Newborn screening for identification & prospective followup of infants with SMA

描述(申请人提供)：脊髓性肌萎缩症(SMA)是最常见的致命性遗传病之一，发病率为每10,000名新生儿中就有一例。在过去的十年中，标准护理方案的制定和日益广泛的实施以及积极的营养和呼吸支持极大地提高了患有严重婴儿变异型SMA的婴儿的存活率，SMA I型占受影响儿童的50%以上。然而，在症状出现后发现的患者中，存活率的提高并没有导致运动结果的改善，这主要是由于急性期的快速进展，以及随后的平台期，其特征是长达数年的功能稳定。Stop SMA研究的初步观察显示，与他们的年长兄弟姐妹以及一组自然历史受试者相比，他们的运动结果和存活率都有所改善。在这项研究中，较小的兄弟姐妹在婴儿早期就被识别出来，并在一家以专科为基础的医疗机构登记，可以获得积极的护理方案。这表明，早期干预可能在限制疾病进展最急性期的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SMN1纯合子缺失检测方法的可行性，以检测有可能发生SMA的婴儿。在这样做的过程中，他们假设：1)受影响的新生儿的发病率将与早期试点数据的预测一致，2)与通过基于专科的医疗机构提供相同的前瞻性营养、呼吸和临床护理方案的自然病史队列相比，通过国家统计局识别有SMA风险的婴儿将改善结果，包括发病率、死亡率和运动功能。在目前的应用中，调查人员还将探索有关使用NBS进行SMA试点筛查以确定最优同意模式的伦理、法规和政策问题。为了改善国家统计局确定的症状前期人群的结果，他们将实施和评估多学科管理方法对通过拟议试点确定的SMA婴儿的健康结果的影响。在对40万名新生儿进行筛查后，调查人员预计至少有40名婴儿有患SMA的风险。具体地说，这些婴儿将被登记在以专科为基础的医疗之家，以协调和提供获得主动护理干预和方案的机会。最后，研究人员将评估早期诊断对SMA婴儿及其家人的心理社会影响。这个项目的成功完成将在许多方面具有价值，为国家统计局社区提供对拟议检测方法识别症状发展风险的准确性的评估，确定基于DNA的初级筛查平台目前的可行性和接受度，提供机会前瞻性地评估一组有症状前诊断的婴儿早期获得协调主动护理的结果，并更好地了解早期诊断对SMA婴儿及其家人的影响。 叙述：在建议将脊髓性肌萎缩症(SMA)等疾病纳入新生儿筛查(NBS)小组之前，必须提供有关筛查和治疗这些疾病的影响的信息。该项目将评估国家统计局的SMA。这项研究有四个目的：1)探索伦理、法规和政策问题；2)实施评估NBS，以发现SMA发展的风险婴儿；3)实施和评估提供早期诊断和护理管理的医疗之家模式；以及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，为影响全国几乎每一名新生儿的公共卫生项目提供循证建议。

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.