Newborn Screening for Adrenoleukodystrophy

新生儿肾上腺脑白质营养不良筛查

• 批准号: 7778360
• 负责人: Gerald V. Raymond
• 金额: $ 30.69万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778360
• 关键词: Addison' s disease; Adrenal Glands; Adrenal gland hypofunction; Adrenoleukodystrophy; Adult; Affect; Age; Biochemical; Biological Assay; Blood; Blood specimen; Brain; Cerebrum; Cessation of life; Child; Childhood; Choline; Cystic Fibrosis; Demyelinations; Detection; Development; Diagnosis; Diet; Disease; Early Diagnosis; Evaluation; Family; Genes; Genetic Medicine; Hematopoietic stem cells; Incidence; Individual; Inflammatory; Intervention; Investigational Therapies; Life; Link; Liquid Chromatography; Lorenzo' s oil; Lysophospholipids; Lysosomal Storage Diseases; Maryland; Masks; Mass Spectrum Analysis; Metabolic; Metabolic Brain Diseases; Metabolic Diseases; Metabolic Pathway; Methodology; Methods; Monitor; Mutation; Neonatal; Neonatal Screening; Neurologic Manifestations; Newborn Infant; Onset of illness; Organelles; Paper; Pathway interactions; Peroxisomal Disorders; Phase; Population; Public Health; Role; Sampling; Screening procedure; Sensitivity and Specificity; Sickle Cell Anemia; Spastic Paraparesis; Specificity; Spottings; Symptoms; Techniques; Therapeutic Intervention; Translations; Very Long Chain Fatty Acid; boys; design; disability; long chain fatty acid; male; oxidation; programs; public health relevance; stem cell therapy; tandem mass spectrometry

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.

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、大脑炎症性脱髓鞘以及成人进行性痉挛性截瘫。在疾病发作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、适当地使用造血干细胞治疗；以及通过饮食和洛伦佐油进行实验性治疗，以降低儿童脑部疾病的发病率。利用超长链脂肪酸升高的生化异常，我们最近开发了一种串联质谱方法，可以检测溶血磷脂升高的变化。该方法适用于代谢性疾病的区域新生儿筛查，为肾上腺脑白质营养不良和其他过氧化物酶体疾病提供早期诊断和干预。在这个提案中，我们提出了三年内完成的三个目标。我们将优化适应大规模筛查的方法，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敏感性，第三阶段是在马里兰州完成 5000 份样本的初步现场试验，以确认敏感性和特异性。成功完成这三个目标将使其成为新生儿筛查的可行补充。公共卫生相关性：该提案对公共卫生的重要性在于，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，这种情况仅发生在有限比例的个体中。我们建议开发一种可与标准区域新生儿筛查一起进行的方法，并确认该技术的敏感性和特异性。这种优化方法的更广泛使用应该可以为家庭提供更快的诊断，并最大限度地转化最近的治疗干预措施。