The Natural History of LCHAD Retinopathy

项目摘要 MS/MS在新生儿筛查（NBS）中的应用有助于早期诊断和治疗 患有脂肪酸氧化障碍（FAOD）的婴儿，导致婴儿死亡率和发病率下降。 线粒体三功能蛋白缺乏症（TFP），包括长链3-羟酰辅酶A 脱氢酶（LCHAD）缺乏症是美国国家统计局目前包括的两种FAOD， 低酮性低血糖、乳酸酸中毒和心肌病通常可通过早期诊断实现， 现代饮食疗法机构。然而，脉络膜视网膜病变的进展伴视力丧失 与LCHAD/TFP缺陷相关，尽管早期诊断，但几乎在所有患者中均观察到， 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，在其他研究中未观察到。 FAOD和视网膜病变的潜在病因尚不完全清楚。这其中的具体重点 本发明的应用是在前瞻性自然史研究中表征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， LCHAD和TFP缺陷患者的视网膜变化率。 我们建议对LCHAD/TFP缺陷性视网膜病变进行前瞻性深入表型研究 在44例诊断为LCHAD/TFP缺陷的患者中，视网膜变性是 视网膜色素上皮细胞（RPE）的缺失被认为是开始的，并且与视网膜色素上皮细胞（RPE）的增加有关。 LCHAD/TFP特异性血浆代谢物、羟酰基肉毒碱、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，包括自体荧光，结构 光学相干断层扫描（OCT），OCT血管造影（OCTA），微视野，我们将成像层 LCHAD/TFP患者的视网膜按不同进展阶段的年龄分层。我们的假设是 RPE的丧失先于脉络膜毛细血管脱落和感光细胞变性，这表明RPE是 在LCHADD/TFPD视网膜病变的进展中受影响的初始细胞层。我们将把这些变化 视网膜结构和视力测量与视网膜病变进展相关的环境因素 退化我们的假设是，增加代谢危机，更高的羟酰基肉毒碱，和老年 将与RPE损失、视功能下降和生活质量下降相关，提示毒性 LCHAD-视网膜病变进展的中间病因。入组队列的每例受试者将 两次评价，间隔约2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，并可能提出一种治疗方法，如视网膜 基因疗法来阻止视网膜退化和防止视力丧失。

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.