The Natural History of LCHAD Retinopathy

LCHAD 视网膜病变的自然史

• 批准号: 10311473
• 负责人: Melanie B Gillingham
• 金额: $ 54.13万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311473
• 关键词: 3-Hydroxyacyl-CoA dehydrogenase; Acute; Address; Affect; Age; Angiography; Atrophic; Blindness; Blood; Cardiomyopathies; Cell Culture Techniques; Cessation of life; Child; Clinical; Coenzyme A; Complication; DNA Sequence Alteration; Data; Development; Diagnosis; Diet therapy; Disease; Dropout; Early Diagnosis; Early treatment; Enrollment; Environmental Risk Factor; Etiology; FDA approved; Fatty Acids; Frequencies; Functional disorder; Future; Genetic; Genotype; Germ Cells; Goals; Histopathology; Hospitalization; Hypoglycemia; Image; Imaging Techniques; Infant; Infant Mortality; Institution; Lactic Acidosis; Leber' s amaurosis; Longevity; Measures; Mediating; Metabolic; Metabolic Control; Mitochondria; Molecular; Multimodal Imaging; Mutation; Natural History; Neonatal Screening; Neural Retina; Optical Coherence Tomography; Oxides; Oxidoreductase; Pathology; Patient Outcomes Assessments; Patients; Phenotype; Photoreceptors; Physiological; Plasma; Prevention; Production; Protein Deficiency; Quality of life; RPE65 protein; Reporting; Retina; Retinal Degeneration; Retinal Diseases; Retinal gene therapy; Secondary to; Structure; Structure of retinal pigment epithelium; Time; Vision; Visual Acuity; acylcarnitine; cohort; fatty acid oxidation; gene therapy; in vivo; infant morbidity; loss of function; mathematical model; novel; photoreceptor degeneration; preservation; prevent; prospective; rate of change; retinal damage; retinal imaging; treatment trial

Project Summary Application of MS/MS to newborn screening (NBS) has facilitated the early diagnosis and treatment of infants with fatty acid oxidation disorders (FAOD) leading to decreased infant mortality and morbidity. Mitochondrial Trifunctional Protein Deficiency (TFP) deficiency, including Long-chain 3-Hdyroxyacyl-CoA Dehydrogenase (LCHAD) deficiency, are two FAOD currently included in US NBS for which prevention of hypoketotic hypoglycemia, lactic acidosis, and cardiomyopathy is generally achieved with early diagnosis and institution of contemporary dietary therapy. However, progression of chorioretinopathy with vision loss associated with LCHAD/TFP deficiencies has been observed in almost all patients despite early diagnosis and initiation of treatment. Progressive retinopathy in LCHAD/TFP is a unique complication not observed in other FAOD and the underlying etiology of the retinopathy is not completely understood. The specific focus of this application is to characterize the progression of chorioretinopathy in a prospective natural history study, determine clinical and physiologic factors that are associated with retinal changes and vision loss and estimate the rate of retinal change in a cohort of patients with LCHAD and TFP deficiencies. We propose conducting a prospective deep phenotyping study of LCHAD/TFP deficient retinopathy among 44 patients diagnosed with LCHAD/TFP deficiencies followed over time. The retinal degeneration is thought to begin with the loss of the retinal pigment epithelium (RPE) and is associated with increased LCHAD/TFP specific plasma metabolites, hydroxyacylcarnitines, increasing age, number of hospitalizations and genetic mutations. Using recent advances in neural retinal imaging including autofluoresence, structural optical coherence tomography (OCT), OCT angiography (OCTA), microperimetry, we will image the layers of the retina in patients with LCHAD/TFP stratified by age at various stages of progression. Our hypothesis is that loss of RPE will precede both choriocapillaris dropout and photoreceptor degeneration suggesting the RPE is the initial cell layer affected in the progression of LCHADD/TFPD retinopathy. We will correlate changes in retinal structure and measures of visual acuity to environmental factors associated with progression of retinal degeneration. Our hypothesis is that increased metabolic crisis, higher hydroxyacylcarnitines, and older age will be associated with RPE loss, visual function decline and decreased quality of life suggesting a toxic intermediate etiology to the progression of LCHAD-retinopathy. Each subject enrolled in the cohort will be evaluated on two occasions, approximately 2 years apart to estimate the rate of change over time. The results will help us understand the etiology of retinopathy and potentially suggest a treatment approach such as retinal gene therapy to halt retinal degeneration and prevent vision loss.

项目概要 MS/MS在新生儿筛查（NBS）中的应用促进了新生儿筛查（NBS）的早期诊断和治疗 患有脂肪酸氧化障碍（FAOD）的婴儿可降低婴儿死亡率和发病率。 线粒体三功能蛋白缺乏症 (TFP) 缺乏症，包括长链 3-羟基酰基辅酶 A 脱氢酶 (LCHAD) 缺乏症是目前美国国家统计局 (NBS) 中纳入的两种FAOD 缺乏症，需要预防 低酮性低血糖、乳酸性酸中毒和心肌病通常可以通过早期诊断和治疗来实现 当代饮食疗法机构。然而，脉络膜视网膜病变进展并伴有视力丧失 尽管早期诊断和治疗，但几乎所有患者都观察到与 LCHAD/TFP 缺乏相关的症状 开始治疗。 LCHAD/TFP 中的进行性视网膜病变是一种独特的并发症，在其他疾病中未观察到 FAOD 和视网膜病变的根本病因尚不完全清楚。本次具体重点 应用是在前瞻性自然史研究中描述脉络膜视网膜病变的进展， 确定与视网膜变化和视力丧失相关的临床和生理因素并进行估计 一组患有 LCHAD 和 TFP 缺陷的患者的视网膜变化率。 我们建议对 LCHAD/TFP 缺陷性视网膜病进行前瞻性深度表型研究 对 44 名诊断为 LCHAD/TFP 缺乏症的患者进行了长期随访。视网膜变性是 据认为始于视网膜色素上皮 (RPE) 的丧失，并与视网膜色素上皮细胞增加有关。 LCHAD/TFP 特异性血浆代谢物、羟酰肉碱、年龄增加、住院次数 和基因突变。利用神经视网膜成像的最新进展，包括自发荧光、结构 光学相干断层扫描 (OCT)、OCT 血管造影 (OCTA)、显微视野检查，我们将对以下各层进行成像 LCHAD/TFP 患者的视网膜按不同进展阶段的年龄进行分层。我们的假设是 RPE 的丧失将发生在脉络膜毛细血管脱落和光感受器变性之前，表明 RPE 是 LCHADD/TFPD 视网膜病变进展中受影响的初始细胞层。我们将关联变化 视网膜结构和视敏度测量与视网膜进展相关的环境因素 退化。我们的假设是，代谢危机增加、羟酰肉碱升高和年龄增长 与 RPE 丧失、视觉功能下降和生活质量下降有关，表明存在有毒物质 LCHAD 视网膜病变进展的中间病因。队列中登记的每个受试者将 评估两次，相隔大约两年，以估计随时间的变化率。结果 将帮助我们了解视网膜病变的病因，并可能提出治疗方法，例如视网膜病变 基因疗法可阻止视网膜变性并防止视力丧失。