Enhancement Newborn Screening to Improve the Efficacy of Cord Blood Transplant for Krabbe Disease

 描述（由申请人提供） Krabbe脑白质营养不良（KD）（据称发病率为1：250，000）是一种常染色体隐性遗传疾病，由于溶酶体酶半乳糖神经酰胺酶（GalC）的功能缺失突变。GalC功能丧失的一个后果是神经系统中代谢副产物和毒素--精神病肽（PSY）的积累。KD最常见的形式是毁灭性的早期婴儿型（EIKD），在生命的前六个月内出现疾病症状，并在症状发作的2-3年内死亡。KD的新生儿筛查（NBS）在纽约州（NYS）已经实施了9年，在密苏里州实施了3年，不久将在新泽西、肯塔基州和伊利诺伊州实施。NBS和早期诊断对于KD的有效治疗至关重要，因为唯一可用的治疗方法，合并脐带血移植（CBT），在术前和尽可能早的生命中开始时更有效。准确识别即将发生的EIKD也特别重要，因为CBT的预备消融方案与20%的生命第一年死亡率相关。不幸的是，尽管包括DNA诊断、GALC酶水平、神经系统检查、脑MRI扫描和电生理检查，但目前NYSNBS对EIKD的诊断范式是不完善的。我们假设，可以在NBS血斑上快速确定的两种测试，即精神病碱水平和GalC酶活性，将更好地预测KD。为了验证这一假设，我们将在亨特·詹姆斯·凯利研究所HJKRI的全球KD登记处（WWR）中测量患者的血斑上的PSY水平，以及来自新NYS-NBS阳性婴儿（GalC水平已知）的血斑上的PSY水平，以及对照组。利用Galc和PSY的双变量分析，我们将开发一种新的范式，旨在早期和准确预测EIKD。如果这一假设被证明是正确的，NYS-NBS算法的变化将提高KD诊断和预后的速度、灵敏度和特异性，从而提高CBT的疗效。它还将为诊断算法提供一个更好的模板， NBS疾病，早期诊断使治疗更有效。

 DESCRIPTION (provided by applicant) Krabbe leukodystrophy (KD) (purported incidence 1:250,000) is an autosomal recessive disease due to loss of function mutations in the lysosomal enzyme Galactosylceramidase (GalC). One consequence of GalC loss of function is accumulation of the metabolic byproduct and toxin, psychosine (PSY) in the nervous system. The most common form of KD is the devastating early infantile type (EIKD), with onset of symptoms of disease in the first six months of life and death within 2-3 years of symptom onset. Newborn screening (NBS) for KD has been available for 9 years in New York State (NYS), 3 years in Missouri and will soon be available in New Jersey, Kentucky and Illinois. NBS and early diagnosis are critical for efficacious treatment of KD because the sole treatment available, pooled cord blood transplantation (CBT), is more effective when started pre-symptomatically and as early in life as possible. Accurate identification of imminent EIKD is also particularly important because the preparatory ablative regimen for CBT is associated with 20% mortality in the first year of life. Unfortunately, the current NYSNBS diagnostic paradigm for EIKD is imperfect, despite comprising DNA diagnosis, GALC enzyme levels, neurological exam, MRI scan of brain and electrophysiological exams. We hypothesize that two tests that can be determined rapidly on NBS blood spots, psychosine levels and GalC enzyme activities, will better predict KD. To test this hypothesis, we will measure PSY levels on bloodspots of patients in the Worldwide Registry of KD (WWR) at the Hunter James Kelly Research Institute HJKRI, and on bloodspots from new NYS-NBS positive babies (GalC levels known), as well as on controls. Using bivariate analysis of Galc and PSY, we will develop a new paradigm aimed at early and accurate prediction of EIKD. If this hypothesis is proven correct, the resulting change in the NYS-NBS algorithm will improve the speed, the sensitivity and the specificity of diagnosis and prognosis of KD, and thereby the efficacy of CBT. It will also provide a better template for a diagnostic algorithm useful for other NBS diseases where early diagnosis renders treatment more efficacious.