Newborn screening and treatment monitoring for patients with pyridoxine-dependent epilepsy

吡哆醇依赖性癫痫患者的新生儿筛查和治疗监测

基本信息

批准号：
10372396
负责人：
Curtis R Coughlin
金额：
$ 23.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-08 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10372396
关键词：
Address Affect Aftercare Biochemistry Biological Markers Birth Blood Brain Diseases Brain Injuries COVID-19 Child Clinic Clinical Cognitive Collection Data Development Developmental Delay Disorders Diagnosis Diagnostic Disease Dry Ice Ensure Enzymes Epilepsy Equilibrium Freezing Future Home Hour Individual Intellectual functioning disability Laboratories Life Liquid Chromatography Lysine Measurement Measures Metabolism Methods Monitor Nature Neonatal Screening Nervous System Trauma Newborn Infant Outcome Outcome Measure Oxidoreductase Patient Monitoring Patients Public Health Recommendation Sampling Seizures Severity of illness Ships Spottings Techniques Temperature Testing Translating Treatment Efficacy Vitamin B6 Work carboxylate clinical diagnostics cognitive development compliance behavior diagnostic biomarker diagnostic screening dietary restriction disease natural history effective therapy epileptic encephalopathies improved inhibitor nervous system disorder novel novel coronavirus novel marker novel therapeutic intervention novel therapeutics oxidation pandemic disease preservation prevent response sample collection screening screening program specific biomarkers tandem mass spectrometry treatment strategy

项目摘要

Project Summary: Pyridoxine-dependent epilepsy (PDE) is a developmental and epileptic encephalopathy that was historically defined by a positive clinical response to pyridoxine. Despite adequate seizure control, the majority of patients have developmental delay and intellectual disability. PDE is due to a deficiency of α-aminoadipic semialdehyde (α-AASA) dehydrogenase, a key enzyme in lysine metabolism that results in the accumulation of α-AASA and related metabolites. We initially focused on reducing the accumulation of α- AASA through a lysine-restricted diet and a competitive inhibitor of lysine transport. These novel treatment strategies improved the overall biochemistry and are associated with normal cognitive development. Although effective, treatment must be started early in life to prevent irreversible brain disease. Unfortunately, most patients are diagnosed after treatment is no longer effective. Our central hypothesis is that the delay in diagnosis and subsequent treatment is the main contributor of intellectual disability associated with this disease. The primary focus of this application is development of a newborn screen method for patients with PDE. Newborn screening provides an opportunity to diagnosis patients before irreversible neurologic damage occurs dramatically changing the natural history of this disease. Previous attempts at newborn screening were unsuccessful as α-AASA is unstable at room temperatures and, therefore, not practical for newborn screening. In our previous work, we identified a novel biomarker (6-oxo-pipecolate) that is stable at room temperatures and overcomes previous hurdles with newborn screening. We will demonstrate that newborns with PDE can be diagnosed at birth using current newborn screening techniques (Aim 1). These results will establish that 6-oxo-pipecoalte is elevated in affected newborns and will provide the basis for future studies focused on the sensitivity of our newborn screening method. Although α-AASA is an excellent diagnostic biomarker, the level of α-AASA does not correlate with disease severity or cognitive outcome. These results are confounded by the unstable nature of α-AASA, which makes it difficult to compare levels between samples and laboratories. We purpose that 6-oxo-pipecolate is an ideal biomarker to monitor treatment efficacy. We will evaluate the use of an at-home collection method for 6-oxo-pipecolate using our existing dried blood spot method. The benefit of at home treatment monitoring has never been more relevant than during this current pandemic due to the novel coronavirus COVID-19. We will demonstrate that measuring 6-oxo-pipecolate from dried blood spots collected at home is a feasible (Aim 2). These results will be critical for futures studies evaluating novel therapeutic approaches to this this treatable but severe neurologic disease.

项目概要：吡哆醇依赖性癫痫（PDE）是一种历史性的发育性癫痫性脑病尽管癫痫发作得到充分控制，但大多数患者对吡哆醇有积极的临床反应。患者出现发育迟缓和智力障碍是由于缺乏α-氨基己二酸。半醛 (α-AASA) 脱氢酶，赖氨酸代谢中的关键酶，可产生 α-AASA 和相关代谢物的积累我们最初的重点是减少 α-AASA 的积累。 AASA 通过限制赖氨酸的饮食和赖氨酸转运的竞争性抑制剂这些新颖的治疗方法。策略改善了整体生物化学并与正常认知发展相关。尽管有效，但治疗必须在生命早期开始，以预防不可逆转的脑部疾病。不幸的是，大多数患者是在治疗不再有效后才被诊断出来的。诊断和后续治疗的延误是智力障碍的主要原因与这种疾病有关。该应用的主要重点是开发针对 PDE 患者的新生儿筛查方法。新生儿筛查提供了在不可逆的神经损伤之前诊断患者的机会发生极大地改变了这种疾病的自然史，以前的新生儿筛查尝试。不成功，因为 α-AASA 在室温下不稳定，因此对新生儿不实用在我们之前的筛选中，我们发现了一种在室温下稳定的新型生物标志物（6-oxo-pipecolate）。我们将证明新生儿筛查能够降低温度并克服以前的障碍。使用当前的新生儿筛查技术可以在出生时诊断出 PDE（目标 1）。确定 6-oxo-pipecoalte 在受影响的新生儿中升高，并将为未来的研究提供基础重点关注我们的新生儿筛查方法的敏感性。尽管 α-AASA 是一种出色的诊断生物标志物，但 α-AASA 水平与疾病无关这些结果与 α-AASA 的不稳定性质相混淆。使得比较样品和实验室之间的水平变得困难。我们的目的是 6-oxo-pipecolate 是。监测治疗效果的理想生物标志物我们将评估家庭收集方法的使用。使用我们现有的干血斑法进行 6-氧代-哌可酯在家治疗的好处。由于新型冠状病毒，当前的大流行期间的监测从未如此重要我们将演示从家里收集的干血斑中测量 6-氧代哌可酯。是可行的（目标 2）。这些结果对于评估新疗法的未来研究至关重要。治疗这种可治疗但严重的神经系统疾病的方法。