RESUMEN
Hypoxia associated with the high metabolic demand of rods has been implicated in the pathology of age-related macular degeneration (AMD), the most common cause of adult blindness in the developed world. The majority of AMD-associated severe vision loss cases are due to exudative AMD, characterized by neovascularization. To further investigate the causes and histopathology of exudative AMD, we conditionally induced hypoxia in a novel preclinical AMD model (Pde6gcreERT2/+;Vhl-/-) by targeting Vhl and used multimodal imaging and immunohistochemistry to track the development of hypoxia-induced neovascularization. In addition to developing a preclinical model that phenocopies exudative AMD, our studies revealed that the photoreceptor hypoxic response initiates and drives type 3 neovascularization, mainly in the outer retina. Activation of the VHL-HIF1a-VEGF-EPO pathway in the adult retina led to long-term neovascularization, retinal hemorrhages and compromised retinal layers. Our novel preclinical model would accelerate the testing of therapies that use metabolomic approaches to ameliorate AMD.
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Hipoxia/metabolismo , Hipoxia/patología , Degeneración Macular/metabolismo , Degeneración Macular/patología , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Animales , Eritropoyetina/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
D190N, a missense mutation in rhodopsin, causes photoreceptor degeneration in patients with autosomal dominant retinitis pigmentosa (adRP). Two competing hypotheses have been developed to explain why D190N rod photoreceptors degenerate: (a) defective rhodopsin trafficking prevents proteins from correctly exiting the endoplasmic reticulum, leading to their accumulation, with deleterious effects or (b) elevated mutant rhodopsin expression and unabated signaling causes excitotoxicity. A knock-in D190N mouse model was engineered to delineate the mechanism of pathogenesis. Wild type (wt) and mutant rhodopsin appeared correctly localized in rod outer segments of D190N heterozygotes. Moreover, the rhodopsin glycosylation state in the mutants appeared similar to that in wt mice. Thus, it seems plausible that the injurious effect of the heterozygous mutation is not related to mistrafficking of the protein, but rather from constitutive rhodopsin activity and a greater propensity for chromophore isomerization even in the absence of light.
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Células Fotorreceptoras Retinianas Bastones/metabolismo , Retinitis Pigmentosa/patología , Rodopsina/genética , Secuencia de Aminoácidos , Animales , Modelos Animales de Enfermedad , Electrorretinografía , Técnicas de Sustitución del Gen , Glicosilación , Ratones , Ratones Endogámicos C57BL , Mutación Missense , Estructura Terciaria de Proteína , Retina/metabolismo , Retina/patología , Retinitis Pigmentosa/metabolismo , Rodopsina/química , Rodopsina/metabolismo , Alineación de SecuenciaRESUMEN
Retinitis pigmentosa (RP) is a category of inherited retinal dystrophies that is best prognosticated using electroretinography (ERG). In this retrospective cohort study of 25 patients with RP, we evaluated the correlation between 30 Hz flicker ERG and structural parameters in the retina. Internationally standardized 30 Hz flicker ERG recordings, short-wavelength autofluorescence (SW-AF), and spectral domain-optical coherence tomography (SD-OCT) were acquired at two visits at least one year apart. Vertical and horizontal hyperautofluorescent ring diameter measurements with SW-AF, as well as ellipsoid zone (EZ) line width measurements with SD-OCT, were used as structural parameters of disease progression. The 30 Hz flicker ERG amplitude decreased by 2.2 ± 0.8 µV/year (p = 0.011), while implicit times remained unchanged. For SD-OCT, the EZ line decreased by 204.1 ± 34.7 µm/year (p < 0.001). Horizontal and vertical hyperautofluorescent ring diameters decreased by 161.9 ± 25.6 µm/year and 146.9 ± 34.6 µm/year, respectively (p = 0.001), with SW-AF. A correlation was found between the progression rates of the 30 Hz flicker amplitude recorded with Burian-Allen electrodes and both the horizontal ring diameter (p = 0.020) and EZ line (p = 0.044). SW-AF and SD-OCT, two readily available imaging techniques, may be used to prognosticate disease progression because of the reliability of their measurements and correlation with functional outcome.
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Electrorretinografía/métodos , Retina/diagnóstico por imagen , Retina/fisiopatología , Retinitis Pigmentosa/diagnóstico por imagen , Retinitis Pigmentosa/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Retina/patología , Distrofias Retinianas/congénito , Distrofias Retinianas/diagnóstico por imagen , Distrofias Retinianas/patología , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/fisiopatología , Estudios Retrospectivos , Tomografía de Coherencia ÓpticaRESUMEN
Microglia cells (MGCs) play a key role in scavenging pathogens and phagocytosing cellular debris in the central nervous system and retina. Their activation, however, contributes to the progression of multiple degenerative diseases. Given the potential damage created by MGCs, it is important to better understand their mechanism of activation. Here, we explored the role of MGCs in the context of retinitis pigmentosa (RP) by using four independent preclinical mouse models. For therapeutic modeling, tamoxifen-inducible CreER was introduced to explore changes in MGCs when RP progression halted. The phenotypes of the MGCs were observed using live optical coherence tomography, live autofluorescence, and immunohistochemistry. We found that, regardless of genetic background, MGCs were activated in neurodegenerative conditions and migrated beyond the layers where they are typically found to the inner and outer segments, where degeneration was ongoing. Genetic rescue not only halted degeneration but also deactivated MGCs, regardless of whether the intervention occurred at the early, middle, or late stage of the disease. These findings suggest that halting long-term disease progression may be more successful by downregulating MGC activity while co-administering the therapeutic intervention.
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Microglía/patología , Hidrolasas Diéster Fosfóricas/genética , Retinitis Pigmentosa/diagnóstico por imagen , Tamoxifeno/farmacología , Animales , Receptor 1 de Quimiocinas CX3C/metabolismo , Modelos Animales de Enfermedad , Terapia Genética , Humanos , Ratones , Hidrolasas Diéster Fosfóricas/administración & dosificación , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/metabolismo , Retinitis Pigmentosa/terapia , Tomografía de Coherencia ÓpticaRESUMEN
Metabolomics studies in the context of ophthalmology have largely focused on identifying metabolite concentrations that characterize specific retinal diseases. Studies involving mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy have shown that individuals suffering from retinal diseases exhibit metabolic profiles that markedly differ from those of control individuals, supporting the notion that metabolites may serve as easily identifiable biomarkers for specific conditions. An emerging branch of metabolomics resulting from biomarker studies, however, involves the study of retinal metabolic dysfunction as causes of degeneration. Recent publications have identified a number of metabolic processes-including but not limited to glucose and oxygen metabolism-that, when perturbed, play a role in the degeneration of photoreceptor cells. As a result, such studies have led to further research elucidating methods for prolonging photoreceptor survival in an effort to halt degeneration in its early stages. This review will explore the ways in which metabolomics has deepened our understanding of the causes of retinal degeneration and discuss how metabolomics can be used to prevent retinal degeneration from progressing to its later disease stages.
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Metaboloma/fisiología , Degeneración Retiniana/metabolismo , Degeneración Retiniana/fisiopatología , Animales , Glucosa/metabolismo , Humanos , Metabolómica/métodos , Oxígeno/metabolismoRESUMEN
Retinal diseases that impair vision can impose heavy physical and emotional burdens on patients' lives. Currently, clustered regularly interspaced short palindromic repeats (CRISPR) is a prevalent gene-editing tool that can be harnessed to generate disease model organisms for specific retinal diseases, which are useful for elucidating pathophysiology and revealing important links between genetic mutations and phenotypic defects. These retinal disease models are fundamental for testing various therapies and are indispensible for potential future clinical trials. CRISPR-mediated procedures involving CRISPR-associated protein 9 (Cas9) may also be used to edit genome sequences and correct mutations. Thus, if used for future therapies, CRISPR/Cas9 genome surgery could eliminate the need for patients with retinal diseases to undergo repetitive procedures such as drug injections. In this review, we will provide an overview of CRISPR/Cas9, discuss the different types of Cas9, and compare Cas9 to other endonucleases. Furthermore, we will explore the many ways in which researchers are currently utilizing this versatile tool, as CRISPR/Cas9 may have far-reaching effects in the treatment of retinal diseases.
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Sistemas CRISPR-Cas , Edición Génica , Terapia Genética , Enfermedades de la Retina/genética , Enfermedades de la Retina/terapia , Terapia Genética/métodos , Genoma Humano , HumanosRESUMEN
PURPOSE: To report a case of deferoxamine-induced retinopathy characterized by electroretinography (ERG), optical coherence tomography angiography (OCT-A), and other multimodal imaging. METHODS: This is an observational case report of one patient. Full-field ERG was performed. OCT-A, spectral-domain optical coherence tomography (SD-OCT), color fundus photography, and fundus autofluorescence were used to characterize the retinopathy induced by deferoxamine use. RESULTS: A 64-year-old man with a history of ß-thalassemia intermedia presented with worsening visual acuity, nyctalopia, and electronegative ERG. OCT-A revealed atrophy of the choriocapillaris in areas of hypoautofluorescence, corresponding to regions of retinal atrophy. SD-OCT showed disruption of the ellipsoid zone, granular hyperreflective deposits within the retinal pigment epithelium, thinning of the retinal layers, and extensive choroidal sclerosis and atrophy of the retinal pigment epithelium. CONCLUSION: Deferoxamine-induced retinopathy can manifest with electronegative maximal ERG responses, and OCT-A can be used to detect deferoxamine toxicity.
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Deferoxamina/toxicidad , Electrorretinografía/efectos de los fármacos , Enfermedades de la Retina/inducido químicamente , Sideróforos/toxicidad , Atrofia , Angiografía con Fluoresceína , Humanos , Sobrecarga de Hierro/prevención & control , Masculino , Persona de Mediana Edad , Imagen Multimodal , Ceguera Nocturna/inducido químicamente , Ceguera Nocturna/diagnóstico , Ceguera Nocturna/fisiopatología , Enfermedades de la Retina/diagnóstico , Enfermedades de la Retina/fisiopatología , Epitelio Pigmentado de la Retina/efectos de los fármacos , Epitelio Pigmentado de la Retina/patología , Tomografía de Coherencia Óptica/métodos , Agudeza Visual/efectos de los fármacosRESUMEN
The endoplasmic reticulum (ER) is the largest intracellular organelle carrying out a broad range of important cellular functions including protein biosynthesis, folding, and trafficking, lipid and sterol biosynthesis, carbohydrate metabolism, and calcium storage and gated release. In addition, the ER makes close contact with multiple intracellular organelles such as mitochondria and the plasma membrane to actively regulate the biogenesis, remodeling, and function of these organelles. Therefore, maintaining a homeostatic and functional ER is critical for the survival and function of cells. This vital process is implemented through well-orchestrated signaling pathways of the unfolded protein response (UPR). The UPR is activated when misfolded or unfolded proteins accumulate in the ER, a condition known as ER stress, and functions to restore ER homeostasis thus promoting cell survival. However, prolonged activation or dysregulation of the UPR can lead to cell death and other detrimental events such as inflammation and oxidative stress; these processes are implicated in the pathogenesis of many human diseases including retinal disorders. In this review manuscript, we discuss the unique features of the ER and ER stress signaling in the retina and retinal neurons and describe recent advances in the research to uncover the role of ER stress signaling in neurodegenerative retinal diseases including age-related macular degeneration, inherited retinal degeneration, achromatopsia and cone diseases, and diabetic retinopathy. In some chapters, we highlight the complex interactions between the ER and other intracellular organelles focusing on mitochondria and illustrate how ER stress signaling regulates common cellular stress pathways such as autophagy. We also touch upon the integrated stress response in retinal degeneration and diabetic retinopathy. Finally, we provide an update on the current development of pharmacological agents targeting the UPR response and discuss some unresolved questions and knowledge gaps to be addressed by future research.
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Retinopatía Diabética , Degeneración Retiniana , Humanos , Degeneración Retiniana/metabolismo , Retinopatía Diabética/metabolismo , Respuesta de Proteína Desplegada , Estrés del Retículo Endoplásmico/fisiología , Retina , Retículo Endoplásmico/metabolismo , Homeostasis/fisiologíaRESUMEN
The mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) is the physical contact site between the ER and the mitochondria and plays a vital role in the regulation of calcium signaling, bioenergetics, and inflammation. Disturbances in these processes and dysregulation of the ER and mitochondrial homeostasis contribute to the pathogenesis of diabetic retinopathy (DR). However, few studies have examined the impact of diabetes on the retinal MAM and its implication in DR pathogenesis. In the present study, we investigated the proteomic changes in retinal MAM from Long Evans rats with streptozotocin-induced long-term Type 1 diabetes. Furthermore, we performed in-depth bioinformatic analysis to identify key MAM proteins and pathways that are potentially implicated in retinal inflammation, angiogenesis, and neurodegeneration. A total of 2664 unique proteins were quantified using IonStar proteomics-pipeline in rat retinal MAM, among which 179 proteins showed significant changes in diabetes. Functional annotation revealed that the 179 proteins are involved in important biological processes such as cell survival, inflammatory response, and cellular maintenance, as well as multiple disease-relevant signaling pathways, e.g., integrin signaling, leukocyte extravasation, PPAR, PTEN, and RhoGDI signaling. Our study provides comprehensive information on MAM protein changes in diabetic retinas, which is helpful for understanding the mechanisms of metabolic dysfunction and retinal cell injury in DR.
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Diabetes Mellitus , Degeneración Retiniana , Animales , Señalización del Calcio , Diabetes Mellitus/metabolismo , Retículo Endoplásmico/metabolismo , Inflamación/metabolismo , Integrinas/metabolismo , Mitocondrias/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Proteómica , Ratas , Ratas Long-Evans , Degeneración Retiniana/metabolismo , Estreptozocina , Inhibidores de la Disociación del Nucleótido Guanina rho-Específico/metabolismoRESUMEN
Retinal disorders are a group of ocular diseases whose onset is associated with a number of aberrant molecular and cellular processes or physical damages that affect retinal structure and function resulting in neural and vascular degeneration in the retina. Current research has primarily focused on delaying retinal disease with minimal success in preventing or reversing neuronal degeneration. In this review, we explore a relatively new field of research involving circular RNAs, whose potential roles as biomarkers and mediators of retinal disease pathogenesis have only just emerged. While knowledge of circular RNAs function is limited given its novelty, current evidence has highlighted their roles as modulators of microRNAs, regulators of gene transcription, and biomarkers of disease development and progression. Here, we summarize how circular RNAs may be implicated in the pathogenesis of common retinal diseases including diabetic retinopathy, glaucoma, proliferative vitreoretinopathy, and age-related macular degeneration. Further, we explore the potential of circular RNAs as novel biomarkers and therapeutic targets for the diagnosis and treatment of retinal diseases.
RESUMEN
Production of proliferative follicle cells (FCs) and quiescent escort cells (ECs) by follicle stem cells (FSCs) in adult Drosophila ovaries is regulated by niche signals from anterior (cap cells, ECs) and posterior (polar FCs) sources. Here we show that ECs, FSCs, and FCs develop from common pupal precursors, with different fates acquired by progressive separation of cells along the AP axis and a graded decline in anterior cell proliferation. ECs, FSCs, and most FCs derive from intermingled cell (IC) precursors interspersed with germline cells. Precursors also accumulate posterior to ICs before engulfing a naked germline cyst projected out of the germarium to form the first egg chamber and posterior polar FC signaling center. Thus, stem and niche cells develop in appropriate numbers and spatial organization through regulated proliferative expansion together with progressive establishment of spatial signaling cues that guide adult cell behavior, rather than through rigid early specification events.
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Drosophila melanogaster/crecimiento & desarrollo , Ovario/crecimiento & desarrollo , Células Madre/metabolismo , Animales , Femenino , Pupa/crecimiento & desarrolloRESUMEN
Inherited retinal dystrophies cause progressive vision loss and are major contributors to blindness worldwide. Advances in gene therapy have brought molecular approaches into the realm of clinical trials for these incurable illnesses. Select phase I, II and III trials are complete and provide some promise in terms of functional outcomes and safety, although questions do remain over the durability of their effects and the prevalence of inflammatory reactions. This article reviews gene therapy as it can be applied to inherited retinal dystrophies, provides an update of results from recent clinical trials, and discusses the future prospects of gene therapy and genome surgery.
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Terapia Genética/tendencias , Inflamación/genética , Degeneración Retiniana/genética , Ensayos Clínicos como Asunto , Progresión de la Enfermedad , Edición Génica , Genoma Humano/genética , Humanos , Inflamación/terapia , Retina/patología , Degeneración Retiniana/patología , Degeneración Retiniana/terapiaRESUMEN
We analyze disease progression in retinitis pigmentosa (RP) according to mode of inheritance by quantifying the progressive decrease of the ellipsoid zone (EZ) line width on spectral domain optical coherence tomography (SD-OCT) and of the dimensions of the hyperautofluorescent ring on short-wave fundus autofluorescence (SW-FAF). In this retrospective study of 96 patients, average follow-up time was 3.2 ± 1.9 years. EZ line width declined at a rate of -123 ± 8 µm per year, while the horizontal diameter and ring area declined at rates of -131 ± 9 µm and -0.5 ± 0.05 mm2 per year, respectively. Disease progression was found to be slowest for autosomal dominant RP and fastest for X-linked RP, with autosomal recessive RP progression rates between those of adRP and XLRP. EZ line width and ring diameter rates of disease progression were significantly different between each mode of inheritance. By using EZ line width and horizontal diameter as parameters of disease progression, our results confirm that adRP is the slowest progressing form of RP while XLRP is the fastest. Furthermore, the reported rates can serve as benchmarks for investigators of future clinical trials for RP and its different modes of inheritance.
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Genes Dominantes , Genes Ligados a X , Retinitis Pigmentosa/patología , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Retinitis Pigmentosa/diagnóstico por imagen , Retinitis Pigmentosa/genética , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: To characterize and bring awareness to the disease spectrum of female choroideremia patients, as severity can vary from mild to severe disease, comparable to that observed in male patients. DESIGN: Retrospective cohort study. METHODS: Twelve female carriers of disease-causing variants in the CHM gene confirmed by molecular genetic sequencing were characterized clinically and imaged with short-wave fundus autofluorescence (SW-FAF), spectral-domain optical coherence tomography (OCT), and color fundus imaging. RESULTS: Twelve unrelated female patients with a clinical and genetic diagnosis of choroideremia carriers were included in this study. Disease severity among these phenotypes ranged from mild to severe, resembling the typical presentation of choroideremia in male patients. Mild disease presented with retinal pigment epithelium mottling, a patchy pattern of hypoautofluorescent speckles on SW-FAF, and intact retinal layers on spectral-domain OCT. Severe disease presented with widespread chorioretinal atrophy as shown by SW-FAF and spectral-domain OCT. Each of the identified genetic variants in CHM was predicted to be disease-causing according to in silico prediction software. Disease progression analysis of 4 patients with follow-up showed a decline in visual acuity for 2 patients, with progression observed on spectral-domain OCT in 1 of the patients. No significant disease progression on SW-FAF was observed for any of the patients. CONCLUSIONS: Female carriers of choroideremia can present with a wide range of clinical phenotypes and disease severity, from mild to severe disease, similar to male subjects. Symptomatic female subjects should be considered for current and upcoming gene replacement therapy clinical trials.
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Coroideremia/diagnóstico , Angiografía con Fluoresceína/métodos , Epitelio Pigmentado de la Retina/patología , Tomografía de Coherencia Óptica/métodos , Agudeza Visual , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adulto , Anciano , Coroideremia/genética , Femenino , Estudios de Seguimiento , Fondo de Ojo , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Oftalmoscopía/métodos , Fenotipo , Estudios Retrospectivos , Secuenciación Completa del Genoma/métodos , Adulto JovenRESUMEN
The PROM1 (prominin 1) gene encodes an 865-amino acid glycoprotein that is expressed in retinoblastoma cell lines and in the adult retina. The protein is localized to photoreceptor outer segment disc membranes, where it plays a structural role, and in the retinal pigment epithelium (RPE), where it acts as a cytosolic protein that mediates autophagy. Mutations in PROM1 are typically associated with cone-rod dystrophy 12 (OMIM#3612657), autosomal dominant retinal macular dystrophy 2 (OMIM#608051), autosomal recessive retinitis pigmentosa 41 (OMIM#612095), and Stargardt disease 4 (OMIM#603786). Here we describe the first case of PROM1-associated Leber congenital amaurosis (LCA) in a 12-yr-old Asian male, caused by two not previously described deleterious frameshift variants in the compound heterozygous state. Clinical features include the presence of bull's eye maculopathy, pendular horizontal nystagmus, and photodysphoria consistent with the clinical diagnosis of LCA. The patient was evaluated using ophthalmic imaging, electroretinography, and whole-exome sequencing. Electroretinography revealed extinguished retinal activity.
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Antígeno AC133/genética , Amaurosis Congénita de Leber/genética , Antígeno AC133/metabolismo , Adulto , Niño , Electrorretinografía , Familia , Femenino , Mutación del Sistema de Lectura/genética , Heterocigoto , Humanos , Amaurosis Congénita de Leber/metabolismo , Masculino , Mutación/genética , Linaje , Fenotipo , Retina , Retinitis Pigmentosa , Secuenciación del ExomaRESUMEN
Unlike adult Drosophila ovaries, pupal ovaries are relatively difficult to access and examine due to their small size, translucence, and encasing within a pupal case. The challenge of dissecting pupal ovaries also lies in their physical location within the pupa: the ovaries are surrounded by fat body cells inside the pupal abdomen, and these fat cells must be removed to allow for proper antibody staining. To overcome these challenges, this protocol utilizes customized Pasteur pipets to extract fat body cells from the pupal abdomen. Moreover, a chambered coverglass is used in place of a microcentrifuge tube during the staining process to improve visibility of the pupae. However, despite these and other advantages of the tools used in this protocol, successful execution of these techniques may still involve several days of practice due to the small size of pupal ovaries. The techniques outlined in this protocol could be applied to time course experiments in which ovaries are analyzed at various stages of pupal development.
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Disección/métodos , Drosophila/embriología , Ovario/cirugía , Pupa/citología , Coloración y Etiquetado/métodos , Animales , Drosophila/crecimiento & desarrollo , Femenino , Pupa/metabolismoRESUMEN
BACKGROUND: The RPE65 gene was recently described to cause autosomal dominant retinitis pigmentosa (adRP), presenting with a phenotype resembling choroideremia. This study presents the 2-year progression of RPE65 adRP in a patient. METHODS: This is an observational case report of one patient. The patient received a full ophthalmic examination during both visits, including diagnostic imaging such as spectral domain optical coherence tomography (SD-OCT), OCT-angiography (OCT-A), short-wave fundus autofluorescence (FAF), and fundus photography. Genetic characterization was obtained by DNA sequencing from peripheral blood lymphocytes obtained during the first visit. RESULTS: RPE65 adRP phenocopied choroideremia at the initial fundoscopy. Upon the patient's return to our clinic 2 years later, DNA sequencing revealed a heterozygous mutation in the RPE65 gene. Diagnostic imaging by SD-OCT and FAF suggested disease progression. In conjunction with clinical examination and imaging, the diagnosis was revised to adRP caused by RPE65. CONCLUSION: adRP due to a mutation in the gene encoding RPE65 phenocopied choroideremia. Based on our analysis of the 2-year disease progression in this patient, RPE65 adRP is mild and has a slow rate of disease progression.
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Mutación , Retinitis Pigmentosa/diagnóstico , Retinitis Pigmentosa/genética , cis-trans-Isomerasas/genética , Anciano , Coroideremia/diagnóstico , Coroideremia/genética , Progresión de la Enfermedad , Electrorretinografía , Angiografía con Fluoresceína , Estudios de Seguimiento , Genes Dominantes , Humanos , Masculino , Fenotipo , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: Gyrate atrophy (GA) is a rare chorioretinal degeneration that results in the deterioration of night and peripheral vision, eventually leading to blindness. The disorder is caused by mutations in the gene encoding ornithine aminotransferase (OAT), causing increased levels of plasma ornithine. Treatment revolves around lowering plasma ornithine levels, with vitamin B6 supplementation being the preferred treatment. Nevertheless, most patients do not respond to this therapy. Here, we report a rare case of vitamin B6-responsive GA caused by a novel mutation in OAT and characterize the presentation with multimodal imaging. METHODS: This is a single-patient case report with a clinical diagnosis based on history, multimodal retinal imaging, laboratory findings, and DNA sequencing analysis. We include a 3D structure prediction of the novel mutant protein. RESULTS: DNA sequencing analysis demonstrated that there is a homozygous, novel variant c.473A>C: p.Y158S in OAT. Upon undergoing two weeks of vitamin B6 supplementation, the patient exhibited a 28.5% reduction in plasma ornithine levels. In a follow-up visit two years later, plasma ornithine levels were reduced by 24.1% from the levels at initial presentation and disease progression was retarded based on clinical findings. CONCLUSION: One novel homozygous missense mutation in OAT was identified and considered to be pathogenic in a patient with GA. The response for the vitamin B6 supplementation was positive, which is rare in all the GA cases reported in the literature. Our data suggests that further studies regarding the relationship between genotype and responsiveness to vitamin B6 should be conducted.
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Atrofia Girata/tratamiento farmacológico , Atrofia Girata/genética , Mutación Missense , Ornitina-Oxo-Ácido Transaminasa/genética , Vitamina B 6/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Anciano , Femenino , Angiografía con Fluoresceína , Genotipo , Atrofia Girata/diagnóstico , Humanos , Imagen Multimodal , Linaje , Tomografía de Coherencia ÓpticaRESUMEN
PURPOSE: To quantitatively compare near-infrared autofluorescence (NIR-AF) and short-wave autofluorescence (SW-AF) as imaging modalities used to monitor retinitis pigmentosa (RP) disease progression, measured as a function of hyperautofluorescent ring constriction over time. DESIGN: Retrospective cohort study. METHODS: NIR-AF and SW-AF images were acquired from 22 participants (44 eyes) at 2 clinic visits separated by an average of 2 years. On the images from each modality, the horizontal and vertical diameters and area of the hyperautofluorescent rings were measured twice, 2 weeks apart. A progression rate for each parameter was obtained. Descriptive and comparative statistics were calculated to analyze these parameters and their respective progression rates. RESULTS: At both visits, the hyperautofluorescent ring exhibited a larger horizontal diameter (both visits: P < .001), vertical diameter (visit 1: P < .001, visit 2: P = .040), and ring area (visit 1: P = .001, visit 2: P = .011) in SW-AF vs NIR-AF images. In SW-AF, the horizontal diameter, vertical diameter, and ring area decreased yearly by 168 ± 204 µm, 131 ± 159 µm, and 0.7 ± 1.1 mm2, respectively, while in NIR-AF, they decreased by 151 ± 156 µm, 135 ± 190 µm, and 0.7 ± 1.0 mm2. No difference was observed in these rates between SW-AF and NIR-AF. Similar results were observed in the left eye. CONCLUSIONS: In SW-AF and NIR-AF images, similar rates of RP disease progression are observed. As such, NIR-AF may confer more advantages as the primary tool for tracking disease progression over the commonly used SW-AF, given the increased patient comfort and cooperation during imaging.