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.

项目摘要 MS/MS在新生儿筛查（NB）中的应用促进了早期诊断和治疗 脂肪酸氧化障碍（FAOD）的婴儿导致婴儿死亡率和发病率降低。 线粒体三功能蛋白缺乏（TFP）缺乏，包括长链3-Hdyroxyacyl-COA 脱氢酶（LCHAD）缺陷，目前在美国NBS中包括两个FAOD，以预防 早期诊断和 当代饮食疗法机构。然而，脉络膜肾上腺病的进展和视力丧失 尽管早期诊断和 开始治疗。 LCHAD/TFP中的进行性视网膜病是其他并不发症 视网膜病的FAOD和基本的病因尚未完全理解。这个的具体重点 应用是在一项前瞻性自然史研究中表征脉络膜结构病的进展， 确定与视网膜变化和视力丧失和估计相关的临床和生理因素 LCHAD和TFP缺陷患者队列的视网膜变化率。 我们建议对LCHAD/TFP缺乏视网膜病变进行前瞻性深度表型研究 在44例被诊断出患有LCHAD/TFP缺陷的患者中，随着时间的流逝。视网膜变性是 被认为始于视网膜色素上皮（RPE）的丧失，与增加有关 LCHAD/TFP特异性等离子体代谢物，羟基囊力，年龄增加，住院数量 和基因突变。利用神经视网膜成像的最新进展，包括自动荧光，结构性 光学相干断层扫描（OCT），OCT血管造影（OCTA），微量测定法，我们将图像层 LCHAD/TFP患者的视网膜在各个进展阶段按年龄分层。我们的假设是 RPE的损失将在脉络膜毛细血管辍学和光感受器变性之前表明RPE为 LCHADD/TFPD视网膜病的进展影响的初始细胞层。我们将相关联的变化 视网膜结构和视敏度与视网膜进展相关的环境因素的度量 退化。我们的假设是，代谢危机增加，羟基囊肿较高和年龄较大 将与RPE丢失，视觉功能下降和生活质量下降有关，这表明有毒 lchad-retinopathy进展的中间病因。参与队列的每个受试者将是 两次进行评估，相距约2年，以估计随时间变化的速度。结果 将帮助我们了解视网膜病的病因，并可能提出一种治疗方法，例如视网膜 基因治疗以停止视网膜变性并防止视力丧失。