Newborn Screening for Adrenoleukodystrophy

描述（由申请人提供）：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、大脑炎性脱髓鞘和成人进行性痉挛性下肢轻瘫。在疾病发作前开始的干预措施可以挽救生命，包括监测肾上腺和脑疾病;早期适当使用造血干细胞治疗;以及用饮食和洛伦佐油进行实验性治疗，以减少儿童脑疾病的发病率。利用升高的极长链脂肪酸的生化异常，我们最近开发了一种串联质谱方法，可以检测溶血磷脂的升高。该方法适用于区域新生儿代谢紊乱筛查，提供肾上腺脑白质营养不良和其他过氧化物酶体疾病的早期诊断和干预。在这个建议中，我们提出了三个目标，在三年内完成。我们将优化方法学以适应大规模筛查，在已知受影响个体百分比的500份新生儿血液样本中确认检测的灵敏度，第三阶段是在马里兰州完成5000份样本的初步现场试验，以确认灵敏度和特异性。成功完成这三个目标将使其成为新生儿筛查的一个可行补充。公共卫生相关性：该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影响儿童和成人的严重疾病，发病率约为1：20，000。已经开发的疗法广泛依赖于症状前诊断和监测，不幸的是，这仅发生在有限百分比的个体中。我们建议开发一种方法，可以发生与标准的区域新生儿筛查，并确认该技术的灵敏度和特异性。更广泛地使用这种优化的方法应该可以更快地诊断家庭和最大限度地翻译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.