Newborn Screening for Adrenoleukodystrophy

描述(申请人提供)：肾上腺脑白质营养不良是一种X连锁疾病，具有多种表现，包括肾上腺功能不全、脑炎性脱髓鞘和成人进行性痉挛瘫痪。在发病前开始干预可以挽救生命，包括监测肾上腺和脑部疾病；早期适当使用造血干细胞疗法；以及通过饮食和洛伦佐油进行实验性治疗，以减少儿童脑部疾病的发生率。利用升高的超长链脂肪酸的生化异常，我们最近开发了一种串联质谱学方法，可以检测溶血磷脂的海拔变化。该方法适用于区域新生儿代谢性疾病的筛查，为肾上腺脑白质营养不良和其他过氧素性疾病提供早期诊断和干预。在这项建议中，我们提出了三个目标，在三年内完成。我们将优化适应大规模筛查的方法，在500个已知受影响个体百分比的新生儿血液样本中确认该分析的敏感性，第三阶段将在马里兰州完成5000个样本的初始现场试验，以确认其敏感性和特异性。成功完成这三个目标将使这项工作成为新生儿筛查的一个可行的补充。公共卫生相关性：这项提案的公共卫生重要性在于，肾上腺脑白质营养不良是一种严重的疾病，影响儿童和成人，发病率约为1：20,000。已经开发的治疗方法广泛依赖于症状前诊断和监测，不幸的是，这种情况只在有限比例的个人中发生。我们建议开发一种方法，该方法可以发生在标准的区域新生儿筛查中，并确认该技术的敏感性和特异性。更广泛地使用这种优化的方法应该可以让家庭更快地诊断，并最大限度地转化最近的治疗干预措施。

DESCRIPTION (provided by applicant): Adrenoleukodystropy is an X-linked disorder that has variable manifestations including adrenal insufficiency, inflammatory demyelination of the brain, and in adults, a progressive spastic paraparesis. Interventions when begun prior to disease onset can be life saving and include monitoring for adrenal and cerebral disease; early, appropriate use of hematopoietic stem cell therapy; and experimental therapy with diet and Lorenzo's oil to reduce the incidence of childhood cerebral disease. Using the biochemical abnormality of elevated very long chain fatty acids, we have recently developed a tandem mass spectrometry methodology that can detect altered elevations in lysophospholipids. This methodology is adaptable to regional newborn screening of metabolic disorders offering early diagnosis and intervention in adrenoleukodystrophy and other peroxisomal disorders. In this proposal, we propose three aims to be completed in three years. We will optimize the methodology for adaptation to large-scale screening, confirm the sensitivity of the assay in 500 newborn blood samples with a known percentage of affected individuals, and the third phase is to complete an initial field trial in Maryland of 5000 samples to confirm the sensitivity and specificity. Successful completion of the three aims would establish this as a viable addition to newborn screening. PUBLIC HEALTH RELEVANCE: The public health importance of this proposal is that adrenoleukodystrophy is a serious disorder affecting children and adults with an incidence of approximately 1:20,000. Therapies, which have been developed, rely extensively on presymptomatic diagnosis and monitoring which unfortunately occurs in only a limited percentage of individuals. We propose to develop a methodology which can occur with standard regional newborn screening and confirm the sensitivity and specificity of the technique. Broader use of this optimized method should allow quicker diagnosis for families and maximum translation of recent therapeutic interventions.