Rapid Carrier and Newborn Diagnostic Testing for MSUD

枫糖浆尿病(MSUD)是一种由支链酮酸脱氢酶复合体(BCKAD)缺陷引起的隐性遗传性疾病。典型的MSUD婴儿出生时看起来很正常，但如果不治疗，可能会在2-3周内死亡。虽然普遍罕见(1：200,000出生)，但在某些门诺派社区，MSUD的发病率相当高(1：176活出生)，并由BCKAD E1A亚单位基因的特定缺陷(Y393N)所致。尽管早期发现和治疗对MSUD患者的良好预后至关重要，但目前还没有商业或州DNA测试可用。通过血清氨基酸分析进行新生儿筛查只在23个州进行，要求推迟检测，直到支链氨基酸积累，增加婴儿神经损伤的风险。应两个门诺派社区的要求，我们开发了一种基于DNA的携带者和新生儿筛查测试。不幸的是，学术研究实验室维持这一测试是不可行的，目前的测试也不是商业用途的最佳选择。我们建议与亲子鉴定公司合作，应用变性高效液相色谱法和分子信标这两种新方法来开发一种改进的快速、灵敏和商业适用的Y393N E1A基因缺陷检测方法。拟议的商业应用：一种商业化的MSUD基因测试将在改善受这种孤儿疾病影响的家庭的预后和结果方面发挥至关重要的作用，特别是在门诺派社区。虽然这种测试本身并不是一个非常有利可图的项目，但它满足了社区的一个重要需求，并将为开发其他被忽视的孤儿疾病的类似测试铺平道路。

Maple Syrup Urine Disease (MSUD) is a recessive genetic disorder resulting from defects in the branched chain a-keto acid dehydrogenase complex (BCKAD). Infants with classic MSUD appear normal at birth, but can die within 2-3 weeks if untreated. Although generally rare (1:200,000 births), the incidence of MSUD in certain Mennonite communities is quite high (1:176 live births), and results from a specific defect (Y393N) in the BCKAD E1a subunit gene. Although early detection and treatment are critical to favorable prognosis for MSUD patients, there is no commercial or state DNA testing available. Newborn screening by serum amino acid analyses occurs in only 23 states, and requires that testing be delayed until branched chain amino acids accumulate, increasing an infant's risk of neurological damage. At the request of two Mennonite communities we developed a DNA-based test for carrier and newborn screening. Unfortunately, it is not feasible for an academic research laboratory to maintain this test, nor is the current test optimal for commercial use. We propose a collaborative effort with Paternity Testing Corporation to apply two novel approaches, denaturing high-performance liquid chromatography and molecular beacons, to developing an improved rapid, sensitive and commercially applicable test for the Y393N E1a gene defect. PROPOSED COMMERCIAL APPLICATIONS: A commercially available genetic test for MSUD would play a vital role in improving prognosis and outcomes for families affected by this orphan disease, especially in the Mennonite community. While not a highly profitable venture in itself, such a test fulfills an important need to the community, and will pave the way for developing analogous tests for other neglected orphan diseases.