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Cystic Fibrosis Newborn Screening: A Model for Neuromuscular Disease Screening? Michele A. Scully, MD,1 Philip M. Farrell, MD, PhD,2 Emma Ciafaloni, MD,1 Robert C. Griggs, MD,1 and Jennifer M. Kwon, MD, MPH1 Congenital neuromuscular disorders, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease (acid maltase deficiency [AMD]), are candidates for universal newborn screening (NBS). In this article, we discuss the future path of NBS for these disorders with particular emphasis on DMD NBS, because of the likely approval of new gene-modifying treatments, the possible benefits of earlier treatment with corticosteroids, and the recently demonstrated feasibility of a 2-tiered approach to NBS with screening by creatine kinase (CK) levels in dried blood spots followed by mutation detection in those with elevated CK. The cystic fibrosis (CF) NBS program is a successful model for NBS. CF outcomes have consistently improved into adulthood following introduction of CF NBS because considerable resources have been devoted to practices that include: attention to improving laboratory screening, consistent confirmatory testing and immediate referral of all newly diagnosed infants to designated CF care centers that follow established practice guidelines, and ongoing evaluation of CF care centers via a centralized clinical database. Like CF, DMD, SMA, and infantile AMD are inexorably debilitating and require lifetime multidisciplinary clinical management. NBS would address the delays in diagnosis that prevent patients from receiving timely treatments. Standardized care following early diagnosis would reduce disparities in clinical care and outcomes. NBS in these neuromuscular disorders should be implemented, utilizing lessons learned from the past 20 years of CF NBS: standardized protocols for all patients identified by DMD NBS, longitudinal follow-up in multidisciplinary clinics, and coordinated oversight of these clinics. ANN NEUROL 2014;00:000–000
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ewborn screening (NBS) detects diseases in infants where early treatment prevents devastating outcomes. There are currently 31 diseases recommended for screening by the federal Recommended Uniform Screening Panel (RUSP) (http://www.hrsa.gov/advisorycommittees/ mchbadvisory/heritabledisorders/recommendedpanel/uniformscreeningpanel.pdf ). The criteria used to determine which disorders are most suitable for screening are based on Wilson and Jungner’s criteria for population screening.1 In practice, however, there has been an understanding that for rare inherited disorders the evidence for treatments may be limited (eg, a lack of controlled clinical trials) and, in many cases, expert judgment has to suffice.2 An effective newborn screening program should include clear guidelines for confirmatory diagnostic studies, follow-up, and treatment protocols.2 Screening programs initiated without such guidelines may not improve outcomes.3,4
Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease or acid maltase deficiency (AMD) have been proposed as candidates for NBS because early diagnoses have the potential to improve clinical management and outcomes. Table 1 compares the clinical characteristics and existing treatments for these disorders. Most patients with SMA present during infancy, but those with the more severe type 1 disease do not survive past early childhood, whereas those with type 2 disease (who can achieve sitting) may live into their second or third decade. In the case of SMA, there are currently only experimental treatment trials in place. Compared to SMA, AMD has even greater clinical variability, with the majority of cases identified as late onset disease as opposed to infantile onset. AMD NBS has been in place in Taiwan since 2005, and the greatest benefit has been demonstrated in infantile AMD
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24316 Received Jun 16, 2014, and in revised form Oct 10, 2014. Accepted for publication Nov 17, 2014. From the 1Department of Neurology, University of Rochester Medical Center, Rochester, NY; and 2Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI
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TABLE 1. Comparison of DMD, SMA, and AMD as Candidates for Newborn Screening
DMD
SMA
AMD
1/5,000 male births
1/10,000 births
1/40,000 births (all types)
Clinical course
Presents in early childhood with delayed motor milestones. Course is progressive due to ongoing muscle injury and fibrosis, with loss of ambulation by 12 years of age.
Variable age of presentation from infancy to adulthood, with progressive weakness and muscle atrophy from loss of anterior horn cells.
30% are infantile onset (incidence of 1/133,000) and present with profound and progressive hypotonia and cardiomyopathy. Later onset forms present heterogeneously with variability in weakness, cardiac involvement, and age of onset (most late onset disease presents in adulthood).
Life expectancy, approximate median age at death
20s–30s.
Patients with SMA1 presenting in first 6 months of life have a life expectancy of 2–3 years without aggressive interventions (G-tube, chronic ventilation). Those with SMA presenting later in childhood generally survive longer with supportive interventions.
In infantile disease with cardiomyopathy (classic form), death in the first 2 years of life. Other forms have more variability in survival.
Existing treatments, in addition to supportive care
Corticosteroids improve strength and duration of mobility.
—
Enzyme replacement therapy.
Issues with treatment
Sides effect of chronic corticosteroid use, obesity, poor linear growth.
N/A.
Treatment very expensive; limited guidelines on who to treat and for how long.
Proposed novel genetic treatments
Yes.
Yes.
—
Incidence
AMD 5 acid maltase deficiency; DMD 5 duchenne muscular dystrophy; N/A 5 not applicable; SMA 5 spinal muscular atrophy.
patients, where presymptomatic treatment with enzyme replacement therapy (ERT) decreased mortality and morbidity (survival and ventilator-free survival) when compared to historical and contemporaneous controls.5,6 One barrier to widespread acceptance of AMD NBS has been the concern over the high cost of ERT, which must be given for the lifetime of the patient. There are also questions about when to initiate treatment in those with late onset AMD.7 Of the 3 disorders, DMD is most consistent in age of onset and has the most predictable rate of progression. DMD is an X-linked disorder affecting 1 in 5,000 males.8 Although no cure exists for the progressive muscle weakness of DMD, corticosteroid treatment improves muscle strength and function, and in combination with supportive medical care is associated with markedly improved survival.9–11 2
For all of these disorders, NBS can only be justified if it can be shown to improve patient outcomes. In SMA and AMD, early identification has been shown to improve clinical outcomes in infants,5,6,12,13 providing compelling arguments for adding these disorders to the RUSP. However, for DMD, the justification for NBS has proven more challenging. Past DMD NBS programs have not been able to show that early identification modifies outcomes in infants or older children, and these programs have been criticized for the lack of meaningful and evidence-based treatments for infants and toddlers.14–16 Despite these concerns, recent developments in DMD diagnosis and genetic treatments, in combination with the well-documented delays in initiation of corticosteroids after muscle fibrosis has occurred, have made DMD a compelling candidate for approval by the RUSP.8,17 Volume 00, No. 00
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An example of a successful NBS program is cystic fibrosis (CF) NBS, which faced challenges similar to those of DMD at its start. Two decades ago, when it was proposed for universal NBS, many argued that timely diagnosis rather than NBS was needed to improve CF outcomes.18,19 CF NBS is a useful screening prototype, and the approach used is applicable to other progressively disabling and ultimately fatal disorders such as those discussed above. In this article, we focus on the elements needed to ensure that NBS of neuromuscular disorders is successful, based on the components of CF NBS. We discuss in particular detail the history of DMD NBS programs, because, unlike SMA and AMD, DMD does not have an infantile presentation, so the benefit of NBS is more difficult to demonstrate.
Results History of DMD NBS There have been >1 million newborns screened for DMD, in 10 countries, since the first systemic DMD screening program in New Zealand in 1976.8,14 The largest program (in Wales) screened 335,045 newborns, identifying 63 DMD patients.20 All of these programs utilized creatine kinase (CK) on dried blood spots as an initial screen, with follow-up confirmatory testing (muscle biopsy or more recently genetic testing) performed at subsequent visits.14,20 The rationale for many of these programs was to provide an early diagnosis so families can better cope with decision making and future family planning, while accurately identifying patients to be followed according to local practices. In most programs, parents “opt-in” to the screening process, with parental reactions to screening assessed by researchers through questionnaires. Critics of DMD screening suggest that early diagnosis of DMD creates greater psychological burdens on family, including adverse effects on bonding and inability to enjoy the initial years of good strength.16,21 However, studies have shown that parents of DMD boys notice, and are anxious about, early motor and cognitive delays and question their own abilities as parents until the DMD diagnosis is made.14,17,20 Recent work demonstrates that expectant parents are much more accepting of newborn screening for DMD and SMA, even without clear evidence of effective interventions in infancy.22 Overall, the early screening programs demonstrated the feasibility of CK testing in newborns, but were not able to show evidence of clear improvement in patient clinical outcomes.15 Issues that challenged these programs included: the fluctuation of CK levels immediately following delivery, the difficulty in setting an arbitrary CK cutoff with good sensitivity and specificity, issues with Month 2014
confirmatory testing, and the anguish of families told that their well-appearing newborn has an untreatable diagnosis.23 Work over the past decade addresses these issues, and patients now live into their third to fourth decade with corticosteroid treatment and multidisciplinary care.24 Recent advances toward DMD NBS include the following. AN IMPROVED DMD SCREENING TEST. A 2-tier dried blood spot test, CK/DNA screening, has been recently tested successfully in 37,649 study participants.8 This strategy is identical in concept to the method applied successfully to CF, that is, use of an initial biomarker followed by a more specific molecular assay.25 In DMD, a fluorometric assay is used to detect elevated CK activity followed, on the same blood spot, by whole genome amplification of the DMD gene.8 Using this methodology, 5 of 37,649 participants had identified DMD mutations, all with CK > 2,000ng/ml (normal < 200ng/ml). Seven patients had CK > 2,000ng/ml without DMD mutation, and upon further genetic testing, 2 were positive for limb girdle muscular dystrophy. The cost of adding this assay to current newborn screening techniques is “approximately $1.00” per newborn, for reagents.8 Confirmatory DNA analysis, for those above the CK cutoff value, is financially feasible and similar to CF NBS cost.26 UPDATED INFORMATION ABOUT THE NATURAL HISTORY OF DMD IN INFANTS. DMD boys as young
as 1 year develop neurocognitive delays, scoring lower in motor, speech, and language function on the Bayley III Motor Assessment compared to age-matched controls. As boys become weaker, this leads to social exclusion.27 Despite awareness that DMD can present in infancy with such delays, there remains a delay of about 2.5 years between symptom onset and diagnosis, which further delays corticosteroid treatment.17,28 TREATMENT WITH CORTICOSTEROIDS. Corticoste-
roids are proven to improve strength in DMD patients.9,10 However, treatment is usually initiated at age 4 to 5 years when diagnosis is first made, after muscle fibrosis has started.17,29 Earlier treatment with corticosteroids, as early as 2 to 4 years, improves motor function in DMD patients and is associated with good long-term outcomes after 14 years of treatment.30 NEW THERAPIES FOR BOYS WITH DMD. A molecular therapy (eteplirsen), a drug that promotes exon skipping to restore the dystrophin reading frame, has shown effectiveness in clinical trials.27 Such therapies are likely to be most effective in boys diagnosed before fibrosis
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replaces muscle fibers, making DMD NBS essential to identify those patients. Polymerase chain reaction can detect 98% of exon deletions, or approximately 65% of DMD patients.31 Treatments focusing on stop codon mutations (ataluren) represent another 20% of DMD cases, and clinical trials focusing on these mutations are in progress.32 SMA and AMD NBS SMA NBS has been proposed as a means of improving the survival in infants born with the more severe form, type 1 SMA. These children have early respiratory and nutritional needs; addressing them in a timely manner can improve survival.33 Unfortunately, many children with SMA experience worsening weakness before accurate diagnosis. Furthermore, trials of treatments in presymptomatic infants cannot be conducted without early screening, further delaying hope of effective treatments. There are promising trials that may expedite approval for SMA NBS.34 In the case of AMD, there is already evidence that early treatment of presymptomatic infants with AMD can improve survival6 (http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/nominatecondition/ reviews/pompereport2013.pdf). These data were compelling enough for the Discretionary Secretary’s Advisory Committee to recommend to the Secretary of Health and Human Services that AMD be included in the RUSP in 2013 (http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendations/correspondence/ uniformpanel060313.pdf ), and final approval awaits the Secretary’s decision. History of CF NBS CF has a similar prevalence to DMD, approximately 1 in 3,500 live births.35 CF is an autosomal recessive condition caused by mutations in the CF transmembrane conductance regulator (CFTR), which alters the CFTR chloride channel protein effecting respiratory, gastrointestinal, and certain epithelial systems such as sweat glands.35 The median age of survival for CF children in 1959 was 6 months, with death from pulmonary complications. By 1986, the natural history of the disease had changed to a median survival of 27 years, and it was recognized that early diagnosis and thus earlier and consistent medical management accounted in large measure for this increased survival.36 The current median survival is 38.3 years, reflecting earlier diagnosis through NBS with organized follow-up in pediatric and associated adult care centers, the addition of new therapies applied with quality improvement (QI) methods, and use of a patient registry.29,37,38 Additionally, NBS and consistent 4
therapies have eliminated disparities in diagnosis, including a previous gender gap, that is, longer delays in the diagnosis of females.39,40 Only recently has molecular therapy become a reality, affecting approximately 2 to 5% of patients.41 The history of feasible CF NBS dates back to 1979, when the first assay to screen for elevated immunoreactive trypsinogen (IRT) was developed on newborn dried blood spots.42 This methodology spurred a paradigm shift in CF care from reliance on symptom-based interventions to treatment of presymptomatic infants, leading to delayed morbidity. A statewide CF NBS pilot using dried blood spots was initiated in Colorado in 1982, under a grant from the Bureau of Maternal and Child Health.43 The results prompted a publication indicating the need for a large, prospective randomized controlled trial (RCT) to assess the benefits, risks, and costs of CF neonatal screening and the epidemiology of the disease.44,45 The trial, initiated in Wisconsin (Wisconsin Cystic Fibrosis Neonatal Screening Project) through support from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health, screened all infants born in Wisconsin between April 15, 1985 and June 30, 1994; one-half of screened infants had results reported to family and primary care physician, and the other half (the control group) were followed with results of the screening undisclosed until unblinding or 4 years of age, unless the infant’s parents or primary care physician requested the screening data, avoiding selection bias.45 Primary outcomes were quantitative and focused on nutritional status and bronchopulmonary disease.46 The study demonstrated the benefit of CF NBS; height/weight differences in screened patients versus unscreened persisted for >16 years,46 and better nutrition was associated with less lung disease.47 The Centers for Disease Control and Prevention (CDC) reviewed the results of the Wisconsin study in 1997 and initiated NBS preimplementation planning. By 2002, a joint CDC/CFF conference recommended staterun CF NBS programs based on long-term benefits from early nutritional treatment and manageable risks.48 To expedite CF NBS in the USA, the CFF appointed a national facilitator (principal investigator of the Wisconsin RCT) to work with all states in their 1- to 3-year planning phases. During the next 5 years, taking advantage of the existing CF center network, all states implemented CF NBS, leading to a new era of routine, early diagnosis and preventive therapies.49 There is now worldwide support for CF NBS, because psychological benefits and survival data far outweigh any potential harm.50 With CF NBS in place, current research has shifted from identifying early benefits to: identifying the Volume 00, No. 00
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cumulative benefit of what is done early in life to influence critical outcomes in adulthood,51 facilitation of clinical trials, best care practices,52 addressing imperfections in state screening systems through a CDC-implemented quality assurance program for both the IRT and DNA components of CF NBS,26 and organization of a national QI program through the CFF to identify the best screening methodology, as methods continue to vary widely.53 The current CF NBS program includes the following components. FOLLOW-UP IN SPECIALIZED CARE CENTERS. There
are 113 care centers across the country, along with some 58 smaller, affiliated satellite clinics.29 The overall number of clinics is limited to ensure an adequate number of patients are followed by each center, maintaining expertise and high standards across all centers (http://www.cff. org/). Recognizing that more than half of US CF patients are >18 years of age, the CFF expects that ultimately each center will establish an adult care program.54 A 5-year accreditation process ensures both pediatric and adult clinics have a multidisciplinary team, participate in the patient registry, and adhere to strict documented evidence and consensus-based guidelines, which have evolved by benchmarking top clinics.29 A report assessing the outcomes of each clinic, in comparison to a carefully selected variety of national outcomes, is published annually.29 Clinics have both financial and professional incentives to maintain follow-up with patients and document adherence to guidelines.29 TIMED FOLLOW-UP AFTER NBS DIAGNOSIS. To limit parental anxiety, follow-up appointments are made in designated care centers as soon as possible after confirmation of diagnosis (even the following day). The availability of this early follow-up visit for discussion of diagnosis promotes positive feelings by parents and an increased confidence in their doctors.55,56 GENETIC COUNSELING. There are >1,900 identified CFTR gene mutations with variable phenotypes. Counseling is complicated, and specialized centers utilizing genetic counselors are more effective than reviewing test results in community settings.57,58 However, communication of results is difficult; only 57% of parents remember that their child is a carrier 4 months after they receive the information.58 Overall, neither carriers nor their families have long-term stigmatization from early diagnosis57,59; parents are overall glad to know their children are carriers.52 QI. Close attention to clinical outcomes and procedures
for annual evaluation and continuous QI has been incorporated into CF NBS by the CFF. Realizing that rapid Month 2014
implementation of screening in 50 states could not be achieved without some imperfections, the CFF focused on QI in 2010, with the following components: (1) accountability for nationwide QI by a National Facilitator; (2) a Quality Improvement Consortium with at least 1 representative from each state (usually a CF center director), a dedicated website, and an annual conference; and (3) a Screening Improvement Program with an annual commitment of $200,000 for 10 competitively funded grants responsive to a request for applications with designated priorities (http://www.cff.org/LivingWithCF/ QualityImprovement/). CFF PATIENT REGISTRY. The CFF patient registry began to monitor national mortality trends in 1966. In 1999, the registry stratified outcomes by individual care centers, identifying variation between clinics in practice patterns and outcomes.29 The combination of adherence to guidelines, high-quality data entry into the CF registry, patient participation, and CF NBS has improved CF outcomes.29
Financial Infrastructure Supporting CF NBS Follow-up The reduction in hospitalizations and increase in years of productive life have shown that CF NBS is cost-effective.60 However, the cost of newborn screening is not only incurred by the state laboratory or patient. In the case of CF NBS, the CFF exerts substantial financial influence on the national process of CF NBS. The net assets for CFF in 2012 were $439,720,900, with $13,074,126 in adult care grants for CF clinics (http:// www.cff.org/UploadedFiles/aboutCFFoundation/AnnualReport/CFF-2012-Financial-Statements.pdf ). Table 2 lists the benefits and harms identified by CF screening, and this is compared to what is known about NBS for other neuromuscular disorders.
Discussion The Secretary of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children uses the best available evidence to determine what diseases should be screened in newborns. The 3 key issues that must be addressed include: (1) screening— methods available using dried blood spots, their analytic and clinical validity, and the number of potential cases identified; (2) diagnosis—the strategy and rapidity of diagnosis for infants with positive screens and the likelihood of other diagnoses being made; and (3) treatment—clinical outcomes can be substantially improved by earlier treatments.61 DMD NBS advocates have begun to address the first 2 points for DMD NBS, with an 5
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TABLE 2. Benefits and Harms of CF NBS
Applicable to DMD, SMA, and AMD NBS? The benefits of CF NBS are demonstrated by: RCT data showing improved morbidity related to improved nutrition and growth and less pulmonary symptoms, leading to fewer hospitalizations and increased survival
DMD: no RCT data available
SMA: no RCT data available AMD: RCT data available Elimination of the diagnostic odyssey: delays in diagnosis, treatment, and family stress
Yes in DMD, SMA, and AMD
Informed decision making about future childbearing, and the ability to diagnose other family members
Yes in DMD, SMA, and AMD
Prompt enrollment in programs of systematic and consistent care whose results are monitored via enrollment in the CF registry
MDA has a network of clinic associations but no standards of care exist across clinics A pilot MDA registry has been implemented within some MDA clinics
These benefits outweigh the following potential harms: Altered parent–child relationships and bonding
Yes in DMD, SMA, and AMD
Psychological distress to families from the screening process: false-positive results and awaiting confirmatory testing results
Yes in DMD, SMA, and AMD
Adapted from Grosse et al.48 AMD 5 acid maltase deficiency; CF 5 cystic fibrosis; DMD 5 duchenne muscular dystrophy; MDA 5 muscular dystrophy association; NBS 5 newborn screening; RCT 5randomized controlled trial; SMA 5 spinal muscular atrophy.
understanding that as with CF, or any disease, early treatment will be beneficial.8,62 A large blinded randomized controlled trial in DMD, as done with the CF Wisconsin study, would take a great deal of time to establish trial evidence that NBS changes outcomes, thus it is important to note the history of CF and apply it to DMD. At its introduction, CF NBS was controversial; many argued that despite benefits to certain infants (ie, those with poor nutrition), it was premature to think that screening newborns would make a difference in a progressive and ultimately fatal disease.18 The Wisconsin RCT established that a combination of early diagnosis with a rigorous system of care improved outcomes while maximizing the benefits and minimizing potential harms, paying attention to the medical and psychosocial needs of both patients and their families.45 In the current CF system of care, interventions are used consistently across care centers, and clinical outcomes arise from a series of ongoing assessments with results recorded in a central patient registry and reported regularly to the public.29 Additionally, ongoing efforts have been invested to link pediatric and adult care clinics, providing a seamless transition from pediatricians to internists with multidisciplinary teams.38 This culture of standardized and 6
scrutinized medical care is challenging for other specialties to develop and maintain, but it is necessary for improving outcomes in rare disease screening programs. Extrapolating from CF NBS practices, NBS programs for DMD, SMA, and AMD will require statewide efforts to preidentify multidisciplinary care centers with committed neuromuscular leaders and nurse specialists, genetic counseling resources, and access to other specialty care such as pulmonology and cardiology. Although the foundation of such multidisciplinary clinics has already been established by the Muscular Dystrophy Association, centers selected to follow DMD, SMA, and AMD patients from infancy must agree to operate under established guidelines from infancy to adulthood, accept criteria accreditation standards, and participate in a patient registry program that monitors outcomes across centers with oversight from a central organization. Based on the CF model, it is likely that each disorder will have its own disease-specific central organizing group (analogous to the CFF) to oversee clinical operations and outcomes in a manner suitable for the respective disorders. These same disease-specific organizations would be responsible for managing funds allocated to the designated neuromuscular care centers. Volume 00, No. 00
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TABLE 3. Components Recommended for a Successful DMD Newborn Screening Program
A CK assay with high specificity and sensitivity that can be used at the state newborn screening laboratory, with criteria in place for state laboratory–based dystrophin mutation detection. Specialized care center follow-up within 4 weeks of confirmation of abnormal DMD screen. Standardized care center components: neuromuscular specialist, nurse practitioners, physical therapist, social worker, and genetic counselor. Documented consensus and evidence-based guidelines for patients from infancy to adulthood, including evaluation for early intervention components. A patient registry with documented outcome measures. Cardiology and pulmonology follow-up within local hospital systems. An overseeing organization with financial support for the care centers and for the patient registry. Care center adherence to guidelines with overseeing by a central organization. A plan for further diagnostic evaluation and management for children with elevated CK and negative dystrophin mutational testing. CK 5 creatine kinase; DMD 5 Duchenne muscular dystrophy.
Each of these neuromuscular disorders poses different challenges in NBS and follow-up. Table 3, using DMD as the example, summarizes the key elements that need to be in place for DMD NBS to be successful. In the case of DMD, the 2-tier methodology of screening has allowed for very specific diagnosis of DMD on a single dried blood spot. However, the dystrophin gene is the largest known human gene, and analysis of such a gene for all deletions/duplications and point mutations is complex, requiring sophisticated molecular technology. CF mutation analysis posed similar challenges for its molecular tier assay 20 years ago, but as technology has advanced, analysis has become routine in every state, and the focus today is on finding the best mutation analysis algorithm. A CK/CK/DNA algorithm, that is, restricting the DNA analyses to infants with persistent CK elevations, might be especially attractive as in CF NBS.63 Actionable screens (that is, those requiring referral for further care) could be limited to only those boys with DMD mutations. However, there will need to be additional discussion within the DMD community about those infants with elevated CK levels who cross a threshold felt to be more indicative of other dystrophic muscle disorders (identified in previous studies as males/females with CK > 2,000U/l).8 In this hypothetical situation, these infants can be classified as having screens concerning for “non-DMD muscle disease” and should be referred for repeat CK testing and follow-up neuromuscular evaluation with likely further directed genetic diagnostic screening for other disorders. In the case of SMA, there is a DNA-based assay for diagnosis from dried blood spots that can identify Month 2014
SMN1 deletions and SMN2 copy numbers, making it a highly specific and informative screening and diagnostic test for SMA and the likely clinical phenotype. In SMA, where there is currently no obvious treatment in infancy, there are still key management decisions to be made in infants with type 1 disease that can affect outcomes. These are among the issues that make SMA NBS appealing to parents22 and the medical community.12 In the case of AMD, the newborn screening assay and program in place in Taiwan have already shown benefits to those diagnosed with infantile AMD, and support the value of AMD NBS.6 However, as with SMA, AMD has later onset presentations where the disease course is not uniformly fatal or even progressively debilitating. Thus, a challenge of NBS programs for SMA and AMD will be in establishing counseling and clinical management guidelines for families of infants who present with later onset phenotypes. However, in many other respects, the elements needed for successful SMA and AMD NBS programs will be similar to those outlined for DMD (see Table 3). Conclusions Newborn screening for DMD, SMA, and AMD should be implemented to address the persistent disparities in diagnosis and care, and allow all patients to receive consistent and standards-based clinical care. Newborn screening would also identify those who could benefit from new genetic therapies, as in DMD and SMA, and those who should receive existing treatments such as corticosteroids for DMD and enzyme replacement for AMD. AMD NBS is awaiting approval, but for DMD and SMA, there are additional challenges to be addressed 7
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before they can be considered for the RUSP. In the case of SMA, advocates have noted a catch-22, where the promising treatments that would support NBS cannot be adequately studied without first identifying presymptomatic patients by NBS.64 Yet even without these treatments, the argument can be made that early effective management of respiratory and nutritional needs can make a difference in survival.33 There are no comparable data in infants with DMD, because this disorder is typically diagnosed later. However, an increasingly compelling argument for DMD NBS is the documented delay in diagnosis, which prevents the initiation of corticosteroids.17,28 Additionally, as research intensifies on mutation-specific molecular pharmaceuticals, a new era in DMD preventive care will emerge as was seen in CF, and upstream strategies will make early diagnosis imperative. The lessons learned from the past 20 years of CF NBS are applicable to DMD NBS and other neuromuscular disorders: standardized protocols for all patients identified by NBS, longitudinal follow-up in multidisciplinary clinics, and coordinated oversight of these clinics.
3.
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Kemper AR, Comeau AM, Green NS, et al. Evidence report: newborn screening for Pompe disease. 2013. http://www.hrsa.gov/ advisorycommittees/mchbadvisory/heritabledisorders/nominate condition/reviews/pompereport2013.pdf; accessed 9/1/2014.
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Prior TW. Spinal muscular atrophy: a time for screening. Curr Opin Pediatr 2010;22:696–702.
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Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A 2010;152A: 1608–1616.
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Ellis JA, Vroom E, Muntoni F. 195th ENMC International Workshop: Newborn screening for Duchenne muscular dystrophy 14– 16th December, 2012, Naarden, the Netherlands. Neuromuscul Disord 2013;23:682–689.
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Authorship M.A.S.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data, conceptualization of the study. P.M.F.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data. E.C.: revising the manuscript for content, including medical writing for content. R.C.G.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data, conceptualization of the study. J.M.K.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data, conceptualization of the study.
Potential Conflicts of Interest R.C.G.: grants, TaroPharma, MDA, Parent Project for Muscular Dystrophy, Italian Telethon; consultancy, PTC Therapeutics (Chair, DSMB), Novartis (DSMB), Marathon Pharmaceuticals, Taro Pharmaceuticals, Viromed.
References 1.
Wilson JM, Jungner YG. Principles and practice of mass screening for disease [in Spanish]. Bol Oficina Sanit Panam 1968;65:281– 393.
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Trotter TL, Fleischman AR, Howell RR, et al. Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children response to the President’s Council on Bioethics report: the changing moral focus of newborn screening. Genet Med 2011;13: 301–304.
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Moxley RT III, Pandya S, Ciafaloni E, et al. Change in natural history of Duchenne muscular dystrophy with long-term corticosteroid treatment: implications for management. J Child Neurol 2010;25:1116–1129. Gregg RG, Wilfond BS, Farrell PM, et al. Application of DNA analysis in a population-screening program for neonatal diagnosis of cystic fibrosis (CF): comparison of screening protocols. Am J Hum Genet 1993;52:616–626.
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Holtzer C, Meaney FJ, Andrews J, et al. Disparities in the diagnostic process of Duchenne and Becker muscular dystrophy. Genet Med 2011;13:942–947.
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Taussig LM, Boat TF, Dayton D, et al. Neonatal screening for cystic fibrosis: position paper. Pediatrics 1983;72:741–745.
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Fost N, Farrell PM. A prospective randomized trial of early diagnosis and treatment of cystic fibrosis: a unique ethical dilemma. Clin Res 1989;37:495–500.
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Farrell PM, Kosorok MR, Rock MJ, et al. Early diagnosis of cystic fibrosis through neonatal screening prevents severe malnutrition and improves long-term growth. Pediatrics 2001;107:1–13.
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Lai HJ, Shoff SM, Farrell PM; Wisconsin Cystic Fibrosis Neonatal Screening Group. Recovery of birth weight z score within 2 years of diagnosis is positively associated with pulmonary status at 6 years of age in children with cystic fibrosis. Pediatrics 2009;123: 714–722.
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Grosse SD, Boyle CA, Botkin JR, et al. Newborn screening for cystic fibrosis: evaluation of benefits and risks and recommendations for state newborn screening programs. MMWR Recomm Rep 2004;53(RR-13):1–36.
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Wagener JS, Zemanick ET, Sontag MK. Newborn screening for cystic fibrosis. Curr Opin Pediatr 2012;24:329–335.
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Southern KW, M erelle MME, Dankert-Roelse JE, Nagelkerke A. Newborn screening for cystic fibrosis. Cochrane Database Syst Rev 2009;(1):CD001402.
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Scully MA, Cwik VA, Marshall BC, et al. Can outcomes in Duchenne muscular dystrophy be improved by public reporting of data? Neurology 2013;80:583–589.
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Merlini L, Gennari M, Malaspina E, et al. Early corticosteroid treatment in 4 Duchenne muscular dystrophy patients: 14-year followup. Muscle Nerve 2012;45:796–802.
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Dijk FN, Fitzgerald DA. The impact of newborn screening and earlier intervention on the clinical course of cystic fibrosis. Paediatr Respir Rev 2012;13:220–225.
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Finkel RS, Flanigan KM, Wong B, et al. Phase 2a study of ataluren-mediated dystrophin production in patients with nonsense mutation Duchenne muscular dystrophy. PLoS One 2013;8: e81302.
Foundation CF, Borowitz D, Parad RB, et al. Cystic Fibrosis Foundation practice guidelines for the management of infants with cystic fibrosis transmembrane conductance regulator-related metabolic syndrome during the first two years of life and beyond. J Pediatr 2009;155:S106–S116.
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Earley MC, Laxova A, Farrell PM, et al. Implementation of the first worldwide quality assurance program for cystic fibrosis multiple mutation detection in population-based screening. Clin Chim Acta 2011;412:1376–1381.
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Yankaskas JR, Marshall BC, Sufian B, et al. Cystic fibrosis adult care: consensus conference report. Chest 2004;125:1S–39S.
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Farrell MH, Farrell PM. Newborn screening for cystic fibrosis: ensuring more good than harm. J Pediatr 2003;143:707–712.
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Kharrazi M, Kharrazi LD. Delayed diagnosis of cystic fibrosis and the family perspective. J Pediatr 2005;147:S21–S25.
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Sparbel KJH, Tluczek A. Patient and family issues regarding genetic testing for cystic fibrosis: a review of prenatal carrier testing and newborn screening. Annu Rev Nurs Res 2011;29:303–329.
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Zanetta C, Nizzardo M, Simone C, et al. Molecular therapeutic strategies for spinal muscular atrophies: current and future clinical trials. Clin Ther 2014;36:128–140.
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Huang NN, Schidlow DV, Szatrowski TH, et al. Clinical features, survival rate, and prognostic factors in young adults with cystic fibrosis. Am J Med 1987;82:871–879.
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Schechter MS. Benchmarking to improve the quality of cystic fibrosis care. Curr Opin Pulm Med 2012;18:596–601.
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Tuchman L, Schwartz M. Health outcomes associated with transition from pediatric to adult cystic fibrosis care. Pediatrics 2013; 132:847–853.
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Lai HC. Delayed diagnosis of US females with cystic fibrosis. Am J Epidemiol 2002;156:165–173.
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Sanders DB, Li Z, Laxova A, et al. Risk factors for the progression of cystic fibrosis lung disease throughout childhood. Ann Am Thorac Soc 2014;11:63–72.
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Watson MS. Current status of newborn screening: decisionmaking about the conditions to include in screening programs. Ment Retard Dev Disabil Res Rev 2006;12:230–235.
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Hammond KB, Abman SH, Sokol RJ, Accurso FJ. Efficacy of statewide neonatal screening for cystic fibrosis by assay of trypsinogen concentrations. N Engl J Med 1991;325:769–774.
Sontag MK, Wright D, Beebe J, et al. A new cystic fibrosis newborn screening algorithm: IRT/IRT1"/DNA. J Pediatr 2009;155:618–622.
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Swoboda KJ. Seize the day: newborn screening for SMA. Am J Med Genet A 2010;152A:1605–1607.
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Cystic Fibrosis Newborn Screening: A Model for Neuromuscular Disease Screening? Michele A. Scully, MD,1 Philip M. Farrell, MD, PhD,2 Emma Ciafaloni, MD,1 Robert C. Griggs, MD,1 and Jennifer M. Kwon, MD, MPH1 Congenital neuromuscular disorders, such as Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease (acid maltase deficiency [AMD]), are candidates for universal newborn screening (NBS). In this article, we discuss the future path of NBS for these disorders with particular emphasis on DMD NBS, because of the likely approval of new gene-modifying treatments, the possible benefits of earlier treatment with corticosteroids, and the recently demonstrated feasibility of a 2-tiered approach to NBS with screening by creatine kinase (CK) levels in dried blood spots followed by mutation detection in those with elevated CK. The cystic fibrosis (CF) NBS program is a successful model for NBS. CF outcomes have consistently improved into adulthood following introduction of CF NBS because considerable resources have been devoted to practices that include: attention to improving laboratory screening, consistent confirmatory testing and immediate referral of all newly diagnosed infants to designated CF care centers that follow established practice guidelines, and ongoing evaluation of CF care centers via a centralized clinical database. Like CF, DMD, SMA, and infantile AMD are inexorably debilitating and require lifetime multidisciplinary clinical management. NBS would address the delays in diagnosis that prevent patients from receiving timely treatments. Standardized care following early diagnosis would reduce disparities in clinical care and outcomes. NBS in these neuromuscular disorders should be implemented, utilizing lessons learned from the past 20 years of CF NBS: standardized protocols for all patients identified by DMD NBS, longitudinal follow-up in multidisciplinary clinics, and coordinated oversight of these clinics. ANN NEUROL 2014;00:000–000
N
ewborn screening (NBS) detects diseases in infants where early treatment prevents devastating outcomes. There are currently 31 diseases recommended for screening by the federal Recommended Uniform Screening Panel (RUSP) (http://www.hrsa.gov/advisorycommittees/ mchbadvisory/heritabledisorders/recommendedpanel/uniformscreeningpanel.pdf ). The criteria used to determine which disorders are most suitable for screening are based on Wilson and Jungner’s criteria for population screening.1 In practice, however, there has been an understanding that for rare inherited disorders the evidence for treatments may be limited (eg, a lack of controlled clinical trials) and, in many cases, expert judgment has to suffice.2 An effective newborn screening program should include clear guidelines for confirmatory diagnostic studies, follow-up, and treatment protocols.2 Screening programs initiated without such guidelines may not improve outcomes.3,4
Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and Pompe disease or acid maltase deficiency (AMD) have been proposed as candidates for NBS because early diagnoses have the potential to improve clinical management and outcomes. Table 1 compares the clinical characteristics and existing treatments for these disorders. Most patients with SMA present during infancy, but those with the more severe type 1 disease do not survive past early childhood, whereas those with type 2 disease (who can achieve sitting) may live into their second or third decade. In the case of SMA, there are currently only experimental treatment trials in place. Compared to SMA, AMD has even greater clinical variability, with the majority of cases identified as late onset disease as opposed to infantile onset. AMD NBS has been in place in Taiwan since 2005, and the greatest benefit has been demonstrated in infantile AMD
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.24316 Received Jun 16, 2014, and in revised form Oct 10, 2014. Accepted for publication Nov 17, 2014. From the 1Department of Neurology, University of Rochester Medical Center, Rochester, NY; and 2Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI
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TABLE 1. Comparison of DMD, SMA, and AMD as Candidates for Newborn Screening
DMD
SMA
AMD
1/5,000 male births
1/10,000 births
1/40,000 births (all types)
Clinical course
Presents in early childhood with delayed motor milestones. Course is progressive due to ongoing muscle injury and fibrosis, with loss of ambulation by 12 years of age.
Variable age of presentation from infancy to adulthood, with progressive weakness and muscle atrophy from loss of anterior horn cells.
30% are infantile onset (incidence of 1/133,000) and present with profound and progressive hypotonia and cardiomyopathy. Later onset forms present heterogeneously with variability in weakness, cardiac involvement, and age of onset (most late onset disease presents in adulthood).
Life expectancy, approximate median age at death
20s–30s.
Patients with SMA1 presenting in first 6 months of life have a life expectancy of 2–3 years without aggressive interventions (G-tube, chronic ventilation). Those with SMA presenting later in childhood generally survive longer with supportive interventions.
In infantile disease with cardiomyopathy (classic form), death in the first 2 years of life. Other forms have more variability in survival.
Existing treatments, in addition to supportive care
Corticosteroids improve strength and duration of mobility.
—
Enzyme replacement therapy.
Issues with treatment
Sides effect of chronic corticosteroid use, obesity, poor linear growth.
N/A.
Treatment very expensive; limited guidelines on who to treat and for how long.
Proposed novel genetic treatments
Yes.
Yes.
—
Incidence
AMD 5 acid maltase deficiency; DMD 5 duchenne muscular dystrophy; N/A 5 not applicable; SMA 5 spinal muscular atrophy.
patients, where presymptomatic treatment with enzyme replacement therapy (ERT) decreased mortality and morbidity (survival and ventilator-free survival) when compared to historical and contemporaneous controls.5,6 One barrier to widespread acceptance of AMD NBS has been the concern over the high cost of ERT, which must be given for the lifetime of the patient. There are also questions about when to initiate treatment in those with late onset AMD.7 Of the 3 disorders, DMD is most consistent in age of onset and has the most predictable rate of progression. DMD is an X-linked disorder affecting 1 in 5,000 males.8 Although no cure exists for the progressive muscle weakness of DMD, corticosteroid treatment improves muscle strength and function, and in combination with supportive medical care is associated with markedly improved survival.9–11 2
For all of these disorders, NBS can only be justified if it can be shown to improve patient outcomes. In SMA and AMD, early identification has been shown to improve clinical outcomes in infants,5,6,12,13 providing compelling arguments for adding these disorders to the RUSP. However, for DMD, the justification for NBS has proven more challenging. Past DMD NBS programs have not been able to show that early identification modifies outcomes in infants or older children, and these programs have been criticized for the lack of meaningful and evidence-based treatments for infants and toddlers.14–16 Despite these concerns, recent developments in DMD diagnosis and genetic treatments, in combination with the well-documented delays in initiation of corticosteroids after muscle fibrosis has occurred, have made DMD a compelling candidate for approval by the RUSP.8,17 Volume 00, No. 00
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An example of a successful NBS program is cystic fibrosis (CF) NBS, which faced challenges similar to those of DMD at its start. Two decades ago, when it was proposed for universal NBS, many argued that timely diagnosis rather than NBS was needed to improve CF outcomes.18,19 CF NBS is a useful screening prototype, and the approach used is applicable to other progressively disabling and ultimately fatal disorders such as those discussed above. In this article, we focus on the elements needed to ensure that NBS of neuromuscular disorders is successful, based on the components of CF NBS. We discuss in particular detail the history of DMD NBS programs, because, unlike SMA and AMD, DMD does not have an infantile presentation, so the benefit of NBS is more difficult to demonstrate.
Results History of DMD NBS There have been >1 million newborns screened for DMD, in 10 countries, since the first systemic DMD screening program in New Zealand in 1976.8,14 The largest program (in Wales) screened 335,045 newborns, identifying 63 DMD patients.20 All of these programs utilized creatine kinase (CK) on dried blood spots as an initial screen, with follow-up confirmatory testing (muscle biopsy or more recently genetic testing) performed at subsequent visits.14,20 The rationale for many of these programs was to provide an early diagnosis so families can better cope with decision making and future family planning, while accurately identifying patients to be followed according to local practices. In most programs, parents “opt-in” to the screening process, with parental reactions to screening assessed by researchers through questionnaires. Critics of DMD screening suggest that early diagnosis of DMD creates greater psychological burdens on family, including adverse effects on bonding and inability to enjoy the initial years of good strength.16,21 However, studies have shown that parents of DMD boys notice, and are anxious about, early motor and cognitive delays and question their own abilities as parents until the DMD diagnosis is made.14,17,20 Recent work demonstrates that expectant parents are much more accepting of newborn screening for DMD and SMA, even without clear evidence of effective interventions in infancy.22 Overall, the early screening programs demonstrated the feasibility of CK testing in newborns, but were not able to show evidence of clear improvement in patient clinical outcomes.15 Issues that challenged these programs included: the fluctuation of CK levels immediately following delivery, the difficulty in setting an arbitrary CK cutoff with good sensitivity and specificity, issues with Month 2014
confirmatory testing, and the anguish of families told that their well-appearing newborn has an untreatable diagnosis.23 Work over the past decade addresses these issues, and patients now live into their third to fourth decade with corticosteroid treatment and multidisciplinary care.24 Recent advances toward DMD NBS include the following. AN IMPROVED DMD SCREENING TEST. A 2-tier dried blood spot test, CK/DNA screening, has been recently tested successfully in 37,649 study participants.8 This strategy is identical in concept to the method applied successfully to CF, that is, use of an initial biomarker followed by a more specific molecular assay.25 In DMD, a fluorometric assay is used to detect elevated CK activity followed, on the same blood spot, by whole genome amplification of the DMD gene.8 Using this methodology, 5 of 37,649 participants had identified DMD mutations, all with CK > 2,000ng/ml (normal < 200ng/ml). Seven patients had CK > 2,000ng/ml without DMD mutation, and upon further genetic testing, 2 were positive for limb girdle muscular dystrophy. The cost of adding this assay to current newborn screening techniques is “approximately $1.00” per newborn, for reagents.8 Confirmatory DNA analysis, for those above the CK cutoff value, is financially feasible and similar to CF NBS cost.26 UPDATED INFORMATION ABOUT THE NATURAL HISTORY OF DMD IN INFANTS. DMD boys as young
as 1 year develop neurocognitive delays, scoring lower in motor, speech, and language function on the Bayley III Motor Assessment compared to age-matched controls. As boys become weaker, this leads to social exclusion.27 Despite awareness that DMD can present in infancy with such delays, there remains a delay of about 2.5 years between symptom onset and diagnosis, which further delays corticosteroid treatment.17,28 TREATMENT WITH CORTICOSTEROIDS. Corticoste-
roids are proven to improve strength in DMD patients.9,10 However, treatment is usually initiated at age 4 to 5 years when diagnosis is first made, after muscle fibrosis has started.17,29 Earlier treatment with corticosteroids, as early as 2 to 4 years, improves motor function in DMD patients and is associated with good long-term outcomes after 14 years of treatment.30 NEW THERAPIES FOR BOYS WITH DMD. A molecular therapy (eteplirsen), a drug that promotes exon skipping to restore the dystrophin reading frame, has shown effectiveness in clinical trials.27 Such therapies are likely to be most effective in boys diagnosed before fibrosis
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replaces muscle fibers, making DMD NBS essential to identify those patients. Polymerase chain reaction can detect 98% of exon deletions, or approximately 65% of DMD patients.31 Treatments focusing on stop codon mutations (ataluren) represent another 20% of DMD cases, and clinical trials focusing on these mutations are in progress.32 SMA and AMD NBS SMA NBS has been proposed as a means of improving the survival in infants born with the more severe form, type 1 SMA. These children have early respiratory and nutritional needs; addressing them in a timely manner can improve survival.33 Unfortunately, many children with SMA experience worsening weakness before accurate diagnosis. Furthermore, trials of treatments in presymptomatic infants cannot be conducted without early screening, further delaying hope of effective treatments. There are promising trials that may expedite approval for SMA NBS.34 In the case of AMD, there is already evidence that early treatment of presymptomatic infants with AMD can improve survival6 (http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/nominatecondition/ reviews/pompereport2013.pdf). These data were compelling enough for the Discretionary Secretary’s Advisory Committee to recommend to the Secretary of Health and Human Services that AMD be included in the RUSP in 2013 (http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendations/correspondence/ uniformpanel060313.pdf ), and final approval awaits the Secretary’s decision. History of CF NBS CF has a similar prevalence to DMD, approximately 1 in 3,500 live births.35 CF is an autosomal recessive condition caused by mutations in the CF transmembrane conductance regulator (CFTR), which alters the CFTR chloride channel protein effecting respiratory, gastrointestinal, and certain epithelial systems such as sweat glands.35 The median age of survival for CF children in 1959 was 6 months, with death from pulmonary complications. By 1986, the natural history of the disease had changed to a median survival of 27 years, and it was recognized that early diagnosis and thus earlier and consistent medical management accounted in large measure for this increased survival.36 The current median survival is 38.3 years, reflecting earlier diagnosis through NBS with organized follow-up in pediatric and associated adult care centers, the addition of new therapies applied with quality improvement (QI) methods, and use of a patient registry.29,37,38 Additionally, NBS and consistent 4
therapies have eliminated disparities in diagnosis, including a previous gender gap, that is, longer delays in the diagnosis of females.39,40 Only recently has molecular therapy become a reality, affecting approximately 2 to 5% of patients.41 The history of feasible CF NBS dates back to 1979, when the first assay to screen for elevated immunoreactive trypsinogen (IRT) was developed on newborn dried blood spots.42 This methodology spurred a paradigm shift in CF care from reliance on symptom-based interventions to treatment of presymptomatic infants, leading to delayed morbidity. A statewide CF NBS pilot using dried blood spots was initiated in Colorado in 1982, under a grant from the Bureau of Maternal and Child Health.43 The results prompted a publication indicating the need for a large, prospective randomized controlled trial (RCT) to assess the benefits, risks, and costs of CF neonatal screening and the epidemiology of the disease.44,45 The trial, initiated in Wisconsin (Wisconsin Cystic Fibrosis Neonatal Screening Project) through support from the Cystic Fibrosis Foundation (CFF) and National Institutes of Health, screened all infants born in Wisconsin between April 15, 1985 and June 30, 1994; one-half of screened infants had results reported to family and primary care physician, and the other half (the control group) were followed with results of the screening undisclosed until unblinding or 4 years of age, unless the infant’s parents or primary care physician requested the screening data, avoiding selection bias.45 Primary outcomes were quantitative and focused on nutritional status and bronchopulmonary disease.46 The study demonstrated the benefit of CF NBS; height/weight differences in screened patients versus unscreened persisted for >16 years,46 and better nutrition was associated with less lung disease.47 The Centers for Disease Control and Prevention (CDC) reviewed the results of the Wisconsin study in 1997 and initiated NBS preimplementation planning. By 2002, a joint CDC/CFF conference recommended staterun CF NBS programs based on long-term benefits from early nutritional treatment and manageable risks.48 To expedite CF NBS in the USA, the CFF appointed a national facilitator (principal investigator of the Wisconsin RCT) to work with all states in their 1- to 3-year planning phases. During the next 5 years, taking advantage of the existing CF center network, all states implemented CF NBS, leading to a new era of routine, early diagnosis and preventive therapies.49 There is now worldwide support for CF NBS, because psychological benefits and survival data far outweigh any potential harm.50 With CF NBS in place, current research has shifted from identifying early benefits to: identifying the Volume 00, No. 00
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cumulative benefit of what is done early in life to influence critical outcomes in adulthood,51 facilitation of clinical trials, best care practices,52 addressing imperfections in state screening systems through a CDC-implemented quality assurance program for both the IRT and DNA components of CF NBS,26 and organization of a national QI program through the CFF to identify the best screening methodology, as methods continue to vary widely.53 The current CF NBS program includes the following components. FOLLOW-UP IN SPECIALIZED CARE CENTERS. There
are 113 care centers across the country, along with some 58 smaller, affiliated satellite clinics.29 The overall number of clinics is limited to ensure an adequate number of patients are followed by each center, maintaining expertise and high standards across all centers (http://www.cff. org/). Recognizing that more than half of US CF patients are >18 years of age, the CFF expects that ultimately each center will establish an adult care program.54 A 5-year accreditation process ensures both pediatric and adult clinics have a multidisciplinary team, participate in the patient registry, and adhere to strict documented evidence and consensus-based guidelines, which have evolved by benchmarking top clinics.29 A report assessing the outcomes of each clinic, in comparison to a carefully selected variety of national outcomes, is published annually.29 Clinics have both financial and professional incentives to maintain follow-up with patients and document adherence to guidelines.29 TIMED FOLLOW-UP AFTER NBS DIAGNOSIS. To limit parental anxiety, follow-up appointments are made in designated care centers as soon as possible after confirmation of diagnosis (even the following day). The availability of this early follow-up visit for discussion of diagnosis promotes positive feelings by parents and an increased confidence in their doctors.55,56 GENETIC COUNSELING. There are >1,900 identified CFTR gene mutations with variable phenotypes. Counseling is complicated, and specialized centers utilizing genetic counselors are more effective than reviewing test results in community settings.57,58 However, communication of results is difficult; only 57% of parents remember that their child is a carrier 4 months after they receive the information.58 Overall, neither carriers nor their families have long-term stigmatization from early diagnosis57,59; parents are overall glad to know their children are carriers.52 QI. Close attention to clinical outcomes and procedures
for annual evaluation and continuous QI has been incorporated into CF NBS by the CFF. Realizing that rapid Month 2014
implementation of screening in 50 states could not be achieved without some imperfections, the CFF focused on QI in 2010, with the following components: (1) accountability for nationwide QI by a National Facilitator; (2) a Quality Improvement Consortium with at least 1 representative from each state (usually a CF center director), a dedicated website, and an annual conference; and (3) a Screening Improvement Program with an annual commitment of $200,000 for 10 competitively funded grants responsive to a request for applications with designated priorities (http://www.cff.org/LivingWithCF/ QualityImprovement/). CFF PATIENT REGISTRY. The CFF patient registry began to monitor national mortality trends in 1966. In 1999, the registry stratified outcomes by individual care centers, identifying variation between clinics in practice patterns and outcomes.29 The combination of adherence to guidelines, high-quality data entry into the CF registry, patient participation, and CF NBS has improved CF outcomes.29
Financial Infrastructure Supporting CF NBS Follow-up The reduction in hospitalizations and increase in years of productive life have shown that CF NBS is cost-effective.60 However, the cost of newborn screening is not only incurred by the state laboratory or patient. In the case of CF NBS, the CFF exerts substantial financial influence on the national process of CF NBS. The net assets for CFF in 2012 were $439,720,900, with $13,074,126 in adult care grants for CF clinics (http:// www.cff.org/UploadedFiles/aboutCFFoundation/AnnualReport/CFF-2012-Financial-Statements.pdf ). Table 2 lists the benefits and harms identified by CF screening, and this is compared to what is known about NBS for other neuromuscular disorders.
Discussion The Secretary of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children uses the best available evidence to determine what diseases should be screened in newborns. The 3 key issues that must be addressed include: (1) screening— methods available using dried blood spots, their analytic and clinical validity, and the number of potential cases identified; (2) diagnosis—the strategy and rapidity of diagnosis for infants with positive screens and the likelihood of other diagnoses being made; and (3) treatment—clinical outcomes can be substantially improved by earlier treatments.61 DMD NBS advocates have begun to address the first 2 points for DMD NBS, with an 5
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TABLE 2. Benefits and Harms of CF NBS
Applicable to DMD, SMA, and AMD NBS? The benefits of CF NBS are demonstrated by: RCT data showing improved morbidity related to improved nutrition and growth and less pulmonary symptoms, leading to fewer hospitalizations and increased survival
DMD: no RCT data available
SMA: no RCT data available AMD: RCT data available Elimination of the diagnostic odyssey: delays in diagnosis, treatment, and family stress
Yes in DMD, SMA, and AMD
Informed decision making about future childbearing, and the ability to diagnose other family members
Yes in DMD, SMA, and AMD
Prompt enrollment in programs of systematic and consistent care whose results are monitored via enrollment in the CF registry
MDA has a network of clinic associations but no standards of care exist across clinics A pilot MDA registry has been implemented within some MDA clinics
These benefits outweigh the following potential harms: Altered parent–child relationships and bonding
Yes in DMD, SMA, and AMD
Psychological distress to families from the screening process: false-positive results and awaiting confirmatory testing results
Yes in DMD, SMA, and AMD
Adapted from Grosse et al.48 AMD 5 acid maltase deficiency; CF 5 cystic fibrosis; DMD 5 duchenne muscular dystrophy; MDA 5 muscular dystrophy association; NBS 5 newborn screening; RCT 5randomized controlled trial; SMA 5 spinal muscular atrophy.
understanding that as with CF, or any disease, early treatment will be beneficial.8,62 A large blinded randomized controlled trial in DMD, as done with the CF Wisconsin study, would take a great deal of time to establish trial evidence that NBS changes outcomes, thus it is important to note the history of CF and apply it to DMD. At its introduction, CF NBS was controversial; many argued that despite benefits to certain infants (ie, those with poor nutrition), it was premature to think that screening newborns would make a difference in a progressive and ultimately fatal disease.18 The Wisconsin RCT established that a combination of early diagnosis with a rigorous system of care improved outcomes while maximizing the benefits and minimizing potential harms, paying attention to the medical and psychosocial needs of both patients and their families.45 In the current CF system of care, interventions are used consistently across care centers, and clinical outcomes arise from a series of ongoing assessments with results recorded in a central patient registry and reported regularly to the public.29 Additionally, ongoing efforts have been invested to link pediatric and adult care clinics, providing a seamless transition from pediatricians to internists with multidisciplinary teams.38 This culture of standardized and 6
scrutinized medical care is challenging for other specialties to develop and maintain, but it is necessary for improving outcomes in rare disease screening programs. Extrapolating from CF NBS practices, NBS programs for DMD, SMA, and AMD will require statewide efforts to preidentify multidisciplinary care centers with committed neuromuscular leaders and nurse specialists, genetic counseling resources, and access to other specialty care such as pulmonology and cardiology. Although the foundation of such multidisciplinary clinics has already been established by the Muscular Dystrophy Association, centers selected to follow DMD, SMA, and AMD patients from infancy must agree to operate under established guidelines from infancy to adulthood, accept criteria accreditation standards, and participate in a patient registry program that monitors outcomes across centers with oversight from a central organization. Based on the CF model, it is likely that each disorder will have its own disease-specific central organizing group (analogous to the CFF) to oversee clinical operations and outcomes in a manner suitable for the respective disorders. These same disease-specific organizations would be responsible for managing funds allocated to the designated neuromuscular care centers. Volume 00, No. 00
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TABLE 3. Components Recommended for a Successful DMD Newborn Screening Program
A CK assay with high specificity and sensitivity that can be used at the state newborn screening laboratory, with criteria in place for state laboratory–based dystrophin mutation detection. Specialized care center follow-up within 4 weeks of confirmation of abnormal DMD screen. Standardized care center components: neuromuscular specialist, nurse practitioners, physical therapist, social worker, and genetic counselor. Documented consensus and evidence-based guidelines for patients from infancy to adulthood, including evaluation for early intervention components. A patient registry with documented outcome measures. Cardiology and pulmonology follow-up within local hospital systems. An overseeing organization with financial support for the care centers and for the patient registry. Care center adherence to guidelines with overseeing by a central organization. A plan for further diagnostic evaluation and management for children with elevated CK and negative dystrophin mutational testing. CK 5 creatine kinase; DMD 5 Duchenne muscular dystrophy.
Each of these neuromuscular disorders poses different challenges in NBS and follow-up. Table 3, using DMD as the example, summarizes the key elements that need to be in place for DMD NBS to be successful. In the case of DMD, the 2-tier methodology of screening has allowed for very specific diagnosis of DMD on a single dried blood spot. However, the dystrophin gene is the largest known human gene, and analysis of such a gene for all deletions/duplications and point mutations is complex, requiring sophisticated molecular technology. CF mutation analysis posed similar challenges for its molecular tier assay 20 years ago, but as technology has advanced, analysis has become routine in every state, and the focus today is on finding the best mutation analysis algorithm. A CK/CK/DNA algorithm, that is, restricting the DNA analyses to infants with persistent CK elevations, might be especially attractive as in CF NBS.63 Actionable screens (that is, those requiring referral for further care) could be limited to only those boys with DMD mutations. However, there will need to be additional discussion within the DMD community about those infants with elevated CK levels who cross a threshold felt to be more indicative of other dystrophic muscle disorders (identified in previous studies as males/females with CK > 2,000U/l).8 In this hypothetical situation, these infants can be classified as having screens concerning for “non-DMD muscle disease” and should be referred for repeat CK testing and follow-up neuromuscular evaluation with likely further directed genetic diagnostic screening for other disorders. In the case of SMA, there is a DNA-based assay for diagnosis from dried blood spots that can identify Month 2014
SMN1 deletions and SMN2 copy numbers, making it a highly specific and informative screening and diagnostic test for SMA and the likely clinical phenotype. In SMA, where there is currently no obvious treatment in infancy, there are still key management decisions to be made in infants with type 1 disease that can affect outcomes. These are among the issues that make SMA NBS appealing to parents22 and the medical community.12 In the case of AMD, the newborn screening assay and program in place in Taiwan have already shown benefits to those diagnosed with infantile AMD, and support the value of AMD NBS.6 However, as with SMA, AMD has later onset presentations where the disease course is not uniformly fatal or even progressively debilitating. Thus, a challenge of NBS programs for SMA and AMD will be in establishing counseling and clinical management guidelines for families of infants who present with later onset phenotypes. However, in many other respects, the elements needed for successful SMA and AMD NBS programs will be similar to those outlined for DMD (see Table 3). Conclusions Newborn screening for DMD, SMA, and AMD should be implemented to address the persistent disparities in diagnosis and care, and allow all patients to receive consistent and standards-based clinical care. Newborn screening would also identify those who could benefit from new genetic therapies, as in DMD and SMA, and those who should receive existing treatments such as corticosteroids for DMD and enzyme replacement for AMD. AMD NBS is awaiting approval, but for DMD and SMA, there are additional challenges to be addressed 7
ANNALS
of Neurology
before they can be considered for the RUSP. In the case of SMA, advocates have noted a catch-22, where the promising treatments that would support NBS cannot be adequately studied without first identifying presymptomatic patients by NBS.64 Yet even without these treatments, the argument can be made that early effective management of respiratory and nutritional needs can make a difference in survival.33 There are no comparable data in infants with DMD, because this disorder is typically diagnosed later. However, an increasingly compelling argument for DMD NBS is the documented delay in diagnosis, which prevents the initiation of corticosteroids.17,28 Additionally, as research intensifies on mutation-specific molecular pharmaceuticals, a new era in DMD preventive care will emerge as was seen in CF, and upstream strategies will make early diagnosis imperative. The lessons learned from the past 20 years of CF NBS are applicable to DMD NBS and other neuromuscular disorders: standardized protocols for all patients identified by NBS, longitudinal follow-up in multidisciplinary clinics, and coordinated oversight of these clinics.
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Authorship M.A.S.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data, conceptualization of the study. P.M.F.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data. E.C.: revising the manuscript for content, including medical writing for content. R.C.G.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data, conceptualization of the study. J.M.K.: drafting/revising the manuscript for content, including medical writing for content, acquisition of data, conceptualization of the study.
Potential Conflicts of Interest R.C.G.: grants, TaroPharma, MDA, Parent Project for Muscular Dystrophy, Italian Telethon; consultancy, PTC Therapeutics (Chair, DSMB), Novartis (DSMB), Marathon Pharmaceuticals, Taro Pharmaceuticals, Viromed.
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