Newborn screening for identification & prospective followup of infants with SMA

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是最常见的致死性遗传疾病之一，发病率为1/10，000。 在过去的十年中，标准护理方案和主动营养以及呼吸支持的发展和日益广泛的实施大大提高了患有严重婴儿变异型SMA I型的婴儿的存活率，该类型占受影响儿童的50%以上。 然而，在症状发作后确定的患者中，生存率的改善并没有导致运动结局的改善，这主要是由于急性期的快速进展，随后是以长达数年的功能稳定为特征的平台期。 STOP SMA研究的初步观察结果表明，与年长的兄弟姐妹以及自然史受试者队列相比，年幼的兄弟姐妹在婴儿期早期被识别并入组基于专科的医疗之家，并获得积极的护理方案，运动结局和生存率有所改善。 这表明，早期干预可能在疾病进展的最急性期限制运动神经元丢失方面发挥重要作用，从而显著改善发病率、死亡率和运动功能。 研究人员建议实施一项多州、多地区的新生儿筛查（NBS）试点研究，以评估在NBS实验室环境中，基于DNA的纯合SMN 1缺失检测法检测有SMA发生风险的婴儿的可行性。 在这样做时，他们假设：1）受影响新生儿的发生率将与早期试点数据的预测平行，2）与通过专科医疗之家提供相同的主动营养，呼吸和临床护理方案的自然史队列相比，通过NBS识别SMA风险婴儿将改善结局，包括发病率，死亡率和运动功能。 在目前的申请中，研究人员还将探讨有关使用NBS进行SMA试点筛查的伦理、监管和政策问题，以确定最佳的知情同意模式。 为了尝试改善NBS确定的症状前人群的结局，他们将实施并评估多学科方法管理对通过拟议试点确定的SMA婴儿健康结局的影响。 研究人员对40万名新生儿进行了筛查，预计至少会发现40名有SMA风险的婴儿。 具体而言，这些婴儿将被登记在一个基于专科的医疗之家，以协调和提供主动护理干预和协议。 最后，研究人员将评估早期诊断对SMA婴儿及其家庭的心理社会影响。 该项目的成功完成将在许多方面具有价值，为NBS社区提供对所提出的检测方法识别具有症状发展风险的人的准确性的评估，确定当前基于DNA的主要筛查平台的可行性和可接受性，提供了前瞻性评估一组经抢先体验获得协调的积极护理的经诊断的婴儿的结果的机会，以及更好地理解早期诊断对SMA婴儿及其家庭的影响。 说明：在建议将这些条件纳入新生儿筛查（NBS）小组之前，必须提供有关筛查和治疗条件（如脊髓性肌萎缩症（SMA））的影响的信息。 本项目将评估SMA的NBS。 这项研究有四个目标; 1）探索伦理、监管和政策问题; 2）实施评估NBS以检测有SMA发展风险的婴儿; 3）实施和评估医疗家庭模式以提供早期诊断和护理管理; 4）评估早期诊断的心理社会影响。 该项目与改善公众健康直接相关，为影响该国几乎每一个新生儿的公共卫生方案提供基于证据的建议。

DESCRIPTION (Provided by Applicant): With an incidence of 1 in 10,000 births, spinal muscular atrophy (SMA) is one of the most common lethal genetic diseases. In the past decade, the development and increasingly widespread implementation of standard of care protocols and proactive nutritional as well as respiratory support has dramatically improved survival in babies with the severe infantile variant, SMA type I, which accounts for more than 50% of affected children. However, improved survival has not resulted in improved motor outcomes in those identified following the onset of symptoms, largely due to rapid progression during the acute phase, followed by a plateau phase characterized by up to several years of functional stability. Preliminary observations from the STOP SMA study, in which younger siblings were identified early in infancy and enrolled in a subspecialty-based medical home with access to proactive care protocols, have demonstrated improved motor outcomes and survival as compared to their older siblings as well as to a cohort of natural history subjects. This suggests that early intervention may play a significant role in limiting motor neuron loss in the most acute phase of disease progression, resulting in a significant improvement in morbidity, mortality, and motor function. The investigators propose to implement a multi-state, multi-region newborn screening (NBS) pilot study to assess the feasibility of a DNA-based assay for homozygous SMN1 deletion to detect infants at risk for the development of SMA, in the NBS laboratory setting. In doing so, they hypothesize: 1) that the incidence of affected newborns will parallel predictions from early pilot data, and 2) that identification of infants at risk for SMA via NBS will improve outcomes, including morbidity, mortality, and motor function, as compared to a natural history cohort provided the same proactive nutritional, respiratory, and clinical care protocols via a subspecialty-based medical home. In the current application, the investigators will also explore ethical, regulatory, and policy issues regarding the use of NBS to pilot screen for SMA to identify the most optimal consent model. To attempt to improve outcomes in the pre-symptomatic population identified with NBS, they will implement and assess the impact of a multidisciplinary approach to management on health outcomes of SMA infants identified via the proposed pilot. Screening 400,000 newborns, the investigators expect to identify at least 40 infants at risk for SMA. Specifically, these infants will be enrolled in a subspecialty-based medical home to coordinate and provide access to proactive care interventions and protocols. Finally, the investigators will evaluate the psychosocial impact of early diagnosis on SMA infants and their families. Successful completion of this project will be of value on many fronts, providing the NBS community with an assessment of the accuracy with which the proposed assay identifies those at risk for symptom development, determining the current feasibility and acceptance for a primary DNA-based screening platform, providing the opportunity to prospectively assess outcomes in a group of pre-symptomatically diagnosed infants with early access to coordinated proactive care, and an improved understanding of the impact of early diagnosis for SMA infants and their families. NARRATIVE: It is imperative to provide information on the impact of screening and treatment of conditions, such as spinal muscular atrophy (SMA), prior to recommendations that such conditions be included in newborn screening (NBS) panels. This project will evaluate NBS for SMA. The study has four aims; 1) explore the ethical, regulatory, and policy issues; 2) implement evaluate NBS to detect infants at risk for development of SMA; 3) implement and assess a medical home model to provide early diagnosis and management of care; and 4) evaluate psychosocial impact of early diagnosis. This project is directly relevant to improving the public's health with evidence-based recommendations for public health programs that affect virtually every newborn in the country.