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.

Public Health Relevance

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 project 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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD069045-04
Application #
8651506
Study Section
Special Emphasis Panel ()
Program Officer
Urv, Tiina K
Project Start
2011-04-20
Project End
2016-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
4
Fiscal Year
2014
Total Cost
$844,277
Indirect Cost
$157,163
Name
University of Utah
Department
Neurology
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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Botkin, Jeffrey R; Lewis, Michelle Huckaby; Watson, Michael S et al. (2014) Parental permission for pilot newborn screening research: guidelines from the NBSTRN. Pediatrics 133:e410-7
Cano, Stefan J; Mayhew, Anna; Glanzman, Allan M et al. (2014) Rasch analysis of clinical outcome measures in spinal muscular atrophy. Muscle Nerve 49:422-30
Kissel, John T; Elsheikh, Bakri; King, Wendy M et al. (2014) SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy. Muscle Nerve 49:187-92
Rothwell, Erin; Anderson, Rebecca A; Swoboda, Kathryn J et al. (2013) Public attitudes regarding a pilot study of newborn screening for spinal muscular atrophy. Am J Med Genet A 161A:679-86
Lewelt, Aga; Newcomb, Tara M; Swoboda, Kathryn J (2012) New therapeutic approaches to spinal muscular atrophy. Curr Neurol Neurosci Rep 12:42-53
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Swoboda, Kathryn J (2011) Of SMN in mice and men: a therapeutic opportunity. J Clin Invest 121:2978-81