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Molecular SMA Testing in Newborns on the Rise as Countries Add Screening Programs


NEW YORK – Three years after the US Department of Health and Human Services added spinal muscular atrophy to the recommended newborn screening panel, state labs and commercial test makers have seen an uptick in molecular testing volumes with millions more infants screened each year in the US alone.

About 98 percent of the 4 million infants born in the US each year are now screened for SMA through state public health programs, up from about 5 percent before HHS added the condition to the federal Recommended Uniform Screening Panel in July 2018, according to information provided by Cure SMA, a nonprofit organization that advocates for SMA screening and research. Screening options expanded last month when Waltham, Massachusetts-based PerkinElmer secured US Food and Drug Administration clearance for its commercial multiplexed molecular assay kit for detection of SMA and severe combined immunodeficiency in newborns (SCID), nabbing de novo authorization for the SMA portion and 510(k) clearance for SCID.

SMA screening is also taking off in Europe, with Belgium, Germany, Lithuania, the Netherlands, Norway, Poland, Slovenia, Turkey, and Ukraine adding or working toward national newborn screening programs in the past several years, according to the website of the European Alliance for Newborn Screening in Spinal Muscular Atrophy, or SMA NBS Alliance. Several other countries are considering national screening proposals, and about a dozen more are conducting pilot programs.

Marie-Christine Ouillade, steering committee chair for the SMA NBS Alliance, said the organization estimates about 45 percent of newborns in Europe are screened for SMA, although only 40 percent are screened in the broader region that extends through Russia, which has implemented a pilot screening program. Newborn screening policies can vary tremendously by country, she said, and the alliance is preparing a campaign to have the European Parliament and European Commission recognize the importance of newborn screening and treatment and equal access to both.

In the US, the rapid rise in SMA screening followed a decade of capacity building at public health laboratories to implement molecular testing for severe combined immunodeficiency (SCID), said Jelili Ojodu, director of newborn screening and genetics for the Association of Public Health Laboratories. With the ability to run a multiplexed SMA and SCID test — as well as funding and guidance from entities including the Centers for Disease Control and Prevention, Health Resources and Services Administration, National Institutes of Health, and nongovernmental advocacy groups — US public health officials have accomplished a rare feat by securing widespread adoption of a newborn screening condition within five years, he said.

Katerina Kucera, director of the Newborn Screening and Genetics Laboratory at the nonprofit research institute RTI International, said the expansion of SMA testing in the US is also possible because the molecular tests used in public health labs have proven to be sensitive and specific enough to provide clear positive and negative results. She also noted that many state labs are required to implement testing for conditions once they are added to the federal RUSP.

Rising test demand

SMA is an autosomal recessive disease that causes weakness and wasting through degeneration of spinal cord neurons, and the severe forms of the disease are deadly for young children left untreated. The Centers for Disease Control and Prevention estimates that one in 10,000 newborns is afflicted.

About 95 percent of cases result from homozygous deletion of exon 7 in the SMN1 gene, which produces most of the body's survival motor neuron proteins. Since 2016, the FDA has approved three treatments for SMA, and European authorities have granted approvals or marketing authorizations for those drugs.

From October 2018 to April 2021, Kucera's lab at RTI ran an NIH-funded pilot study that found three SMA-positive newborns among about 14,000 newborns in North Carolina using the CDC-developed real-time PCR assay, a test first described in 2014 in Clinical Chemistry. Her team found that the test was scalable and it could be implemented with high throughput, short time to results, and a manageable amount of labor typical for screening tests. North Carolina now screens about 120,000 newborns for SMA annually, and Kucera's lab is currently piloting screening for Duchenne muscular dystrophy.

New York state screened about 650,000 infants for SMA in the three years after it added the condition to the state newborn screening program, with 34 screened positive and referred to a neuromuscular specialty care center, according to results published this year in Neurology. California state public health officials reported this year in the Journal of Neuromuscular Diseases that they screened a similar number of newborns in half that time (18 months), and they, too, identified 34 SMA cases out of a similar total of 630,000 newborns. In both states, most SMA-positive newborns received treatment before they were 6 weeks old.

Beyond the US and Europe, Taiwan implemented countrywide opt-in SMA screening in 2018, and Australia and Japan have started implementing regional screening programs, according to study results published in 2021 by Neuromuscular Disorders.

Muscular Dystrophy Canada, which has advocated for nationwide SMA screening, said in July governments in all but two of the country's provinces and one of its territories had committed to implementing SMA screening, and one of those provinces, British Columbia, has since said it was also adding SMA screening, leaving only the province of Newfoundland and Labrador and the Yukon territory without announced SMA testing plans.

The global expansion of SMA screening has also been a boon to commercial test providers.

PerkinElmer's general manager for reproductive health, Petra Furu, said in an email that the firm is experiencing double-digit growth in SMA testing and predicts that will continue. The company performs SMA testing through its StepOne newborn screening platform, second-tier testing to help determine disease severity, and carrier screening for future or prospective parents. In addition, the firm gained clearance in November for its CE-marked Eonis SCID-SMA kit, a PCR assay for detection of SMA and severe combined immunodeficiency in newborns.

Megan McSweeney, head of product for women's and reproductive health genetics at Invitae, said the company has increased its SMA testing volume in Australia as the national Medicare system has expanded coverage to SMA and fragile X syndrome. Invitae is also seeing slower, steadier growth of SMA screening volume in Canada. The firm provides standalone testing for SMA and broader genetic screening panels, as well as carrier screening for prospective or future parents.

Early screening improves outcomes

Ouillade, of the SMA NBS Alliance, said newborns with undetected SMA soon run out of functional SMN proteins from their mothers and irreversible nervous system damage begins, typically manifesting in symptoms at 3 or 4 months old. By then, "part of your nervous system is already destroyed."

Officials with the US-based Cure SMA declined to comment on the expansion of newborn SMA screening, but they said in previous statements that early diagnosis and access to SMA treatment leads to long-lasting developmental improvements and predicted SMA screening by states would have profound benefits.

During a one-year SMA screening pilot project in the German states of Bavaria and North Rhine Westphalia, the children who were positive in screening and received treatment before symptoms developed showed no muscle weakness in their first year, the researchers said in a 2019 article in the Journal of Neuromuscular Diseases.

"With the advent of effective pharmacological treatment for SMA, there is a worldwide discussion about strategies to identify patients as early as possible," the authors wrote. "This is especially so for children with an expected severe form of SMA who in our view should be treated immediately."

Researchers from Belgium, in reporting on results of a three-year pilot screening program in the country's Liège region, said in a 2021 article in Scientific Reports that their project showed that a pilot program could rapidly transition into an official newborn screening program and other countries should embark on similar programs.

"Given the effective treatments now available for SMA and the importance of treatment prior to the onset of symptoms, testing for SMA should be incorporated into screening of all newborns," they said.