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 患有脂肪酸氧化紊乱(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，包括长链3-羟基辅酶A缺乏症 脱氢酶(LCHAD)缺乏症是美国国家统计局目前包括的两种疾病，可预防 低酮症低血糖、乳酸酸中毒和心肌病通常是通过早期诊断和 现代饮食治疗机构。然而，伴有视力丧失的脉络膜视网膜病变的进展 与LCHAD/TFP缺陷相关的几乎所有患者都观察到，尽管早期诊断和 开始治疗。LCHAD/TFP的进行性视网膜病变是一种独特的并发症，在其他患者中没有观察到 FAOD和视网膜病变的潜在病因尚不完全清楚。这件事的具体焦点是 应用是在一项前瞻性的自然历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，并估计 LCHAD和TFP缺乏症患者队列中的视网膜变化率。 我们建议对LCHAD/TFP缺陷性视网膜病变进行前瞻性的深层表型研究。 在44名被诊断为LCHAD/TFP的患者中，随着时间的推移，患者出现了缺陷。视网膜变性是 认为始于视网膜色素上皮(RPE)的丧失，并与 LCHAD/TFP特异性血浆代谢物、羟基肉碱、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，包括自体荧光、结构 光学相干断层扫描(OCT)、OCT血管成像(OCTA)、微视野，我们将对 LCHAD/TFP患者的视网膜在进展的不同阶段按年龄分层。我们的假设是 RPE的丧失将先于脉络膜毛细血管的消失和光感受器的退化，这表明RPE是 起始细胞层在LCHADD/TFPD视网膜病变的进展中起作用。我们将关联以下方面的变化 视网膜结构和对与视网膜进展相关的环境因素的视力测量 退化。我们的假设是，代谢危机增加，羟基肉碱增加，年龄增大 会与RPE丧失、视觉功能下降和生活质量下降有关，这表明 LCHAD-视网膜病变进展的中间病因学。在队列中登记的每个科目将是 评估了两次，大约相隔2年，以估计随时间变化的速度。结果是 将帮助我们了解视网膜病变的病因，并可能建议一种治疗方法，如视网膜 阻止视网膜退化和防止视力丧失的基因疗法。

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.