Newborn screening for PKU and BH4 responsiveness

新生儿 PKU 和 BH4 反应性筛查

• 批准号: 7339046
• 负责人: Steven F Dobrowolski
• 金额: $ 37.29万
• 依托单位: BIOFIRE DEFENSE, LLC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7339046
• 关键词: Address; Affect; Biological Assay; Bion; Blood; Blood specimen; Brain Injuries; Cataloging; Catalogs; Classical phenylketonuria; Code; DNA; DNA Sequence Analysis; Data; Defect; Diagnostic; Diet; Disease; Early identification; Effectiveness; Emerging Technologies; Enzymes; Frequencies; Functional disorder; Genes; Genetic Polymorphism; Goals; Hand; Hospitals; Individual; Introns; Lead; Measures; Medical; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Methods; Mutation; Neonatal Screening; Newborn Infant; Patients; Phenylalanine; Phenylalanine Hydroxylase; Physiological; Play; Polymerase Chain Reaction; Population; Process; Purpose; Reagent; Research; Research Personnel; Resolution; Retrospective Studies; Role; Scanning; Screening Result; Secondary to; Site; Source; Specimen; Technology; Testing; Tyrosine; Withdrawal; base; cost; cost effective; day; dietary restriction; genetic analysis; melting; neuropsychological; prospective; response; tandem mass spectrometry; tertiary care; tetrahydrobiopterin; theories

In 1958, Dr Robert Guthrie was approached by Dr Robert Warner seeking aid to develop a better means to measure phenylalanine in the blood of newborns. Of this interaction was born the bacterial inhibition assay and the beginning of population-based newborn screening for phenylketonuria (PKU). Early identification of affected newborns avoided irreversible brain damage using a phenylalanine-restricted diet. While the BIA has been replaced by tandem mass spectrometry as the means to measure phenylalanine, PKU remains the paradigm for a disorder effectively treated by prospective identification of asymptomatic patients. PKU results from defects in phenylalanine hydroxylase (PAH) causing an inability to convert phenylalanine to tyrosine. Treating PKU by dietary means remained largely unchanged until several groups identified a sub- set of patients treatable using 6R-tetrahydrobiopterin (BH4), the obligatory co-factor of the PAH enzyme, without the phenylalanine restricted diet. While BH4-responsive patients are skewed to mild PKU and hyperphenyla'ianemia; classic PKU patients have been characterized as BH4 responsive. Analysis of the PAH gene is becoming an important aspect to determining BH4 response. Comprehensive analysis of the PAH gene may be performed using the universally collected newborn screening dried blood card as a source of DNA. Using the dried blood card and the emerging technology of high-resolution melt profiling, comprehensive analysis of PAH may be easily completed within 1.5 days of abnormal newborn screening results. Genotypic data will be in hand when results of the physiological Phe/ BH4 loading test are complete. Combining physiological analysis and genetic analysis will lead to effective identification of BH4 responsive PKU patients. Cataloging PAH mutations resulting in BH4 responsive disease is underway thus developing a sensitive, rapidly, and cost effective means to analyze the PAH gene will have utility to clinicians and researchers. Herein is proposed the use of high resolution melt profiling to develop a simplified and streamlined means of assessing the coding sequence and intronic regions critical to mRNA processing in the PAH gene. High resolution melt profiling is rapid with sensitivity at least equal to DNA sequence analysis and in excess of other pre-sequence scanning technologies. High resolution melt profiling will play a role to identify BH4 responsive PKU patients.

1958年，罗伯特·华纳博士找到罗伯特·格思里博士，寻求帮助，以开发一种更好的方法