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）是最常见的致命性遗传疾病之一，发病率为万分之一。在过去十年中，标准护理方案的制定和日益广泛的实施，以及主动营养和呼吸支持，极大地提高了患有严重婴儿型SMA的婴儿的存活率，占患病儿童的50%以上。然而，对于那些在症状出现后确诊的患者，生存率的提高并未导致运动预后的改善，这主要是由于急性期的快速进展，随后是一个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显示，与年长的兄弟姐妹以及一组自然史受试者相比，年幼的兄弟姐妹在婴儿期早期就被识别出来，并进入了一个基于亚专科的医疗之家，并获得了积极的护理方案。这表明，在疾病进展的最急性阶段，早期干预可能在限制运动神经元丧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状态、多地区新生儿筛查（NBS）试点研究，以评估在NBS实验室环境下，基于dna的纯合SMN1缺失检测婴儿罹患SMA风险的可行性。在此过程中，他们假设：1)受影响新生儿的发病率将与早期试点数据的预测相一致；2)与通过亚专科医疗家庭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识别有SMA风险的婴儿将改善结果，包括发病率、死亡率和运动功能。在当前的应用中，研究人员还将探讨有关使用NBS进行SMA试点筛选的伦理、监管和政策问题，以确定最优的同意模型。为了尝试改善NBS症状前人群的结果，他们将实施并评估多学科方法对通过拟议试点确定的SMA婴儿健康结果的管理影响。研究人员对40万名新生儿进行了筛查，希望能找出至少40名有罹患SMA风险的婴儿。具体来说，这些婴儿将被登记在一个以亚专科为基础的医疗之家，以协调和提供积极的护理干预和协议。最后，研究人员将评估早期诊断对SMA婴儿及其家庭的社会心理影响。该项目的成功完成将在许多方面具有价值，为NBS社区提供评估所提议的检测方法识别症状发展风险的准确性，确定当前基于初级dna的筛查平台的可行性和可接受性，为早期获得协调主动护理的一组未出现症状的婴儿提供前瞻性评估结果的机会。以及更好地了解早期诊断对SMA婴儿及其家庭的影响。

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.