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

• 批准号: 10640061
• 负责人: Curtis R Coughlin
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-08 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10640061
• 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; Dryness; 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; Spottings; Techniques; Temperature; Testing; Translating; Treatment Efficacy; Vitamin B6; Work; carboxylate; carboxylation; clinical diagnostics; cognitive development; compliance behavior; current pandemic; diagnostic biomarker; diagnostic screening; dietary restriction; disease natural history; epileptic encephalopathies; improved; inhibitor; nervous system disorder; novel; novel coronavirus; novel marker; novel therapeutic intervention; novel therapeutics; oxidation; preservation; prevent; response; sample collection; screening; screening program; specific biomarkers; tandem mass spectrometry; treatment strategy

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.

项目摘要： 吡ido醇依赖性癫痫（PDE）是一种发育和癫痫性脑病，历史上是 由对吡啶多醇的阳性临床反应定义。尽管有足够的癫痫发作控制，但大多数 患者患有发育迟缓和智力障碍。 PDE是由于α-氨基磷脂的不足 半甲醛（α-AASA）脱氢酶，赖氨酸代谢中的关键酶，导致导致的酶 α-AASA和相关代谢产物的积累。我们最初专注于减少α-的积累 AASA通过赖氨酸限制的饮食和赖氨酸运输的竞争抑制剂。这些新颖的治疗方法 策略改善了整体生物化学，并与正常的认知发展有关。 尽管有效，但必须在生命的早期开始治疗，以预防不可逆的脑部疾病。 不幸的是，在治疗后大多数患者被诊断出不再有效。我们的中心假设是 诊断和随后治疗的延迟是智力残疾的主要因素 与这种疾病有关。 该应用的主要重点是为PDE患者开发新生儿筛查方法。 新生儿筛查提供了一个机会，可以在不可逆的神经系统损害之前诊断患者 发生这种疾病的自然史发生了巨大变化。以前的新生儿筛查尝试 由于α-AASA在室温下不稳定，因此不成功 筛选。在我们以前的工作中，我们确定了一种新型的生物标志物（6-氧化二叶酸酯），在房间里很稳定 温度并克服了以前的新生儿筛查。我们将证明新生儿 使用当前的新生儿筛查技术可以在出生时诊断出PDE（AIM 1）。这些结果将会 确定在受影响的新生儿中，6-氧化物pipecoalte升高，将为以后的研究提供基础 专注于我们新生儿筛查方法的灵敏度。 尽管α-AASA是一种极好的诊断生物标志物，但α-AASA的水平与疾病无关 严重性或认知结果。这些结果与α-AASA的不稳定性相混淆，α-aasa的性质 很难比较样品和实验室之间的水平。我们目的是6-氧化物二叶酸是 一种监测治疗效率的理想生物标志物。我们将评估使用家庭收集方法的使用 使用我们现有的干血点法进行6-氧化二叶酸酯。家庭治疗的好处 由于新的冠状病毒，监测从来没有比目前的大流行中更重要 新冠肺炎。我们将证明，从家里收集的干血点测量6-氧 是可行的（AIM 2）。这些结果对于评估新疗法的期货研究至关重要 这是这种可治疗但严重的神经系统疾病的方法。