this overlap is unclear but probably arises from disrupting common functional module components within primary cilia. To identify additional module elements associated with JSRDs, we performed homozygosity mapping followed by next-generation sequencing (NGS) and uncovered mutations in TMEM237 (previously known as ALS2CR4). We show that loss of the mammalian TMEM237, which localizes to the ciliary transition zone (TZ), results in defective ciliogenesis and deregulation of Wnt signaling. Furthermore, disruption of Danio rerio (zebrafish) tmem237 expression produces gastrulation defects consistent with ciliary dysfunction, and Caenorhabditis elegans jbts-14 genetically interacts with nphp-4, encoding another TZ protein, to control basal body-TZ anchoring to the membrane and ciliogenesis. Both mammalian and C. elegans TMEM237/JBTS-14 require RPGRIP1L/MKS5 for proper TZ localization, and we demonstrate additional functional interactions between C. elegans JBTS-14 and MKS-2/TMEM216, MKSR-1/B9D1, and MKSR-2/B9D2. Collectively, our findings integrate TMEM237/JBTS-14 in a complex interaction network of TZ-associated proteins and reveal a growing contribution of a TZ functional module to the spectrum of ciliopathy phenotypes.

Exaggerated eye growth in IRBP-deficient mice in early development.

PURPOSE: Because interphotoreceptor retinoid-binding protein (IRBP) is expressed before being needed in its presumptive role in the visual cycle, we tested whether it controls eye growth during development. METHODS: The eyes of congenic IRBP knockout (KO) and C57BL/6J wild-type (WT) mice ranging in age from postnatal day (P)2 to P440 were compared by histology, laser micrometry, cycloplegic photorefractions, and partial coherence interferometry. RESULTS: The size and weight of IRBP KO mouse eyes were greater than those of the WT mouse, even before eye-opening. Excessive ocular enlargement started between P7 and P10, with KO retinal arc lengths becoming greater compared with WT from P10 through P30 (18%; P < 0.01). The outer nuclear layer (ONL) of KO retinas became 20% thinner between P12 to P25, and progressed to 38% thinner at P30. At P30, there were 30% fewer cones per vertical section in KO than in WT retinas. Bromodeoxyuridine (BrdU) labeling indicated the same number of retinal cells were born in KO and WT mice. A spike in apoptosis was observed in KO outer nuclear layer at P25. These changes in size were accompanied by a large decrease in hyperopic refractive error, which reached -4.56 ± 0.70 diopters (D) versus +9.98 ± 0.993 D (mean ± SD) in WT, by postnatal day 60 (P60). CONCLUSIONS; In addition to its role in the visual cycle, IRBP is needed for normal eye development. How IRBP mediates ocular development is unknown.

Characterization of the pituitary tumor transforming gene 1 knockout mouse retina.

Recent gene expression studies on mouse models for retinal degeneration identified deregulation of Pituitary tumor transforming gene 1 (Pttg1) as a potential susceptibility factor involved in photoreceptor cell death. Pttg1 is a transcription regulatory protein involved in sister chromatid segregation, and Pttg1(-/-) mice exhibit testicular and splenic hypoplasia, thymic hyperplasia, aberrant cell cycle progression, chromosome instability, and impaired glucose homeostasis leading to diabetes, particularly in older males. Due to Pttg1 deregulation in dystrophic retinas, we characterized Pttg1(-/-) retinas using Hematoxylin and Eosin (H&E) staining, immunohistochemistry (IHC), and electroretinography (ERG). Seven month old Pttg1(-/-) mice were also examined for a diabetic retinopathy phenotype using Fluorescein Angiography (FA) to test for neovascularization. Our data reveal that up to 9 months of age, Pttg1(-/-) retinas have a healthy morphology and normal photoreceptor function. This study lays the groundwork for further investigation into the relevance of Pttg1 in retinal dystrophy.

KASH protein Syne-2/Nesprin-2 and SUN proteins SUN1/2 mediate nuclear migration during mammalian retinal development.

Nuclear movement relative to cell bodies is a fundamental process during certain aspects of mammalian retinal development. During the generation of photoreceptor cells in the cell division cycle, the nuclei of progenitors oscillate between the apical and basal surfaces of the neuroblastic layer (NBL). This process is termed interkinetic nuclear migration (INM). Furthermore, newly formed photoreceptor cells migrate and form the outer nuclear layer (ONL). In the current study, we demonstrated that a KASH domain-containing protein, Syne-2/Nesprin-2, as well as SUN domain-containing proteins, SUN1 and SUN2, play critical roles during INM and photoreceptor cell migration in the mouse retina. A deletion mutation of Syne-2/Nesprin-2 or double mutations of Sun1 and Sun2 caused severe reduction of the thickness of the ONL, mislocalization of photoreceptor nuclei and profound electrophysiological dysfunction of the retina characterized by a reduction of a- and b-wave amplitudes. We also provide evidence that Syne-2/Nesprin-2 forms complexes with either SUN1 or SUN2 at the nuclear envelope to connect the nucleus with dynein/dynactin and kinesin molecular motors during the nuclear migrations in the retina. These key retinal developmental signaling results will advance our understanding of the mechanism of nuclear migration in the mammalian retina.

Neovascularization, enhanced inflammatory response, and age-related cone dystrophy in the Nrl-/-Grk1-/- mouse retina.

PURPOSE: The effects of aging and light exposure on cone photoreceptor survival were compared between mouse retinas of neural retina leucine zipper knockout (Nrl(-/-)) mice and double-knockout mice lacking G-protein-coupled receptor kinase 1 (Nrl(-/-)Grk1(-/-)). METHODS: Mice were reared in total darkness, ambient cyclic light, or constant light, and their retinas were evaluated from 1 to 9 months of age using immunohistochemistry, electroretinography, and fluorescein angiography. Retinal gene expression and statistically significant probe sets were categorized using analysis software. Select gene expression changes were confirmed with quantitative RT-PCR. RESULTS: In contrast to retinas from Nrl(-/-), those from Nrl(-/-)Grk1(-/-) exhibit a progressive loss of the outer nuclear layer, retinal physiology deficits, and a higher rate of degeneration with increasing age that is independent of environmental light exposure. Changes in retinal neovascularization occur in the Nrl(-/-)Grk1(-/-) at 1 month, before the onset of significant cone functional deficits. Microarray analyses demonstrate statistically significant changes in transcript levels of more than 400 genes, of which the oncostatin M signaling pathway and the inflammatory disease response network were identified. CONCLUSIONS: These data demonstrate that the loss of functional Grk1 on the enhanced S-cone Nrl(-/-) background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway and neovascularization. According to these findings, Grk1 helps to maintain a healthy cone environment, and the Nrl(-/-)Grk1(-/-) mouse allows examination of the alternative roles of Grk1 in cone photoreceptor homeostasis.

Visual Arrestin 1 acts as a modulator for N-ethylmaleimide-sensitive factor in the photoreceptor synapse.

In the G-protein-coupled receptor phototransduction cascade, visual Arrestin 1 (Arr1) binds to and deactivates phosphorylated light-activated opsins, a process that is critical for effective recovery and normal vision. In this report, we discovered a novel synaptic interaction between Arr1 and N-ethylmaleimide-sensitive factor (NSF) that is enhanced in a dark environment when mouse photoreceptors are depolarized and the rate of exocytosis is elevated. In the photoreceptor synapse, NSF functions to sustain a higher rate of exocytosis, in addition to the compensatory endocytosis to retrieve and to recycle vesicle membrane and synaptic proteins. Not only does Arr1 bind to the junction of NSF N-terminal and its first ATPase domains in an ATP-dependent manner in vitro, but Arr1 also enhances both NSF ATPase and NSF disassembly activities. In in vivo experiments in mouse retinas with the Arr1 gene knocked out, the expression levels of NSF and other synapse-enriched components, including vGLUT1 (vesicular glutamate transporter 1), EAAT5 (excitatory amino acid transporter 5), and VAMP2 (vesicle-associated membrane protein 2), are markedly reduced, which leads to a substantial decrease in the exocytosis rate with FM1-43. Thus, we propose that the Arr1 and NSF interaction is important for modulating normal synaptic function in mouse photoreceptors. This study demonstrates a vital alternative function for Arr1 in the photoreceptor synapse and provides key insights into the potential molecular mechanisms of inherited retinal diseases, such as Oguchi disease and Arr1-associated retinitis pigmentosa.

Deciphering the structure and function of Als2cr4 in the mouse retina.

PURPOSE: The role of Als2cr4 (amyotrophic lateral sclerosis 2 [juvenile] chromosome region, candidate 4; also known as hypothetical protein FLJ33282) in the mouse retina was determined by characterizing the molecular structure, cellular interacting partners, and potential biochemical functions. Previous in situ hybridization and gene expression profiles show that the mRNAs encoding Als2cr4 are abundant in the eye, hippocampus, cerebellum, and olfactory bulb. METHODS: From predicted antigenic epitopes of Als2cr4, two novel antibodies were developed to examine protein expression and morphologic localization in retinas from light-adapted and dark-adapted mice by immunohistochemistry, immunoblot analysis, and immunoelectron microscopy, and then immunoprecipitation was performed to identify interacting proteins by mass spectroscopy. RESULTS: Peptide antibodies with Als2cr4 antigenic epitopes from either the amino- or carboxyl terminus were characterized with Als2cr4 recombinant proteins and peptide competition assays. Als2cr4 is a 45-kDa insoluble protein, highly enriched in retina, and localizes to photoreceptor outer segments, ciliary complex, and horizontal cells in the outer plexiform layer. Immunoelectron microscopy for Als2cr4 verified its expression in the discs of photoreceptor outer segments. Immunoprecipitation and mass spectroscopy identified eight potential interacting partners: vimentin, actin, myosin Va, myosin VI, myosin X, myosin XIV, kinesin 1, Als2cr4, and lamin B-1. CONCLUSIONS: Als2cr4 is a novel protein, with a probable tetraspanin-like membrane structure, that is localized in photoreceptors and in the postsynaptic outer plexiform layer and that interacts with cytoskeletal proteins. Als2cr4 may be involved in membrane transport between the photoreceptor inner and outer segments and may be a key component in maintaining the structural integrity of the outer segment.

Taurine deficiency damages photoreceptors and retinal ganglion cells in vigabatrin-treated neonatal rats.

The anti-epileptic drug vigabatrin induces an irreversible constriction of the visual field, but is still widely used to treat infantile spasms and some forms of epilepsy. We recently reported that vigabatrin-induced cone damage is due to a taurine deficiency. However, optic atrophy and thus retinal ganglion cell degeneration was also reported in children treated for infantile spasms. We here show in neonatal rats treated from postnatal days 4 to 29 that the vigabatrin treatment triggers not only cone photoreceptor damage, disorganisation of the photoreceptor layer and gliosis but also retinal ganglion cell loss. Furthermore, we demonstrate in these neonatal rats that taurine supplementation partially prevents these retinal lesions and in particular the retinal ganglion cell loss. These results provide the first evidence of retinal ganglion cell neuroprotection by taurine. They further confirm that taurine supplementation should be administered with the vigabatrin treatment for infantile spasms or epilepsy.

Effect of g protein-coupled receptor kinase 1 (Grk1) overexpression on rod photoreceptor cell viability.

PURPOSE: Photoreceptor rhodopsin kinase (Rk, G protein-dependent receptor kinase 1 [Grk1]) phosphorylates light-activated opsins and channels them into an inactive complex with visual arrestins. Grk1 deficiency leads to human retinopathy and heightened susceptibility to light-induced photoreceptor cell death in the mouse. The goal of this study was to determine whether excess Grk1 activity is protective against photoreceptor cell death. METHODS: Grk1-overexpressing transgenic mice (Grk1(+)) were generated by using a bacterial artificial chromosome (BAC) construct containing mouse Grk1, along with its flanking sequences. Quantitative reverse transcription-PCR, immunoblot analysis, immunostaining, and activity assays were combined with electrophysiology and morphometric analysis, to evaluate Grk1 overexpression and its effect on physiologic and morphologic retinal integrity. Morphometry and nucleosome release assays measured differences in resistance to photoreceptor cell loss between control and transgenic mice exposed to intense light. RESULTS: Compared with control animals, the Grk1(+) transgenic line had approximately a threefold increase in Grk1 transcript and immunoreactive protein. Phosphorylated opsin immunochemical staining and in vitro phosphorylation assays confirmed proportionately higher Grk1 enzyme activity. Grk1(+) mice retained normal rod function, normal retinal appearance, and lacked evidence of spontaneous apoptosis when reared in cyclic light. In intense light, Grk1(+) mice showed photoreceptor damage, and their susceptibility was more pronounced than that of control mice with prolonged exposure times. CONCLUSIONS: Enhancing visual pigment deactivation does not appear to protect against apoptosis; however, excess flow of opsin into the deactivation pathway may actually increase susceptibility to stress-induced cell death similar to some forms of retinal degeneration.

Visual Arrestin 1 contributes to cone photoreceptor survival and light adaptation.

PURPOSE: To evaluate morphologic and functional contributions of Arrestin 1 (Arr1) and Arrestin 4 (Arr4) in cone photoreceptors, the authors examined the phenotypes of visual arrestin knockout mice (Arr1(-/-), Arr4(-/-), Arr1(-/-)Arr4(-/-) [Arr-DKO]) reared in darkness. METHODS: Retinal rods and cones were evaluated in wild-type (WT), Arr1(-/-), Arr4(-/-), and Arr-DKO mice using quantitative morphologic analysis, immunoblot, immunohistochemistry, TUNEL, and electroretinographic (ERG) techniques. RESULTS: Compared with either Arr4(-/-) or WT, Arr1(-/-) and Arr-DKO mice had increased apoptotic nuclei in their retinal outer nuclear layer (ONL) at postnatal day (P) 22. By P60, cone density was significantly diminished, but the ONL appeared normal. After 1 minute of background illumination, cone ERG b-wave amplitudes were similar in WT and all Arr KO mice. However, by 3 minutes and continuing through 15 minutes of light adaptation, the cone b-wave amplitudes of WT and Arr4(-/-) mice increased significantly over those of the Arr1(-/-) and Arr-DKO mice, which demonstrated no cone b-wave amplitude increase. In contrast, ERG flicker analysis after the 15-minute light adaptation period demonstrated no loss in amplitude for either Arr1(-/-) or Arr4(-/-) mice, whereas Arr-DKO had significantly lower amplitudes. When Arr1 expression was restored in Arr1(-/-) mice (+p48(Arr1-/-)), normal cone density and light-adapted ERG b-wave amplitudes were observed. CONCLUSIONS: In the adult dark-reared Arr1(-/-) and Arr-DKO mice, viable cones diminish over time. Arr1 expression is essential for cone photoreceptor survival and light adaptation, whereas either Arr1 or Arr4 is necessary for maintaining normal flicker responses.

Maximizing functional photoreceptor differentiation from adult human retinal stem cells.

Retinal stem cells (RSCs) are present in the ciliary margin of the adult human eye and can give rise to all retinal cell types. Here we show that modulation of retinal transcription factor gene expression in human RSCs greatly enriches photoreceptor progeny, and that strong enrichment was obtained with the combined transduction of OTX2 and CRX together with the modulation of CHX10. When these genetically modified human RSC progeny are transplanted into mouse eyes, their retinal integration and differentiation is superior to unmodified RSC progeny. Moreover, electrophysiologic and behavioral tests show that these transplanted cells promote functional recovery in transducin mutant mice. This study suggests that gene modulation in human RSCs may provide a source of photoreceptor cells for the treatment of photoreceptor disease.

Taurine deficiency is a cause of vigabatrin-induced retinal phototoxicity.

OBJECTIVE: Although vigabatrin irreversibly constricts the visual field, it remains a potent therapy for infantile spasms and a third-line drug for refractory epilepsies. In albino animals, this drug induces a reduction in retinal cell function, retinal disorganization, and cone photoreceptor damage. The objective of this study was to investigate the light dependence of the vigabatrin-elicited retinal toxicity and to screen for molecules preventing this secondary effect of vigabatrin. METHODS: Rats and mice were treated daily with 40 and 3mg vigabatrin, respectively. Retinal cell lesions were demonstrated by assessing cell function with electroretinogram measurements, and quantifying retinal disorganization, gliosis, and cone cell densities. RESULTS: Vigabatrin-elicited retinal lesions were prevented by maintaining animals in darkness during treatment. Different mechanisms including taurine deficiency were reported to produce such phototoxicity; we therefore measured amino acid plasma levels in vigabatrin-treated animals. Taurine levels were 67% lower in vigabatrin-treated animals than in control animals. Taurine supplementation reduced all components of retinal lesions in both rats and mice. Among six vigabatrin-treated infants, the taurine plasma level was found to be below normal in three patients and undetectable in two patients. INTERPRETATION: These results indicate that vigabatrin generates a taurine deficiency responsible for its retinal phototoxicity. Future studies will investigate whether cotreatment with taurine and vigabatrin can limit epileptic seizures without inducing the constriction of the visual field. Patients taking vigabatrin could gain immediate benefit from reduced light exposures and dietetic advice on taurine-rich foods.