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PURPOSE OF REVIEW: This paper provides an update on intravitreal (IVT) enzyme replacement therapy (ERT) in metabolic retinal diseases; particularly neuronal ceroid lipofuscinosis type 2 (CLN2) also known as Batten disease. RECENT FINDINGS: ERT is being explored in CLN2 related Batten disease, a fatal neurodegenerative condition associated with retinopathy and blindness that is caused by the deficiency of lysosomal enzyme TPP1. Cerliponase alfa, a recombinant human tripeptidyl-peptidase1 (rhTPP1) administered by intraventricular infusions has been demonstrated to slow the rate of neurodegenerative decline but not retinopathy. A preclinical study of IVT rhTPP1 in a CLN2 canine model demonstrated efficacy in preserving retinal function and retinal morphology shown on histology. More recently, intravitreal (IVT) administration of rhTPP1 was reported in a first-in-human compassionate use study. Patients received 12-18âmonths of 8-weekly IVT ERT (0.2âmg rhTPP-1 in 0.05âml) in one eye. No significant ocular adverse reactions were reported. Treatment decreased the rate of retinal thinning but modestly. SUMMARY: The evidence suggests that IVT ERT with rhTPP1 may be a safe and effective treatment for CLN2 retinopathy. However, the optimal dosage and frequency to achieve the best possible outcomes requires further investigation as does patient selection.
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Lipofuscinoses Ceroides Neuronais , Degeneração Retiniana , Humanos , Animais , Cães , Tripeptidil-Peptidase 1 , Aminopeptidases/genética , Aminopeptidases/efeitos adversos , Serina Proteases/uso terapêutico , Serina Proteases/efeitos adversos , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Lipofuscinoses Ceroides Neuronais/complicações , Degeneração Retiniana/tratamento farmacológico , Terapia de Reposição de Enzimas/efeitos adversosRESUMO
Biallelic mutations in G-Protein coupled receptor kinase 1 (GRK1) cause Oguchi disease, a rare subtype of congenital stationary night blindness (CSNB). The purpose of this study was to identify disease causing GRK1 variants and use in-depth bioinformatic analyses to evaluate how their impact on protein structure could lead to pathogenicity. Patients' genomic DNA was sequenced by whole genome, whole exome or focused exome sequencing. Disease associated variants, published and novel, were compared to nondisease associated missense variants. The impact of GRK1 missense variants at the protein level were then predicted using a series of computational tools. We identified twelve previously unpublished cases with biallelic disease associated GRK1 variants, including eight novel variants, and reviewed all GRK1 disease associated variants. Further structure-based scoring revealed a hotspot for missense variants in the kinase domain. In addition, to aid future clinical interpretation, we identified the bioinformatics tools best able to differentiate disease associated from nondisease associated variants. We identified GRK1 variants in Oguchi disease patients and investigated how disease-causing variants may impede protein function in-silico.
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Oftalmopatias Hereditárias , Receptor Quinase 1 Acoplada a Proteína G , Cegueira Noturna , Oftalmopatias Hereditárias/genética , Receptor Quinase 1 Acoplada a Proteína G/genética , Humanos , Cegueira Noturna/genéticaRESUMO
PURPOSE: Proteus syndrome arises as a result of a post-zygotic mosaic activating mutation in the AKT1 oncogene, causing a disproportionate overgrowth of affected tissues. A small number of ocular complications have been reported. We present the unique findings in a patient who had molecular confirmation of AKT1 mosaicism alongside fulfilling the clinical criteria for Proteus syndrome. METHODS: Pattern electroretinography, visual evoked potentials and multifocal electroretinography testing were performed alongside detailed retinal imaging and clinical examination to detail the ophthalmic characteristics. RESULTS: Electrophysiological findings characterised unilateral macular dysfunction alongside sector retinal dysfunction of the right eye. This was demonstrated through optical coherence tomography and ultra-wide-field imaging to be associated with a misaligned foveal morphology and sector retinal dysfunction extending into the temporal retina. CONCLUSION: We propose this patient has asymmetric foveal development and concomitant sector retinal dysfunction as the result of the mosaic AKT1 mutation, either through disruption in the retinal PI3K-AKT1 signalling pathway or through mechanical distortion of ocular growth, resulting in disproportionate inner retinal development. The findings expand the ocular phenotype of Proteus syndrome and encourage early assessment to identify any incipient ocular abnormalities.
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Síndrome de Proteu , Eletrorretinografia , Potenciais Evocados Visuais , Fóvea Central , Humanos , Síndrome de Proteu/diagnóstico , Síndrome de Proteu/genética , Proteínas Proto-Oncogênicas c-akt/genética , Tomografia de Coerência ÓpticaRESUMO
Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in CHM in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.
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Análise Mutacional de DNA , Variação Genética/genética , Genoma Humano/genética , Doenças Retinianas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Sequência de Bases , Coroideremia/genética , Etnicidade/genética , Exoma/genética , Feminino , Genes Recessivos/genética , Humanos , Íntrons/genética , Masculino , Mutação , Doenças Raras/genéticaRESUMO
Structural eye disorders are increasingly recognised as having a genetic basis, although current genetic testing is limited in its success. De novo missense variants in WDR37 are a recently described cause of a multisystemic syndromic disorder featuring ocular coloboma. This study characterises the phenotypic spectrum of this disorder and reports 2 de novo heterozygous variants (p.Thr115Ile, p.Ser119Tyr) in three unrelated Caucasian individuals. All had a clinical phenotype consisting of bilateral iris and retinal coloboma, developmental delay and additional, variable multisystem features. The variants fall within a highly conserved region upstream of the WD-repeat domains, within an apparent mutation cluster. Consistent with the literature, intellectual disability, structural eye disorders, epilepsy, congenital heart disease, genitorenal anomalies and dysmorphic facial features were observed. In addition, a broader developmental profile is reported with a more specific musculoskeletal phenotype described in association with the novel variant (p.Thr115Ile). We further expand the phenotypic spectrum of WDR37-related disorders to include those with milder developmental delay and strengthen the association of ocular coloboma and musculoskeletal features. We promote the inclusion of WDR37 on gene panels for intellectual disability, epilepsy and structural eye disorders.
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Coloboma/genética , Oftalmopatias/genética , Deficiência Intelectual/genética , Anormalidades Musculoesqueléticas/genética , Proteínas Nucleares/genética , Adolescente , Adulto , Criança , Pré-Escolar , Coloboma/complicações , Coloboma/patologia , Epilepsia/complicações , Epilepsia/genética , Epilepsia/patologia , Oftalmopatias/complicações , Oftalmopatias/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/complicações , Deficiência Intelectual/patologia , Masculino , Anormalidades Musculoesqueléticas/complicações , Anormalidades Musculoesqueléticas/patologia , Mutação/genética , Mutação de Sentido Incorreto/genética , Fenótipo , Adulto JovemRESUMO
IMPORTANCE: There is variation in the literature for sclerotomy and intravitreal injection placement in young children, ranging from 0.5 to 3.0 mm from the limbus. We assess the accuracy of scleral transillumination to identify the ciliary body in infants for safe sclerotomy and intravitreal injections in young children. BACKGROUND: The study compares the perilimbal "dark band" seen on scleral transillumination (STI) with the ultrasound biomicroscopy (UBM), and compares these measurements with the current guidelines for sclerotomy in infants. DESIGN: Prospective case series in a tertiary paediatric hospital. PARTICIPANTS: Children aged ≤36 months undergoing general anaesthesia for eye procedures. METHODS: Scleral transillumination was performed to measure the perilimbal dark band. UBM of the ciliary body region was then performed, and correlated with transillumination findings. MAIN OUTCOME MEASURES: The midpoints of STI and UBM were compared to current cadaver-based guidelines to assess the safe point for sclerotomy. RESULTS: Twenty children were recruited, 36 STI and 35 UBM measurements were obtained. The posterior edge of the dark band had good correlation with the posterior border of the ciliary body. Transillumination and UBM correlated well for midpoint measurements. The midpoint of the dark band on transillumination was confirmed to be in the ciliary body by UBM in all cases. CONCLUSIONS AND RELEVANCE: The STI technique is a useful and fast technique to demonstrate the ciliary body. The midpoint of the dark band on STI correlates well with the UBM, and has a potential use for confirming safe-entry into the posterior segment if using current guidelines. The current cadaver-based paediatric guidelines safely avoid retinal injury.
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Corpo Ciliar/diagnóstico por imagem , Injeções Intravítreas , Esclera/efeitos da radiação , Esclerostomia , Transiluminação/métodos , Anestesia Geral , Pré-Escolar , Retinopatia Diabética/cirurgia , Feminino , Humanos , Lactente , Luz , Masculino , Microscopia Acústica , Estudos Prospectivos , Reprodutibilidade dos Testes , Vitrectomia , Hemorragia Vítrea/cirurgiaRESUMO
Retinal dystrophies are a heterogeneous group of disorders of visual function leading to partial or complete blindness. We report the genetic basis of an unusual retinal dystrophy in five families with affected females and no affected males. Heterozygous missense variants were identified in the X-linked phosphoribosyl pyrophosphate synthetase 1 (PRPS1) gene: c.47C > T, p.(Ser16Phe); c.586C > T, p.(Arg196Trp); c.641G > C, p.(Arg214Pro); and c.640C > T, p.(Arg214Trp). Missense variants in PRPS1 are usually associated with disease in male patients, including Arts syndrome, Charcot-Marie-Tooth, and nonsyndromic sensorineural deafness. In our study families, affected females manifested a retinal dystrophy with interocular asymmetry. Three unrelated females from these families had hearing loss leading to a diagnosis of Usher syndrome. Other neurological manifestations were also observed in three individuals. Our data highlight the unexpected X-linked inheritance of retinal degeneration in females caused by variants in PRPS1 and suggest that tissue-specific skewed X-inactivation or variable levels of pyrophosphate synthetase-1 deficiency are the underlying mechanism(s). We speculate that the absence of affected males in the study families suggests that some variants may be male embryonic lethal when inherited in the hemizygous state. The unbiased nature of next-generation sequencing enables all possible modes of inheritance to be considered for association of gene variants with novel phenotypic presentation.
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Genes Ligados ao Cromossomo X , Mutação de Sentido Incorreto , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Ribose-Fosfato Pirofosfoquinase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Modelos Moleculares , Linhagem , Fenótipo , Conformação Proteica , Ribose-Fosfato Pirofosfoquinase/química , Adulto JovemRESUMO
PURPOSE: To determine the feasibility and safety of bilateral simultaneous vitreoretinal surgery in pediatric patients. DESIGN: International, multicenter, interventional, retrospective case series. PARTICIPANTS: Patients 17 years of age or younger from 24 centers worldwide who underwent immediate sequential bilateral vitreoretinal surgery (ISBVS)-defined as vitrectomy, scleral buckle, or lensectomy using the vitreous cutter-performed in both eyes sequentially during the same anesthesia session. METHODS: Clinical history, surgical details and indications, time under anesthesia, and intraoperative and postoperative ophthalmic and systemic adverse events were reviewed. MAIN OUTCOME MEASURES: Ocular and systemic adverse events. RESULTS: A total of 344 surgeries from 172 ISBVS procedures in 167 patients were included in the study. The mean age of the cohort was 1.3±2.6 years. Nonexclusive indications for ISBVS were rapidly progressive disease (74.6%), systemic morbidity placing the child at high anesthesia risk (76.0%), and residence remote from surgery location (30.2%). The most common diagnoses were retinopathy of prematurity (ROP; 72.7% [P < 0.01]; stage 3, 4.8%; stage 4A, 44.4%; stage 4B, 22.4%; stage 5, 26.4%), familial exudative vitreoretinopathy (7.0%), abusive head trauma (4.1%), persistent fetal vasculature (3.5%), congenital cataract (1.7%), posterior capsular opacification (1.7%), rhegmatogenous retinal detachment (1.7%), congenital X-linked retinoschisis (1.2%), Norrie disease (2.3%), and viral retinitis (1.2%). Mean surgical time was 143±59 minutes for both eyes. Higher ROP stage correlated with longer surgical time (P = 0.02). There were no reported intraoperative ocular complications. During the immediate postoperative period, 2 eyes from different patients demonstrated unilateral vitreous hemorrhage (0.6%). No cases of endophthalmitis, choroidal hemorrhage, or hypotony occurred. Mean total anesthesia time was 203±87 minutes. There were no cases of anesthesia-related death, malignant hyperthermia, anaphylaxis, or cardiac event. There was 1 case of reintubation (0.6%) and 1 case of prolonged oxygen desaturation (0.6%). Mean follow-up after surgery was 103 weeks, and anatomic success and globe salvage rates were 89.8% and 98.0%, respectively. CONCLUSIONS: This study found ISBVS to be a feasible and safe treatment paradigm for pediatric patients with bilateral vitreoretinal pathologic features when repeated general anesthesia is undesirable or impractical.
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Extração de Catarata , Recurvamento da Esclera/métodos , Vitrectomia/métodos , Cirurgia Vitreorretiniana , Adolescente , Anestesia/métodos , Catarata/complicações , Criança , Pré-Escolar , Estudos de Viabilidade , Feminino , Humanos , Lactente , Internacionalidade , Masculino , Duração da Cirurgia , Vítreo Primário Hiperplásico Persistente/complicações , Vítreo Primário Hiperplásico Persistente/cirurgia , Doenças Retinianas/complicações , Doenças Retinianas/congênito , Doenças Retinianas/cirurgia , Retinopatia da Prematuridade/complicações , Retinopatia da Prematuridade/cirurgia , Retinosquise/complicações , Retinosquise/cirurgia , Estudos Retrospectivos , Vitreorretinopatia Proliferativa/complicações , Vitreorretinopatia Proliferativa/cirurgiaRESUMO
BACKGROUND: Careful surgical management of traumatic wounds is important in open globe injury repair. This study examines the clinical outcomes following repair of open globe injuries with particular focus on wound-related issues. DESIGN: Retrospective, cohort study of consecutive open globe injuries presenting to a tertiary referral eye hospital from 1 January 2009 to 31 December 2011. PARTICIPANTS: A total of 267 eyes of 263 patients, mainly male (82.5%) with a mean age of 44.8 (range: 4-97) years. Average follow up was 6.9 months. METHODS: All cases classified according to Ocular Trauma Classification Group. MAIN OUTCOME MEASURES: Visual outcomes, risk factors for and rates of postoperative complications and endophthalmitis. RESULTS: There were 83 globe ruptures, 182 penetrating and 2 perforating eye injuries, of which 43 cases had intraocular foreign body. Factors contributing to final visual acuity (VA) <6/60 were poor presenting VA (odds ratio [OR] = 16.0, 95% confidence interval [CI]: 4.81-53.1), globe rupture (OR = 4.64, [1.99-10.8]), retinal detachment (OR = 3.40, [1.19-9.74]) and age ≥50 (OR = 2.45, [1.05-5.74]). Wound leak occurred in 44 eyes (16%). Of these, 18 (41%) proceeded to re-suturing. Factors contributing to wound leak were stellate-shaped wound (OR = 3.28, [1.39-7.73]) and delayed presentation (OR = 2.80, [1.02-7.71]). Ten eyes (3.7%) developed endophthalmitis. Factors associated with endophthalmitis were delayed presentation (OR = 8.91, [1.71-46.6]), microbial keratitis (OR = 12.5, [1.85-85.0]) and lens capsule breach (OR = 12.4, [1.85-83.1]). CONCLUSIONS: Wound leak is an important postoperative complication of open globe injury repair. Delayed presentation is an important risk factor for postoperative wound leak and endophthalmitis. Prompt and meticulous wound management of open globe injury may reduce these complications.
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Corpos Estranhos no Olho/cirurgia , Ferimentos Oculares Penetrantes/cirurgia , Complicações Pós-Operatórias , Deiscência da Ferida Operatória/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Lesões da Córnea/fisiopatologia , Lesões da Córnea/cirurgia , Endoftalmite/etiologia , Corpos Estranhos no Olho/fisiopatologia , Ferimentos Oculares Penetrantes/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Oftalmológicos , Estudos Retrospectivos , Fatores de Risco , Esclera/lesões , Deiscência da Ferida Operatória/fisiopatologia , Deiscência da Ferida Operatória/cirurgia , Acuidade Visual/fisiologia , Cicatrização/fisiologiaRESUMO
BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.
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Lipofuscinoses Ceroides Neuronais , Distrofias Retinianas , Criança , Humanos , Animais , Cães , Tripeptidil-Peptidase 1 , Aminopeptidases/efeitos adversos , Serina Proteases/efeitos adversos , Dipeptidil Peptidases e Tripeptidil Peptidases/uso terapêutico , Lipofuscinoses Ceroides Neuronais/tratamento farmacológico , Terapia de Reposição de Enzimas , Injeções Intravítreas , Distrofias Retinianas/induzido quimicamente , Distrofias Retinianas/complicações , Distrofias Retinianas/tratamento farmacológicoRESUMO
BACKGROUND: Ciliopathies responsible for retinitis pigmentosa can also cause systemic manifestations. RPGR is a ciliary gene and pathogenic variants in RPGR cause a retinal ciliopathy, the commonest cause of X-linked recessive retinitis pigmentosa. The RPGR protein interacts with numerous other ciliary proteins present in the transition zone of both motile and sensory cilia, and may play an important role in regulating ciliary protein transport. There has been a growing, putative association of RPGR variants with systemic ciliopathies: mainly sino-respiratory infections and primary ciliary dyskinesia. MATERIALS AND METHODS: Retrospective case series of patients with RPGR-RP presenting to Oxford Eye Hospital with systemic disease. RESULTS: We report three children with RPGR-related rod-cone dystrophy, all of whom have mutations in the N-terminus of RPGR. Two cases co-presented with confirmed diagnoses of primary ciliary dyskinesia and one case with multiple sino-respiratory symptoms strongly suggestive of primary ciliary dyskinesia. These and all previously reported RPGR co-pathologies relate to ciliopathies and have no other systemic associations. CONCLUSIONS: The link between RPGR variants and a systemic ciliopathy remains plausible, but currently unproven.
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Transtornos da Motilidade Ciliar , Proteínas do Olho , Distrofias Retinianas , Distrofias Retinianas/complicações , Distrofias Retinianas/genética , Humanos , Proteínas do Olho/genética , Masculino , Criança , Adolescente , Transtornos da Motilidade Ciliar/complicações , Transtornos da Motilidade Ciliar/genéticaRESUMO
PURPOSE: To assess the safety and efficacy of AAV8-hCARp.hCNGB3 in participants with CNGB3-associated achromatopsia (ACHM). DESIGN: Prospective, phase 1/2 (NCT03001310), open-label, nonrandomized clinical trial. METHODS: The study enrolled 23 adults and children with CNGB3-associated ACHM. In the dose-escalation phase, adult participants were administered 1 of 3 AAV8-hCARp.hCNGB3 dose levels in the worse-seeing eye (up to 0.5 mL). After a maximum tolerated dose was established in adults, an expansion phase was conducted in children ≥3 years old. All participants received topical and oral corticosteroids. Safety and efficacy parameters, including treatment-related adverse events and visual acuity, retinal sensitivity, color vision, and light sensitivity, were assessed for 6 months. RESULTS: AAV8-hCARp.hCNGB3 (11 adults, 12 children) was safe and generally well tolerated. Intraocular inflammation occurred in 9 of 23 participants and was mainly mild or moderate in severity. Severe cases occurred primarily at the highest dose. Two events were considered serious and dose limiting. All intraocular inflammation resolved following topical and systemic steroids. There was no consistent pattern of change from baseline to week 24 for any efficacy assessment. However, favorable changes were observed for individual participants across several assessments, including color vision (nâ¯=â¯6/23), photoaversion (nâ¯=â¯11/20), and vision-related quality-of-life questionnaires (nâ¯=â¯21/23). CONCLUSIONS: AAV8-hCARp.hCNGB3 for CNGB3-associated ACHM demonstrated an acceptable safety and tolerability profile. Improvements in several efficacy parameters indicate that AAV8-hCARp.hCNGB3 gene therapy may provide benefit. These findings, with the development of additional sensitive and quantitative end points, support continued investigation.
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Defeitos da Visão Cromática , Humanos , Adulto , Criança , Pré-Escolar , Defeitos da Visão Cromática/genética , Defeitos da Visão Cromática/terapia , Estudos Prospectivos , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Terapia Genética , InflamaçãoRESUMO
OBJECTIVES: To audit the structural and functional outcomes of surgery for acute tractional retinal detachment due to retinopathy or prematurity between 2004 and 2014 in Oxford UK. METHODS: Consecutive operations were identified from a surgical log. Clinical data including demography, perioperative data, and retinal outcomes were extracted into a spreadsheet and compared against two international data sets referenced in the method section. Nonparametric tests (Fisher's exact, and the Mann-Whitney U-tests) were used for statistical analysis with a p-value < 0.05 considered significant. RESULTS: Twenty-nine eyes of 19 babies underwent surgery. The mean age (SD) at final follow-up was 6.4 (3.7) years of age and comparable to the reference data sets. The mean birth weight and gestational age of babies matched the ETROP data set referenced in the method section. Anatomical success was obtained in 16/29 (55.2%) of eyes and more likely with stage 4 ROP than stage 5 disease (p < 0.05). Thirteen of 29 eyes (44.8%) obtained form vision post-operatively. All instances of macular retinal reattachment during follow up were verified with post-operative OCT. CONCLUSIONS: Surgery for stage 5 ROP is not worthwhile. For stage 4 ROP it yielded better visual outcomes than ETROP but registration for visual impairment was not prevented. Innovation such as endoscopic vitrectomy could yield better outcomes. Earlier detection of vitreoretinal fibrosis could result in timelier referral. A formally funded national service is needed to ring-fence resource to avoid delays in access to surgery, which has a narrow surgical window.
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Descolamento Retiniano , Retinopatia da Prematuridade , Criança , Seguimentos , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Descolamento Retiniano/etiologia , Descolamento Retiniano/cirurgia , Retinopatia da Prematuridade/complicações , Retinopatia da Prematuridade/diagnóstico , Retinopatia da Prematuridade/cirurgia , Estudos Retrospectivos , Resultado do Tratamento , Acuidade Visual , Vitrectomia/métodosRESUMO
PURPOSE: To identify patients with autosomal recessive retinal dystrophy caused by mutations in the gene, retinal dehydrogenase 12 (RDH12), and to report the associated phenotype. METHODS: After giving informed consent, all patients underwent full clinical evaluation. Patients were selected for mutation analysis based upon positive results from the Asper Ophthalmics Leber congenital amaurosis arrayed primer extansion (APEX) microarray screening, linkage analysis, or their clinical phenotype. All coding exons of RDH12 were screened by direct Sanger sequencing. Potential variants were checked for segregation in the respective families and screened in controls, and their pathogenicity analyzed using in silico prediction programs. RESULTS: Screening of 389 probands by the APEX microarray and/or direct sequencing identified bi-allelic mutations in 29 families. Seventeen novel mutations were identified. The phenotype in these patients presented with a severe early-onset rod-cone dystrophy. Funduscopy showed severe generalized retinal pigment epithelial and retinal atrophy, which progressed to dense, widespread intraretinal pigment migration by adulthood. The macula showed severe atrophy, with pigmentation and yellowing, and corresponding loss of fundus autofluorescence. Optical coherence tomography revealed marked retinal thinning and excavation at the macula. CONCLUSIONS: RDH12 mutations account for approximately 7% of disease in our cohort of patients diagnosed with Leber congenital amaurosis and early-onset retinal dystrophy. The clinical features of this disorder are highly characteristic and facilitate candidate gene screening. The term RDH12 retinopathy is proposed as a more accurate description.
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Oxirredutases do Álcool/genética , Proteínas do Olho/genética , Amaurose Congênita de Leber/genética , Retina/metabolismo , Degeneração Retiniana/genética , Retinose Pigmentar/genética , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Éxons , Feminino , Ligação Genética , Testes Genéticos , Genótipo , Humanos , Lactente , Amaurose Congênita de Leber/diagnóstico , Masculino , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Reação em Cadeia da Polimerase , Retina/patologia , Degeneração Retiniana/diagnóstico , Retinose Pigmentar/diagnóstico , Reino UnidoRESUMO
BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (CLN2 Batten disease) is a rare, progressive neurodegenerative disease of childhood. The natural history of motor and language regression is used to monitor the efficacy of CNS treatments. Less is known about CLN2 retinopathy. Our aim is to elaborate the nature, age of onset, and symmetry of CLN2 retinopathy using visual electrophysiology and ophthalmic imaging. SUBJECTS AND METHODS: We reviewed 22 patients with genetically confirmed CLN2 disease; seventeen showing classical and five atypical disease. Flash electroretinograms (ERGs), flash and pattern reversal visual evoked potentials (VEPs), recorded from awake children were collated. Available fundus images were graded, optical coherence tomography (OCT) central subfoveal thickness (CST) measured, and genotype, age, clinical vision assessment and motor language grades assembled. RESULTS: ERGs show cone/rod system dysfunction preceded by localised macular ellipsoid zone disruption on OCT from 4.8 years. Electroencephalogram (EEG) time-locked spikes confounded both pattern 6/17 (35%) and flash VEPs 12/16 (75%). Paired right eye (RE) and left eye (LE) ERG amplitudes did not differ significantly for each flash stimulus at the p 0.001 level, Wilcoxon ranked signed test. Cone ERGs show a functional deficit before CST thinning in classical disease. Optomap hyper fundus autofluorescence (FAF) at the fovea was noted in three patients with normal ERGs. The oldest patient showed an ovoid aggregate above the external limiting membrane at the fovea, which did not affect the PERG. CONCLUSION: ERG findings in CLN2 retinopathy show symmetrical cone-rod dysfunction, from 4y10m in this series, but a broad range of ages when ERG function is preserved.
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Lipofuscinoses Ceroides Neuronais , Doenças Retinianas , Criança , Eletrorretinografia , Potenciais Evocados Visuais , Humanos , Lipofuscinoses Ceroides Neuronais/diagnóstico , Lipofuscinoses Ceroides Neuronais/genética , Tomografia de Coerência Óptica , Tripeptidil-Peptidase 1RESUMO
Background: SRD5A3-CDG is a rare N-glycosylation defect caused by steroid 5 alpha reductase type 3 deficiency. Its key feature is an early severe visual impairment with variable ocular anomalies often leading to diagnosis. Additional symptoms are still poorly defined. In this case study, we discuss 11 genetically confirmed cases, and report on emerging features involving other systems in addition to the eye phenotype. Methods: In total, 11 SRD5A3-CDG patients in five sets of sibships were included in the study. Data on 9 of 11 patients are as of yet unpublished. Patients' results on biochemical and genetic investigations and on in-depth phenotyping are presented. Results: Key diagnostic features of SRD5A3-CDG are ophthalmological abnormalities with early-onset retinal dystrophy and optic nerve hypoplasia. SRD5A3-CDG is also characterized by variable neurological symptoms including intellectual disability, ataxia, and hypotonia. Furthermore, ichthyosiform skin lesions, joint laxity, and scoliosis have been observed in our cohort. We also report additional findings including dystonia, anxiety disorder, gastrointestinal symptoms, and MRI findings of small basal ganglia and mal-rotated hippocampus, whereas previous publications described dysmorphic features as a common finding in SRD5A3, which could not be confirmed in our patient cohort. Conclusion: The detailed description of the phenotype of this large cohort of patients with SRD5A3-CDG highlights that the key clinical diagnostic features of SRD5A3-CDG are an early onset form of ophthalmological problems in patients with a multisystem disorder with variable symptoms evolving over time. This should aid earlier diagnosis and confirms the need for long-time follow-up of patients.
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PURPOSE: To describe the clinical characteristics, surgical outcomes, and management recommendations in patients with traumatic rhegmatogenous retinal detachment (RRD) resulting from self-injurious behavior (SIB). DESIGN: International, multicenter, retrospective, interventional case series. PARTICIPANTS: Patients with SIB from 23 centers with RRD in at least 1 eye. METHODS: Clinical histories, preoperative assessment, surgical details, postoperative management, behavioral intervention, and follow-up examination findings were reviewed. MAIN OUTCOME MEASURES: The rate of single-surgery anatomic success (SSAS) was the primary outcome. Other outcomes included new RRD in formerly attached eyes, final retinal reattachment, and final visual acuity. RESULTS: One hundred seven eyes with RRDs were included from 78 patients. Fifty-four percent of patients had bilateral RRD or phthisis bulbi in the fellow eye at final follow-up. The most common systemic diagnoses were autism spectrum disorder (35.9%) and trisomy 21 (21.8%) and the most common behavior was face hitting (74.4%). The average follow-up time was 3.3 ± 2.8 years, and surgical outcomes for operable eyes were restricted to patients with at least 3 months of follow-up (81 eyes). Primary initial surgeries were vitrectomy alone (33.3%), primary scleral buckle (SB; 26.9%), and vitrectomy with SB (39.7%), and 5 prophylactic SBs were placed. Twenty-three eyes (21.5%) with RRDs were inoperable. The SSAS was 23.1% without tamponade (37.2% if including silicone oil), and final reattachment was attained in 80% (36.3% without silicone oil tamponade). Funnel-configured RRD (P = 0.006) and the presence of grade C proliferative vitreoretinopathy (P = 0.002) correlated with re-detachment. The use of an SB predicted the final attachment rate during the initial surgery (P = 0.005) or at any surgery (P = 0.008. These associations held if restricting to 64 patients with ≥12 months followup. Anatomic reattachment correlated with better visual acuity (P < 0.001). CONCLUSIONS: RRD resulting from SIB poses therapeutic challenges because of limited patient cooperation, bilateral involvement, chronicity, and ongoing trauma in vulnerable and neglected patients. The surgical success rates were some of the lowest in the modern retinal detachment literature. The use of an SB may result in better outcomes, and visual function can be restored in some patients.
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Traumatismos Oculares/etiologia , Retina/lesões , Descolamento Retiniano/etiologia , Recurvamento da Esclera/métodos , Comportamento Autodestrutivo/complicações , Acuidade Visual , Vitrectomia/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Tamponamento Interno/métodos , Traumatismos Oculares/diagnóstico , Traumatismos Oculares/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Retina/diagnóstico por imagem , Retina/cirurgia , Descolamento Retiniano/diagnóstico , Descolamento Retiniano/cirurgia , Estudos Retrospectivos , Óleos de Silicone/administração & dosagem , Fatores de Tempo , Índices de Gravidade do Trauma , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: To describe the clinical findings and mutations in affected members of two families with an autosomal recessive retinal dystrophy associated with mutations in the protocadherin-21 (PCDH21) gene. METHODS: A full genome scan of members of two consanguineous families segregating an autosomal recessive retinal dystrophy was performed and regions identical by descent identified. Positional candidate genes were identified and sequenced. All patients had a detailed ophthalmic examination, including electroretinography and retinal imaging. RESULTS: Affected members of both families showed identical homozygosity for an overlapping region of chromosome 10q. Sequencing of a candidate gene, PCDH21, showed two separate homozygous single-base deletions, c.337delG (p.G113AfsX1) and c.1459delG (p.G487GfsX20), which were not detected in 282 control chromosomes. Affected members of the two families first reported nyctalopia in late teenage years and retained good central vision until their late 30s. No color vision was detected in any proband. The fundus appearance included the later development of characteristic circular patches of pigment epithelial atrophy at the macula and in the peripheral retina. CONCLUSIONS: Biallelic mutations in the photoreceptor-specific gene PCDH21 cause recessive retinal degeneration in humans.
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Alelos , Caderinas/genética , Mutação/genética , Proteínas do Tecido Nervoso/genética , Degeneração Retiniana/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Proteínas Relacionadas a Caderinas , Caderinas/química , Segregação de Cromossomos/genética , Análise Mutacional de DNA , Eletrorretinografia , Éxons/genética , Família , Feminino , Fundo de Olho , Humanos , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Linhagem , Estrutura Terciária de ProteínaRESUMO
PURPOSE: To report the clinical phenotype in patients with a retinal dystrophy associated with novel mutations in the MER tyrosine kinase (MERTK) gene. METHODS: A consanguineous family of Middle Eastern origin was identified, and affected members underwent a full clinical evaluation. Linkage analysis was performed using the Affymetrix 50K chip. Regions of homozygosity were identified. The positional candidate genes protocadherin 21 (PCDH21), retinal G protein-coupled receptor (RGR), and MERTK were polymerase chain reaction (PCR) amplified and sequenced. Long-range PCR was performed to characterize the deletion. Two hundred and ninety-two probands with autosomal recessive, childhood onset, retinal dystrophies were analyzed using the Asper Ophthalmics Leber congenital amaurosis chip to screen for known MERTK mutations. RESULTS: Analysis of a 50K-Affymetrix whole genome scan identified three regions of homozygosity on chromosomes 2 and 10. Screening of the candidate gene MERTK showed a possible deletion of exon 8. Long-range PCR identified a ~9 kb deletion within MERTK that removes exon 8. Screening of DNA from a panel of Saudi Arabian patients with autosomal recessive retinitis pigmentosa identified a second consanguineous family with the same mutation. One patient with a known MERTK mutation (p.R651X) was identified using the Asper Ophthalmics Leber congenital amaurosis chip. Further screening of the gene identified a second novel splice site mutation in intron 1. The phenotype associated with these identified MERTK mutations is of a childhood onset rod-cone dystrophy with early macular atrophy. The optical coherence tomography (OCT) appearance is distinctive with evidence of debris beneath the sensory retina. CONCLUSIONS: Mutations in MERTK are a rare cause of retinal dystrophy. Non homologous recombination between Alu Y repeats near or within disease genes may be an important cause of retinal dystrophies.
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Predisposição Genética para Doença , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Retinose Pigmentar/epidemiologia , Retinose Pigmentar/genética , Adolescente , Adulto , Idade de Início , Criança , Análise Mutacional de DNA , Eletroforese em Gel de Ágar , Éxons/genética , Família , Feminino , Fundo de Olho , Genoma Humano/genética , Haplótipos/genética , Humanos , Amaurose Congênita de Leber/enzimologia , Amaurose Congênita de Leber/genética , Masculino , Linhagem , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único/genética , Retinose Pigmentar/enzimologia , Adulto Jovem , c-Mer Tirosina QuinaseRESUMO
Grouped congenital hypertrophy of the retinal pigment epithelium is a conspicuous ocular anomaly wherein highly pigmented, demarcated but flat retinal lesions arise from the retinal pigment epithelium. These lesions ("bear tracks") typically increase in size as they approach the retinal periphery. The discovery of pigmentary lesions in a young infant with a poor red reflex warrants urgent ophthalmological and electrodiagnostic review to exclude serious diagnoses, including an early-onset severe retinal dystrophy. We present the case of a 2-month-old boy with marked bear-tracks over the entirety of each retina, but with normal electrodiagnostic findings, genetics, and visual behavior.