Can Psychosine and Galactocerebrosidase Activity Predict Early-Infantile Krabbe's Disease Presymptomatically?
Can Psychosine and Galactocerebrosidase Activity Predict Early-Infantile Krabbe's Disease Presymptomatically?
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DOI：
10.1002/jnr.23793
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发表时间：
2016-11-01
影响因子：
4.2
通讯作者：
Langan, Thomas J.
中科院分区：
文献类型：
--
作者：
Carter, Randy L.;Wrabetz, Lawrence;Langan, Thomas J.
Krabbe病（KD）是一种致命的神经退行性疾病，早期婴儿型（EIKD）定义为6个月前出现症状。为了使造血干细胞移植治疗的益处最大化，需要早期和高度准确地识别EIKD。本研究基于一种新的新生儿筛查（NBS）工具，从两个生物标志物，半乳糖苷酶（GALC）酶活性和半乳糖基鞘氨醇浓度（精神病[PSY]），探讨了准确预测EIKD的潜力。来自正常新生儿不同样本的关于PSY和GALC的规范性信息被用于开发新的诊断工具。假设正常新生儿GALC和PSY的自然值服从多元正态分布，构建了二元正态限（BVNL）。在不同的“异常组”中新生儿的（lnGALC，lnPSY）点，包括一组随后患有EIKD的婴儿，绘制在BVNL图上。所有EIKD患者的评分均超出BVNL（100%灵敏度）。在一项模拟研究中，我们将现有单变量诊断方法的假阳性率与我们新的基于BVNL的方法进行了比较，我们生成了1亿个正常新生儿数据点。都在BVNL范围内（即，零假阳性），而当应用文献中建议的类型的两层单变量方法时，观察到5，682个假阳性。这些结果表明，（lnGALC，lnPSY）BVNL将允许高度准确的预测EIKD，而两层单变量方法不会。使用NBS需要基于对正常新生儿的常见大样本测量的GALCs和PSYs的BVNL的重建。(C)2016 Wiley Periodicals，Inc.
Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early-infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various "abnormal groups," including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false-positive rate of existing univariate methods of diagnosis with our new BVNL-based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two-tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two-tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. (C) 2016 Wiley Periodicals, Inc.