RESUMEN
In the April issue of this Journal, Boffa and coworkers put forward a new therapeutic approach for Gyrate Atrophy of the Choroid and Retina (GACR; OMIM 258870) (Boffa et al, 2023). The authors propose to apply gene therapy to the liver for GACR, a metabolic disease primarily affecting eyesight due to retinal degeneration. Their vision is enthusiastically supported by a News and Views comment in the same issue (Seker Yilmaz and Gissen, 2023). However, based on disease pathology, patient's needs, ethical considerations, therapeutic developmental time lines, and current state of the art of gene therapy for liver and eye, we have a different view on this issue: We argue below that local treatment of the eye is the preferred option for GACR.
Asunto(s)
Atrofia Girata , Degeneración Retiniana , Humanos , Atrofia Girata/genética , Atrofia Girata/patología , Atrofia Girata/terapia , Retina/patología , Coroides , Degeneración Retiniana/terapia , Degeneración Retiniana/patología , Atrofia/patologíaAsunto(s)
Atrofia Girata , Humanos , Atrofia Girata/patología , Ornitina , Atrofia/patología , Retina/patologíaRESUMEN
Gyrate atrophy of choroid and retina (GACR) is a chorioretinal degeneration caused by pathogenic variants in the gene encoding ornithine aminotransferase (OAT), an enzyme mainly expressed in liver. Affected patients have increased ornithine concentrations in blood and other body fluids and develop progressive constriction of vision fields leading to blindness. Current therapies are unsatisfactory and better treatments are highly needed. In two mouse models of OAT deficiency that recapitulates biochemical and retinal changes of GACR, we investigated the efficacy of an intravenously injected serotype 8 adeno-associated (AAV8) vector expressing OAT under the control of a hepatocyte-specific promoter. Following injections, OAT-deficient mice showed reductions of ornithine concentrations in blood and eye cups compared with control mice injected with a vector expressing green fluorescent protein. AAV-injected mice showed improved electroretinogram response and partial restoration of retinal structure up to one-year post-injection. In summary, hepatic OAT expression by AAV8 vector was effective at correction of hyperornithinemia and improved function and structure of the retina. In conclusion, this study provides proof-of-concept of efficacy of liver-directed AAV-mediated gene therapy of GACR.
Asunto(s)
Atrofia Girata , Degeneración Retiniana , Animales , Ratones , Atrofia Girata/genética , Atrofia Girata/patología , Ornitina-Oxo-Ácido Transaminasa/genética , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Degeneración Retiniana/genética , Degeneración Retiniana/patología , Ornitina/genética , Ornitina/metabolismo , Terapia Genética , Hígado/patologíaRESUMEN
Gyrate atrophy is a metabolic disorder characterised by typical progressive circular chorioretinal atrophy, myopia and early developmental cataract. The disease is caused by deficiency of ornithine aminotransferase (OAT) enzyme. Although OAT is expressed in most tissues of the body, but the main target of the disease appears to be the retina. A case is presented here of a 21-year woman, who came to our clinic with the complaint of decline in central vision for eight months. She had progressive poor night vision and was diagnosed with OAT deficiency five years ago. Her systemic history was unremarkable, except for femoral deep vein thrombosis (DVT) which occurred two years ago. Laboratory tests performed at that time had revealed elevated serum ornithine and low serum lysin levels. Optic coherence tomography (OCT) scans showed foveoschisis bilaterally. In summary, gyrate atrophy may present as macular involvement in the form of foveoschisis and may lead to impaired central vision. Key Words: Foveoschisis, Gyrate atrophy, Ornithine aminotransferase.
Asunto(s)
Atrofia Girata , Atrofia/patología , Femenino , Angiografía con Fluoresceína , Atrofia Girata/complicaciones , Atrofia Girata/diagnóstico , Atrofia Girata/patología , Humanos , Ornitina , Ornitina-Oxo-Ácido Transaminasa/genética , Retina/patologíaRESUMEN
Gyrate Atrophy (GA) of the choroid and retina (MIM# 258870) is an autosomal recessive disorder due to mutations of the OAT gene encoding ornithine-delta-aminotransferase (OAT), associated with progressive retinal deterioration and blindness. The disease has a theoretical global incidence of approximately 1:1,500,000. OAT is mainly involved in ornithine catabolism in adults, thus explaining the hyperornithinemia as hallmark of the disease. Patients are treated with an arginine-restricted diet, to limit ornithine load, or the administration of Vitamin B6, a precursor of the OAT coenzyme pyridoxal phosphate. Although the clinical and genetic aspects of GA are known for many years, the enzymatic phenotype of pathogenic variants and their response to Vitamin B6, as well as the molecular mechanisms explaining retinal damage, are poorly clarified. Herein, we provide an overview of the current knowledge on the biochemical properties of human OAT and on the molecular, cellular, and clinical aspects of GA.
Asunto(s)
Coenzimas/administración & dosificación , Atrofia Girata/dietoterapia , Atrofia Girata/enzimología , Ornitina-Oxo-Ácido Transaminasa/deficiencia , Fosfato de Piridoxal/administración & dosificación , Vitamina B 6/administración & dosificación , Arginina/metabolismo , Coroides/enzimología , Coroides/patología , Cromosomas Humanos Par 10 , Dieta/métodos , Expresión Génica , Atrofia Girata/genética , Atrofia Girata/patología , Humanos , Modelos Moleculares , Mutación , Ornitina/metabolismo , Ornitina-Oxo-Ácido Transaminasa/química , Ornitina-Oxo-Ácido Transaminasa/genética , Multimerización de Proteína , Estructura Secundaria de Proteína , Retina/enzimología , Retina/patologíaRESUMEN
Background: Gyrate atrophy of the choroid and retina (GA) is a rare autosomal recessive disorder characterized by nyctalopia, myopia, sharply demarcated expanding peripheral chorioretinal atrophic lesions, early cataract, progressive visual loss and hyperornithinemia. Only three cases of GA associated with rhegmatogenous retinal detachments (RRD) have been reported. The genotype-phenotype correlation of RRD in GA is limited by lack of genetic information in the previously reported cases. Here we report two young sisters with a characteristic GA phenotype associated with a novel variant in the ornithine aminotransferase gene (OAT), in whom one developed unilateral RRD at the age of 9 years.Materials and Methods: Retrospective report of two cases including genetic analysis and multimodal retinal imaging.Results: A 9-year-old Saudi girl presented with a funnel-shaped RRD, extensive proliferative vitreoretinopathy, peripheral choroidal detachment and neovascular glaucoma in her right eye. Fundus examination of her left eye showed an attached retina with sharply-demarcated peripheral chorioretinal atrophic patches suggestive of GA. Whole exome sequencing confirmed GA by revealing a homozygous c.980 C > G (p. Pro327Arg) variant in exon 8 of OAT. The RRD was inoperable. The chorioretinal lesions in the left eye enlarged slowly over 3 years of follow up. Examination of the proband's older sister revealed a similar but more advanced GA phenotype in both eyes.Conclusions: A characteristic GA phenotype associated with a novel variant in OAT is reported. This variant might be associated with childhood-onset RRD in the proband.
Asunto(s)
Atrofia Girata/patología , Mutación , Ornitina-Oxo-Ácido Transaminasa/genética , Fenotipo , Desprendimiento de Retina/patología , Adolescente , Niño , Femenino , Atrofia Girata/complicaciones , Atrofia Girata/genética , Humanos , Pronóstico , Desprendimiento de Retina/complicaciones , Desprendimiento de Retina/genética , Estudios RetrospectivosRESUMEN
BACKGROUND AND OBJECTIVE: To understand the microvascular abnormalities in cystoid macular edema (CME) in gyrate atrophy. PATIENTS AND METHODS: Spectral-domain optical coherence tomography (SD-OCT) and OCT angiography (OCTA) were used in four consecutive female patients (eight eyes) with clinically and biochemistry-confirmed cases of gyrate atrophy and associated CME. Foveal avascular zone (FAZ) area and macular vessel density percentage were calculated and compared with normal subjects. RESULTS: The average age was 20 years (range: 13 years to 32 years). The mean refractive error was -6.5 diopters (D) (range: -1.0 D to -11.0 D). The average central macular thickness was 509 µm (range: 291 µm to 750 µm). OCTA showed an enlarged FAZ in the deep capillary plexus (DCP) with presence of hyporeflective cysts in both the superficial and deep capillary layers corresponding to CME. Compared to the normal subjects, the mean FAZ area was enlarged and macular vessel density was reduced in both the superficial capillary plexus and DCP; this was statistically significant (P < .05). En face OCT of the DCPs showed classical hyporeflective honeycomb pattern delineating the structural pattern of CME in the inner plexiform and outer plexiform layer. CONCLUSION: OCTA helps understand the basic pathophysiologic mechanisms in gyrate atrophy of choroid as well as etiology for CME and macular schisis. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:423-427.].
Asunto(s)
Angiografía con Fluoresceína/métodos , Atrofia Girata/complicaciones , Mácula Lútea/irrigación sanguínea , Edema Macular/patología , Vasos Retinianos/patología , Tomografía de Coherencia Óptica/métodos , Adolescente , Adulto , Femenino , Atrofia Girata/patología , Humanos , Edema Macular/diagnóstico por imagen , Edema Macular/etiología , Masculino , Adulto JovenRESUMEN
Gyrate atrophy (GA) is a rare recessive disorder characterized by progressive blindness, chorioretinal degeneration and systemic hyperornithinemia. GA is caused by point mutations in the gene encoding ornithine δ-aminotransferase (OAT), a tetrameric pyridoxal 5'-phosphate-dependent enzyme catalysing the transamination of l-ornithine and α-ketoglutarate to glutamic-γ-semialdehyde and l-glutamate in mitochondria. More than 50 OAT variants have been identified, but their molecular and cellular properties are mostly unknown. A subset of patients is responsive to pyridoxine administration, although the mechanisms underlying responsiveness have not been clarified. Herein, we studied the effects of the V332M mutation identified in pyridoxine-responsive patients. The Val332-to-Met substitution does not significantly affect the spectroscopic and kinetic properties of OAT, but during catalysis it makes the protein prone to convert into the apo-form, which undergoes unfolding and aggregation under physiological conditions. By using the CRISPR/Cas9 technology we generated a new cellular model of GA based on HEK293 cells knock-out for the OAT gene (HEK-OAT_KO). When overexpressed in HEK-OAT_KO cells, the V332M variant is present in an inactive apodimeric form, but partly shifts to the catalytically-competent holotetrameric form in the presence of exogenous PLP, thus explaining the responsiveness of these patients to pyridoxine administration. Overall, our data represent the first integrated molecular and cellular analysis of the effects of a pathogenic mutation in OAT. In addition, we validated a novel cellular model for the disease that could prove instrumental to define the molecular defect of other GA-causing variants, as well as their responsiveness to pyridoxine and other putative drugs.
Asunto(s)
Atrofia Girata/genética , Ornitina-Oxo-Ácido Transaminasa/genética , Agregación Patológica de Proteínas/genética , Fosfato de Piridoxal/metabolismo , Complejo Vitamínico B/farmacología , Sistemas CRISPR-Cas/genética , Coenzimas/metabolismo , Pruebas de Enzimas , Técnicas de Inactivación de Genes , Atrofia Girata/tratamiento farmacológico , Atrofia Girata/patología , Células HEK293 , Holoenzimas/genética , Holoenzimas/metabolismo , Humanos , Mutagénesis Sitio-Dirigida , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Mutación Puntual , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/patología , Piridoxina/farmacología , Piridoxina/uso terapéutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Resultado del Tratamiento , Complejo Vitamínico B/uso terapéuticoRESUMEN
The study aims to determine the progression of gyrate atrophy by measuring the area growth of chorioretinal atrophic lesions using ultra-wide-field images (UWFI). A retrospective, observational, and comparative study was conducted and UWFI (200°) were obtained from two patients with gyrate atrophy at baseline and follow-up. Measurements of atrophy were obtained for three types of lesions: Solitary atrophic lesions (SAL), De novo solitary lesions (DNSL), and peripapillary atrophy (PPA). Comparison of baseline and follow-up was done using t tests. Two patients with gyrate atrophy were included. Patient 1 presented 16 SAL, 5 DNSL, and PPA measured for both eyes (BE). Overall area growth (OAG) for SAL (expressed in decimals) presented a mean of 3.41, σ 3.07. DNSL area for BE presented a mean of 1586.08 P (2), σ 1069.55. OAG for PPA presented a mean of 1.21, σ 0.17. Patient 2 presented 5 SAL, no DNSL, and PPA was measured for BE. OAG for SAL presented a mean of 1.58, σ 1.05 (range 1.02-3.47). OAG for PPA presented a mean of 1.05, σ 0.001. Gyrate atrophy progression can be determined by measuring the changes in area using UWFI.
Asunto(s)
Técnicas de Diagnóstico Oftalmológico , Atrofia Girata/patología , Adulto , Coroides/patología , Progresión de la Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Fotograbar , Retina/patología , Degeneración Retiniana/patología , Estudios RetrospectivosRESUMEN
We studied eight kindreds with gyrate atrophy of choroid and retina (GA), a rare autosomal recessive disorder caused by mutations of the OAT gene, encoding the homoexameric enzyme ornithine-delta-aminotransferase. We identified four novel and five previously reported mutations. Missense alleles were expressed in yeast strain carrying a deletion of the orthologous of human OAT. All mutations markedly reduced enzymatic activity. However, the effect on the yeast growth was variable, suggesting that some mutations retain residual activity, below the threshold of the enzymatic assay. Mutant proteins were either highly unstable and rapidly degraded, or failed to assemble to form the active OAT hexamer. Where possible, fibroblast analysis confirmed these data. We found no correlation between the residual enzymatic activity and the age of onset, or the severity of symptoms. Moreover, the response to B6 was apparently not related to the specific mutations carried by patients. Overall these data suggest that other factors besides the specific OAT genotype modulate (GA) phenotype in patients. Finally, we found that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), an AMPK activator known to increase mitochondrial biogenesis, markedly stimulates OAT expression, thus representing a possible treatment for a subset of GA patients with hypomorphic alleles.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Atrofia Girata/genética , Mutación Missense , Ornitina-Oxo-Ácido Transaminasa/genética , Secuencia de Aminoácidos , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Células Cultivadas , Análisis Mutacional de ADN , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Prueba de Complementación Genética , Genotipo , Atrofia Girata/enzimología , Atrofia Girata/patología , Células HEK293 , Humanos , Immunoblotting , Modelos Moleculares , Datos de Secuencia Molecular , Ornitina-Oxo-Ácido Transaminasa/química , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Fenotipo , Estructura Terciaria de Proteína , Ribonucleótidos/farmacología , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crecimiento & desarrollo , Homología de Secuencia de AminoácidoRESUMEN
Differentiation methods for human induced pluripotent stem cells (hiPSCs) typically yield progeny from multiple tissue lineages, limiting their use for drug testing and autologous cell transplantation. In particular, early retina and forebrain derivatives often intermingle in pluripotent stem cell cultures, owing to their shared ancestry and tightly coupled development. Here, we demonstrate that three-dimensional populations of retinal progenitor cells (RPCs) can be isolated from early forebrain populations in both human embryonic stem cell and hiPSC cultures, providing a valuable tool for developmental, functional, and translational studies. Using our established protocol, we identified a transient population of optic vesicle (OV)-like structures that arose during a time period appropriate for normal human retinogenesis. These structures were independently cultured and analyzed to confirm their multipotent RPC status and capacity to produce physiologically responsive retinal cell types, including photoreceptors and retinal pigment epithelium (RPE). We then applied this method to hiPSCs derived from a patient with gyrate atrophy, a retinal degenerative disease affecting the RPE. RPE generated from these hiPSCs exhibited a disease-specific functional defect that could be corrected either by pharmacological means or following targeted gene repair. The production of OV-like populations from human pluripotent stem cells should facilitate the study of human retinal development and disease and advance the use of hiPSCs in personalized medicine.
Asunto(s)
Evaluación Preclínica de Medicamentos/métodos , Células Madre Pluripotentes/fisiología , Enfermedades de la Retina/terapia , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Línea Celular , Expresión Génica , Terapia Genética , Atrofia Girata/patología , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Potenciales de la Membrana , Técnicas de Placa-Clamp , Células Fotorreceptoras/metabolismo , Células Fotorreceptoras/patología , Células Fotorreceptoras/fisiología , Medicina de Precisión , Prosencéfalo/embriología , Retina/embriología , Retina/patología , Epitelio Pigmentado de la Retina/patología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Gyrate atrophy is a rare metabolic disease characterized by hyperornithinemia, typical retinal and choroidal lesions, high myopia with marked astigmatism, early cataract formation, and autosomal recessive inheritance pattern. In this paper, we describe a 12-year-old boy presenting with high myopia and gyrate fundus lesions, in addition to 10-times elevated serum ornithine level.
Asunto(s)
Enfermedades de la Retina/diagnóstico , Niño , Angiografía con Fluoresceína , Atrofia Girata/diagnóstico , Atrofia Girata/patología , Atrofia Girata/terapia , Humanos , Masculino , Ornitina/sangre , Enfermedades de la Retina/sangre , Enfermedades de la Retina/patología , Enfermedades de la Retina/terapiaRESUMEN
Gene-corrected patient-specific induced pluripotent stem (iPS) cells offer a unique approach to gene therapy. Here, we begin to assess whether the mutational load acquired during gene correction of iPS cells is compatible with use in the treatment of genetic causes of retinal degenerative disease. We isolated iPS cells free of transgene sequences from a patient with gyrate atrophy caused by a point mutation in the gene encoding ornithine-δ-aminotransferase (OAT) and used homologous recombination to correct the genetic defect. Cytogenetic analysis, array comparative genomic hybridization (aCGH), and exome sequencing were performed to assess the genomic integrity of an iPS cell line after three sequential clonal events: initial reprogramming, gene targeting, and subsequent removal of a selection cassette. No abnormalities were detected after standard G-band metaphase analysis. However, aCGH and exome sequencing identified two deletions, one amplification, and nine mutations in protein coding regions in the initial iPS cell clone. Except for the targeted correction of the single nucleotide in the OAT locus and a single synonymous base-pair change, no additional mutations or copy number variation were identified in iPS cells after the two subsequent clonal events. These findings confirm that iPS cells themselves may carry a significant mutational load at initial isolation, but that the clonal events and prolonged cultured required for correction of a genetic defect can be accomplished without a substantial increase in mutational burden.
Asunto(s)
Atrofia Girata/enzimología , Atrofia Girata/genética , Ornitina-Oxo-Ácido Transaminasa/genética , Ornitina-Oxo-Ácido Transaminasa/metabolismo , Células Madre Pluripotentes/enzimología , Células Cultivadas , Marcación de Gen/métodos , Estudio de Asociación del Genoma Completo , Inestabilidad Genómica/genética , Atrofia Girata/patología , Atrofia Girata/terapia , Humanos , Células Madre Pluripotentes/patología , Recombinación GenéticaRESUMEN
A 4-year-old girl was hospitalized for psychomotor delay, low vision, and horizontal nystagmus. She was found to have bilateral chorioretinal atrophic scars and 2 large occipital porencephalic cavities. High plasma ornithine levels led to the presumed diagnosis of gyrate atrophy of the choroid and retina. After 6 months of arginine-restricted diet and high-dose pyridoxine (300 mg/d), there was no change of plasma ornithine level or ocular findings. To our knowledge, this is the first report showing an association of porencephaly with gyrate atrophy of the choroid and retina.
Asunto(s)
Encefalopatías/etiología , Enfermedades de la Coroides/etiología , Atrofia Girata/etiología , Degeneración Retiniana/etiología , Atrofia , Encefalopatías/patología , Preescolar , Enfermedades de la Coroides/patología , Femenino , Atrofia Girata/complicaciones , Atrofia Girata/patología , Atrofia Girata/terapia , Humanos , Imagen por Resonancia Magnética , Degeneración Retiniana/patologíaRESUMEN
The authors describe a case of gyrate atrophy detected in a one-month baby born at 34 weeks post-conception age. Up to 2 months of life, the disease progressed--an increase in the number of foci of atrophy of the choriod and retinal pigment epithelium, there was a trend towards their fusion. The condition stabilized after the use of vitamin B6.
Asunto(s)
Atrofia Girata/diagnóstico , Atrofia Girata/tratamiento farmacológico , Vitamina B 6/uso terapéutico , Complejo Vitamínico B/uso terapéutico , Femenino , Atrofia Girata/patología , Humanos , Lactante , Resultado del TratamientoRESUMEN
PURPOSE: To describe the use of 4 mg intravitreal triamcinolone acetonide (IVTA) for gyrate atrophy-related macular edema (ME) and to report anatomic and functional outcomes, during a nine-month period. CASE REPORT: A 27-year-old female complained of decreased vision since diagnosis of gyrate athrophy (GA), six years before admission. At presentation visual acuity was 20/100 in OD and 20/80 in OS. Ophthalmological examination disclosed significant cataract in OD, pseudophakia in OS and typical GA findings. Fluorescein angiography (FA) disclosed ME that was confirmed by optical coherence tomography (OCT), which also showed subfoveal fluid. OS was treated with a 4-mg IVTA injection. One month later, vision improved to 20/50+1 and foveal thickness decreased, with less leakage in FA. This picture was maintained up to six months, when there was recurrence of ME to a level similar to the baseline. At nine months, visual acuity dropped to 20/80, and ME was maintained, with remodeling in macular profile. CONCLUSION: There is a transient therapeutic effect with 4-mg IVTA injection for GA-related ME. After drug clearance, edema recurs, with return of visual acuity to pretreatment level.
Asunto(s)
Glucocorticoides/uso terapéutico , Atrofia Girata/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Triamcinolona Acetonida/uso terapéutico , Adulto , Femenino , Angiografía con Fluoresceína , Glucocorticoides/administración & dosificación , Atrofia Girata/complicaciones , Atrofia Girata/patología , Humanos , Edema Macular/etiología , Edema Macular/patología , Recurrencia , Factores de Tiempo , Tomografía de Coherencia Óptica , Triamcinolona Acetonida/administración & dosificación , Agudeza Visual/fisiología , Cuerpo VítreoRESUMEN
PURPOSE: To describe the use of 4 mg intravitreal triamcinolone acetonide (IVTA) for gyrate atrophy-related macular edema (ME) and to report anatomic and functional outcomes, during a nine-month period. CASE REPORT: A 27-year-old female complained of decreased vision since diagnosis of gyrate athrophy (GA), six years before admission. At presentation visual acuity was 20/100 in OD and 20/80 in OS. Ophthalmological examination disclosed significant cataract in OD, pseudophakia in OS and typical GA findings. Fluorescein angiography (FA) disclosed ME that was confirmed by optical coherence tomography (OCT), which also showed subfoveal fluid. OS was treated with a 4-mg IVTA injection. One month later, vision improved to 20/50+1 and foveal thickness decreased, with less leakage in FA. This picture was maintained up to six months, when there was recurrence of ME to a level similar to the baseline. At nine months, visual acuity dropped to 20/80, and ME was maintained, with remodeling in macular profile. CONCLUSION:There is a transient therapeutic effect with 4-mg IVTA injection for GA-related ME. After drug clearance, edema recurs, with return of visual acuity to pretreatment level.
OBJETIVO: Descrever o uso de acetonida de triancinolona intravítrea (TAIV) em caso de edema macular (EM) associado a atrofia girata (AG). RELATO DE CASO: Paciente de 27 anos, do sexo feminino, queixava-se de baixa de visão desde o diagnóstico de AG, há seis anos. À admissão, apresentava acuidade visual corrigida de 20/100 no OD e 20/80 no OE. Exame oftalmológico revelava catarata significativa no OD, pseudofacia no OE e achados típicos de AG. Angiografia fluoresceínica (AFG) mostrou EM, confirmado pela tomografia de coerência óptica (OCT), que também revelou líquido subfoveal. Foi então realizada injeção de 4 mg de TAIV no OE. Após um mês, a visão melhorou para 20/50+1 e a espessura foveal se reduziu, com menos extravasamento à AFG. Esse quadro foi mantido até os seis meses, quando houve recorrência do edema macular em nível semelhante ao inicial. Aos nove meses, a visão retornou a 20/80 e o edema se manteve, com remodelamento no perfil macular. CONCLUSÃO: A injeção de 4 mg de TAIV tem efeito transitório no EM associado a AG. Após a eliminação da droga, há recorrência do EM, com retorno da visão aos níveis pré-tratamento.
Asunto(s)
Adulto , Femenino , Humanos , Glucocorticoides/uso terapéutico , Atrofia Girata/tratamiento farmacológico , Edema Macular/tratamiento farmacológico , Triamcinolona Acetonida/uso terapéutico , Angiografía con Fluoresceína , Glucocorticoides/administración & dosificación , Atrofia Girata/complicaciones , Atrofia Girata/patología , Edema Macular/etiología , Edema Macular/patología , Recurrencia , Factores de Tiempo , Tomografía de Coherencia Óptica , Triamcinolona Acetonida/administración & dosificación , Cuerpo Vítreo , Agudeza Visual/fisiologíaRESUMEN
Gyrate atrophy of the choroid and retina is an autosomal recessive chorioretinal dystrophy which leads to a slowly progressive loss of vision. The primary defect is due to a deficiency of the enzyme ornithine delta-aminotransferase, which is responsible for markedly elevated levels of ornithine in plasma and other body fluids. Although several therapeutic regimens have been proposed, the reduction in ornithine accumulation obtained by reducing the intake of its precursor arginine (semisynthetic low-arginine diet) is the one most practised. In this clinical and molecular study we report a patient with hyperornithinaemia and gyrate atrophy of the choroid and retina who had been diagnosed when she was 3 years 9 months old. She also presented mild mental retardation, delayed language development and speech defects. The patient has recently been found to be homozygous for the new Gly91Arg amino acid substitution of the enzyme ornithine delta-aminotransferase. This mutation lies in a region of the mature protein that is considered crucial for the mitochondrial targeting activity. In this patient, a 28-year treatment with a completely natural low-protein diet (0.8 g/kg per day of natural protein) has been able to significantly reduce ornithine plasma levels, and to greatly delay the natural progression of the chorioretinal changes. This study suggests that, in the long-term treatment of gyrate atrophy, the efficacy in slowing the progression of chorioretinal changes and the palatability of a completely natural low-protein diet make this treatment a potentially viable alternative in patients refusing the semisynthetic diet.