Two Articles on Spinal Muscular Atrophy Newborn Screening in the Latest Issue of the American Journal of Medical Genetics.
July 7, 2010.

In the latest issue of the American Journal of Medical Genetics, two articles appear on genetic screening for Spinal Muscular Atrophy.  Dr. Prior at OSU publishes a research article on the technical feasibility of both carrier and newborn screening for SMA, and Dr. Swoboda at the University of Utah publishes an editorial on the critical importance of newborn screening in SMA.

Dr. Swoboda's article, entitled "Seize the Day: New Born Screening for SMA" delineates the reasons why newborn screening is of vital importance to SMA and urgent need for it exists.   An Excerpt from her editorial can be found below:

The decision of which disorders to screen for in newborns is left to the discretion of individual States currently, but the Federal government has taken a much more proactive role in the past decade. Congress recognized the need for Federal involvement due to the increasing discrepancies between State screening programs, the evolving sophistication of screening technologies, and the complexity of the ethical, legal, and social issues involved. The Children's Health Act of 2000 mandated the creation of an Advisory Committee within the U.S. Department of Health and Human Services to bring greater uniformity to the nation's NBS efforts. The Secretary's Advisory Committee on Heritable Disorders in Newborns and Children worked with the American College of Medical Genetics (ACMG) to create such a panel and, subsequently, to develop a formal methodology for the nomination, review, and approval of additional disorders to the Federal Panel. The Advisory Committee continues to work closely with the ACMG, the Health Resources and Services Administration, the National Institute of Child Health and Human Development, and others on these important matters [Howell, [2006]; Calonge et al., [2010]].

SMA was nominated as a candidate for NBS to the Advisory Committee in 2008, by a collaborative group of physicians, scientists, and support organizations led by Families of SMA, who were motivated by the remarkable progress in therapeutics development targeting SMA in the past decade. This process resulted in specific guidance as to the next steps forward, as indicated from this quote from the final committee report:  the [committee] recommends the Nominator to conduct prospective pilot studies in one or more traditional public health laboratories in order to show reproducibility of the preliminary findings in Dr. Prior's laboratory. The time frame required to collect the analytical evidence mentioned above could also lead to a better assessment of the efficacy of novel treatment modalities under investigation.

The Committee's recommendations are clear and consistent with the existing NBS paradigm: perfect the technology and await an effective treatment. Unfortunately, this leaves SMA in a Catch-22. That is, NBS for SMA cannot be implemented until an effective treatment is in place, but testing of an effective treatment requires a population of pre-symptomatic SMA patients likely only to be identified in numbers large enough to support clinical trials by using NBS. SMA is not the only disorder for which this dilemma exists. However, given the incidence and impact of the disease, the proven capabilities of the SMA NBS technology as demonstrated by Prior and colleagues, and the rapid advances toward the identification of effective treatments, SMA is an attractive candidate for a pilot to test a new paradigm whereby NBS is used to help facilitate the development of an effective therapy.

SMA is a common and frequently lethal disorder of childhood. The condition is medically serious, and associated with significant muscle weakness, respiratory and feeding difficulties in the majority of affected children. Most affected individuals manifest symptoms prior to 18 months of age. The spectrum of the disorder is well described, and SMN2 dosage is a well-characterized modifier that helps to predict the phenotypic range of those to be identified via NBS. In fact, one of the unique aspects of SMA, compared to other neurodegenerative diseases, is that the positive predictive power of SMN2 dosage makes is feasible to predict, at the population level, those most likely to benefit from early intervention or treatment.

The characteristics of the screening test for SMA are robust. High specificity is a particularly desirable attribute for a DNA-based screening test, to reduce risk of anxiety resulting from false-positive diagnoses. In fact, the testing paradigm used by Prior and colleagues performs considerably better than most of the metabolite-based NBS tests currently in use.

Finally, while the spectrum of disease is broad, those who are most likely to benefit from treatment, and those who are at greatest risk of imminent decline, are identifiable. This is a significant advantage as new therapeutic interventions become available, some of which might pose substantial risk in those otherwise expected to have a reasonably good outcome.

Compelling evidence supports a role for early intervention via proactive nutrition and respiratory support in improving outcomes for the most severely affected infants [Oskoui et al., [2007]]. The type of nutritional support has been demonstrated to significantly impact survival in an SMA mouse model of the disease [Butchbach et al., [2010a]]. Furthermore, a synergistic effect of nutritional supplementation and pharmacologic therapeutic intervention has been demonstrated in SMA animal models, further strengthening the hypothesis that early proactive nutritional support likely would considerably improve disease outcomes [Narver et al., [2008]]. However, data from prospective controlled studies in patients are currently lacking, and unequivocal evidence of benefit could take several years to obtain.

Please click here for the abstract of this editorial.  

Dr. Prior and his colleagues at OSU present data in their research article on the technical feasibility of the both newborn and carrier screening for SMA.  In this article, the authors describe data from two pilot projects addressing the clinical applicability of testing in the newborn period and carrier screening in the general population. Those studies demonstrate effective technology does exist for newborn screening of SMA.  They also provide an estimate of the carrier frequency among individuals who accepted carrier screening, and report on patient's knowledge and attitudes toward SMA testing.

Dr. Prior has said about this study, ""We have demonstrated that an effective technology does exist for newborn screening of SMA," said Prior. "A newborn screening program for SMA not only allows parents to enter their children into clinical trials earlier, but would enable patients to obtain proactive treatment, for nutrition, physical therapy, and respiratory care, earlier in the disease progression." 

There has been a major expansion in newborn screening throughout the United States and many in the SMA community have been arguing that newborn screening should not be limited to disorders for which there is a clear treatment.

Please click here to read the paper abstract.

Please click here to read a recent press release about Dr. Prior's paper released by the American Journal of Medical Genetics.