by Nancy Maddox, MPH, writer
When Stella Turnbull was born in 2007, she showed all the signs of a healthy baby. At one month of age, however, everything changed. “I went to give her a bath,” said her mother, Sarah Turnbull, “and her head, her arm, her legs were all very floppy.” On the advice of Stella’s pediatrician, Sarah and her husband rushed the baby “that very night” to the emergency department at Mayo Clinic in Rochester, Minnesota—a five-hour drive from their home in Iowa.
Over the next week, the parents learned that their daughter has spinal muscular atrophy (SMA), a rare genetic disorder that has left Stella, now age 12, dependent on a trach tube for breathing, a gastrointestinal tube for feeding and 24-hour care. When the family finally left Mayo Clinic after Stella’s diagnosis, the parents were told, “Just take her home and love her, because there’s nothing we can do.”
Fast forward to 2019, and the outlook for infants with SMA is dramatically different. The US Food and Drug Administration (FDA) approved the first drug to treat the disorder, Spinraza®, in 2016. And FDA is expected to approve a potentially curative gene therapy this year. But both interventions work best when delivered soon after birth, while infants are pre-symptomatic and their motor neurons fully functional; although Spinraza® has given Stella some movement in her legs and neck, and potentially stopped her disease progression, neither Spinraza® nor gene therapy can replace the motor neurons that have died. “Her independence,” said Sarah, “is limited to finger movements to operate her power chair.”
Heartbreaking stories like Stella’s epitomize the strongest case for newborn screening (NBS): to detect congenital disorders at birth, so effective treatments can be implemented before dire health consequences set in.
Just last year, SMA was added to the federal government’s list of disorders recommended for inclusion in state NBS programs—the Recommended Uniform Screening Panel (RUSP) maintained by the US Department of Health and Human Services. Six states currently conduct routine NBS for SMA. And Stella’s own state, Iowa, will begin a pilot SMA screening program sometime this year.
NBS is a public health success story, ongoing for 56 years. Today, the field is full of both promise and challenge. On the one hand, new treatment and laboratory testing options open up the possibility of expanded screening panels. Already, the RUSP has grown from an initial 29 core conditions in 2006 to 35 today, and fragile X syndrome and Duchenne muscular dystrophy are expected to be next up for consideration.
On the other hand, however, testing laboratories and follow-up providers are generally under-resourced and straining to keep pace with growing workloads. In the laboratory, there is pressure to simultaneously enhance quality, reduce test turn-around-time and rigorously evaluate new high-throughput screening methods. In providers’ offices, there is the need to care for increasing numbers of patients with conditions whose progression and management may be poorly understood.
“The easy disorders have already been done”
Currently, virtually all of the four million or so babies born in the United States each year receive NBS within the first 24 to 48 hours of life. Since 97% of this screening is the responsibility of state public health laboratories (PHLs), PHL scientists have spearheaded the implementation of new screening technologies and generally embraced the expansion of screening panels. But as NBS candidate disorders become rarer and rarer, their diagnosis less clear-cut, and their treatments less effective, NBS advocates have grappled with what Michele Caggana, ScD, FACMG, calls the “push and pull of adding new conditions.”
Caggana, who heads the NBS Program and the Genetic Testing Quality Assurance Program at New York’s Wadsworth Center—the state PHL—said, “New York has always been an early adopter” of NBS candidate conditions, just last year adding SMA, mucopolysaccharidosis Type I (MPS-I) and guanidinoacetate methyltransferase deficiency to its screening panel. Yet, she said, “We have to be thoughtful about how we do NBS expansion. The low hanging fruit, the easy disorders, have already been done.”
One unresolved issue, said Patrick Hopkins, the semi-retired former NBS chief at the Missouri State Public Health Laboratory, is the “growing challenge of deciding on what we’re screening for, such as newborn disorders, childhood disorders and late onset disorders. Often we cannot safely sort out the difference between these on the screening test, and if we could, where would we draw the line?”
Pompe disease, for example, has a classic infantile form, requiring immediate intervention, and later onset forms (about 72% of cases) in which serious symptoms may be delayed until adulthood. Babies with either of these variants will screen positive for Pompe, as well as babies with a less-urgent, non-classic infantile form and babies with pseudo-deficiency, who have biochemical Pompe disease markers, but will never go on to develop the disease. Follow-up providers must determine the appropriate diagnosis and counsel families based on limited clinical guidance, since there is little medical experience with Pompe, especially over the long term.
Molecular testing raises similar issues. Now used for discrete NBS applications—mostly second or third tier testing—it is expected to become more prominent in the NBS laboratory.
Said Caggana, “What we’re seeing with molecular [technology]—the ability to multiplex and look at several different genes at once—harkens back to when mass spectrometry came on the scene [in the early 2000s].... It really pushed the field.”
Yet molecular testing comes with its own challenges, including the need for added infrastructure (including new instrumentation, a dedicated “clean” room and space to accommodate a unidirectional flow of testing), highly specialized staff training and capacity to analyze massive amounts of genetic data.
Moreover, Caggana noted that “no one’s assessed molecular [findings] on a broad stroke of the population of healthy babies” to inform data analysis and interpretation of novel gene variants.
Kimberly Noble Piper, RN, CPH, CPHG, genetics coordinator for the Iowa Department of Public Health (IDPH) said molecular screening “comes with a whole lot of ethical considerations.” She explained, “When you test the genome, you’re going to find mutations that may not mean anything, and we won’t know what’s significant and what’s not. And how do you tell the family that; that you found a variant and you don’t know what that means, maybe nothing?”
Equivocal and false-positive findings come at a cost.
Neena Champaigne, MD, FACMG, FAAP, director of the metabolic treatment program at South Carolina’s Greenwood Genetic Center, diagnoses and follows patients with metabolic NBS disorders from birth onward. False-positives and findings of unknown clinical significance, she said “cause us a lot of concern.” Among the consequences are:
- “Running the risk of inundating providers,” who may then develop a lack of urgency “because they now have so many infants with abnormal results and they don’t know how to sift through them and triage them.”
- Placing unnecessary psycho-social burdens on families. Champaigne said, “I personally have seen families who have medicalized their children even after it’s proven that they don’t have a NBS condition; they have a hyper-awareness for that child, more doctor visits, which can have ramifications for years.”
- Compromising medical specialists who are already “stretched thin,” and must then follow individuals who may never develop symptoms. Champaigne, for example, is one of only two biochemical geneticists serving the entire state of South Carolina, plus the nearby border regions of Georgia and North Carolina. Some states, she said, “don’t even have a biochemical geneticist.” Although her training is in pediatrics, of necessity, Champaigne has followed some patients well into adulthood.
“External pressures to meet challenging timelines”
NBS programs are working diligently to address these challenges; to improve the accuracy and precision of existing tests and to bring on new disorders, even as they continue the high-stakes work of screening tens of thousands of infants a year—in some states a six- or seven-day-a-week job.
Hopkins oversaw one of the first Pompe disease screening programs in the world, demonstrating proof-of-concept for Pompe NBS. To do so, his team adapted and validated a brand-new methodology called digital microfluidics fluorometry. A statewide hiring freeze at the time meant that no additional help was available in a laboratory already screening 93,000 NBS specimens/year for over 60 other disorders.
An early success, said Hopkins, was detecting a child with infantile Pompe on the second day of pilot screening. And data from the first six months of population-wide screening revealed about twice as many Pompe cases as predicted in the scientific literature. These outcomes bolstered the case for adding Pompe to the RUSP in 2013.
Caggana is working with colleagues to create a forum for sharing molecular test data to reduce ambiguous findings. “If we see a [genetic] variant twice in New York and the baby is, and remains, asymptomatic,” she said, “it’s more likely to be identified in asymptomatic infants across the country.”
Wadsworth is also working to enhance long-term follow-up, so, Caggana said, data “can feed back to [the laboratory] to help us modify the testing algorithm so we don’t catch the babies who will never develop disease.”
Wadsworth scientists are in the midst of refining the laboratory’s screening algorithm for cystic fibrosis (CF) to reduce the number of false-positive results—an example that showcases the complexity of modern-day NBS. In the first phase of analysis, specimens are winnowed via a biochemical test to measure levels of the CF marker, immunoreactive trypsinogen (IRT). Those with IRT levels among the top 5% of specimens screened in the past ten days then advance to molecular testing.
New York is transitioning from a two-tier genetic screening protocol—a 39-mutation CF panel, followed by CFTR gene sequencing for specimens meeting certain criteria—to an enhanced process: “We’ll take a bioinformatic look to interrogate all the [CFTR gene] variants we’ve seen in babies in New York,” said Caggana. “If a baby has one variant, we’ll look at the rest of the gene.” Infants with two CF variants are reported as screen-positive and those with one as “single variant detected.”
Although this multi-step process increases test turn-around-time, it also increases specificity. “We’re able to reduce the number of families impacted and the downstream number of babies who have to undergo [a diagnostic] sweat test,” said Caggana. “That makes the longer time palatable.”
Further complicating the work of NBS scientists, said Hopkins, are “external pressures to meet challenging timelines and quality in a very sensitive and oftentimes emotional area of laboratory testing.”
Earlier this year, Sanofi US—which manufactures enzyme replacement therapies for a group of NBS conditions known as lysosomal storage disorders (LSDs)—lobbied the Iowa legislature and got bills introduced that would essentially require the state to screen for all LSDs on the RUSP by 2020—an impossible feat. (By way of comparison, Wadsworth screened tens of thousands of infants for Pompe, a LSD, during its pilot program, before the disorder was added to routine NBS.)
Piper, who participated in an analysis of the bill, said the health department concluded that there was “no way we could add these conditions to our panel by next January.” She said, “We don’t have the physical capacity and infrastructure to screen for LSDs on a population level. We would require additional equipment, more electrical resources, more data resources. It would take a capital outlay that is not insignificant.”
Declining to appropriate the funding, the legislature backed down. As of early spring, it seems likely the final bill will instead ask IDPH to review every new condition added to the RUSP—which it already does—and then submit a report to the governor’s office.
“We dodged a bullet,” said Piper.
Most states—all except, FL, KS, NY, PA and DC—fund their NBS programs at least in part through fees, ranging from $30/infant in Louisiana to $162.98/infant in Rhode Island. But increasing these fees is rarely easy. After Missouri added screening for Pompe disease and other select LSDs in 2013 (an effort costing a few hundred thousand dollars), it took two years to raise the statutory cap on NBS fees so the state could charge an extra $20/baby—an adjustment requiring the approval of both the state legislature and governor.
Given budgetary constraints, NBS laboratories continually work to increase efficiency. New York’s Wadsworth Center has implemented “lean” methods to streamline its processes. Recent improvements include using state health department systems to enhance electronic communications with hospital newborn coordinators, and tweaking laboratory systems to assure more timely data entry.
“We save two babies every three days”
What does the future hold for NBS?
The experts cited in this article predict continued expansion of the NBS panel due to advances in gene therapies that will target more candidate disorders and a greater willingness to screen for conditions whose symptoms can only be attenuated through early intervention.
The growing NBS panel, in turn, will require growing the nation’s pipeline of NBS laboratory scientists—for example, through efforts like the APHL NBS fellowship program—and follow-up providers. Currently, Champaigne said, there is one biochemical geneticist for every 2.2 million US residents, and new professionals are added at the rate of only 15 every two years—not enough to replace those retiring from this demanding specialty.
On a technical level, multiplexing, whereby several different disorders can be tested simultaneously from the same NBS dried blood spot, is likely to expand, via platforms like mass spectrometry.
“There’s only so much blood on a card,” said Caggana, “so we have to depend on using the same specimen.”
At the same time, a push to decrease false-positives will likely mean more second and third tier screens. And, because of limited capacity and funding, more state NBS laboratories may opt to outsource this work.
In place of disease-specific screening, Caggana foresees “analyzing a collection of data more broadly across each baby,” based on results from next generation sequencing or metabolomic methods, like mass spectrometry, which capture data on metabolites associated with many different cellular processes.
Finally, data management—APHL’s top federal priority for this fiscal year—will loom large. Within the laboratory, there will be a need to analyze the massive datasets produced by newer technologies. And outside the laboratory, there will be a need to better manage and share follow-up data, especially across states.
As Champaigne explains, “We won’t know what we don’t know until we start [screening for new disorders]. We have to be mindful that we’re going to have some results that are indeterminate and will require long-term follow-up, and we should make some attempt to collect this information in an organized and meaningful way so we can learn how to improve test precision, as well as disease management further down the line.”
Overall, said Caggana, “NBS is definitely at an interesting time, with a lot of change over the last few years” and a lot of change in progress.
In the midst of this flux, children like Madison Braddock, age 7, are a reminder of why NBS matters so much. Madison, one of Champaigne’s South Carolina patients, was diagnosed at two weeks of age with glutaric aciduria, Type 1—added to the state’s NBS panel in late 2004. Her mother, Victoria, said, “She didn’t have any abnormal signs at all.”
Without the early alert provided by NBS, Victoria said, “Definitely over the next couple of months of infancy she could have had a metabolic stroke that could lead to cerebral palsy, low muscle tone and ultimately death, without the proper medical formula.” Instead, she is a happy child whose main disease complication is “a feeding tube in her tummy” to deliver her formula.
And therein lie the rewards of the work: “We save two babies [from death or disability] every three days here in Missouri,” said Hopkins. “How cool is that?”