- Email: [email protected]
Newborn Screening for Spinal Muscular Atrophy and Lysosomal Storage Disorders Takes Advantage of Novel Therapies
Volume 190
References 1. Rysavy MA, Li L, Bell EF, Das A, Hintz SR, Stoll BJ, et al. Betweenhospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 2015;372:1801-11. 2. Inoue H, Ochiai M, Yasuoka K, Tanaka K, Kurata H, Fujiyoshi J, et al. Early mortality and morbidity in infants with birth weight ≤500g in Japan. J Pediatr 2017;190:112-7. 3. Schmidt B, Roberts RS, Davis PG, Doyle LW, Asztalos EV, Opie G, et al. Prediction of late death or disability at age 5 years using a count of 3 neonatal morbidities in very low birth weight infants. J Pediatr 2015;167:9826.e2. 4. Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19. 5. Doyle LW, Cheong JL, Burnett A, Roberts G, Lee KJ, Anderson PJ. Biological and social influences on outcomes of extreme-preterm/lowbirth weight adolescents. Pediatrics 2015;136:e1513-20.
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November 2017
6. James J, Munson D, DeMauro SB, Langer JC, Dworetz AR, Natarajan G. Outcomes of preterm infants following discussions about withdrawal or withholding of life support. J Pediatr 2017;190:11823. 7. Dupont-Thibodeau A, Barrington KJ, Farlow B, Janvier A. End-of-life decisions for extremely low-gestational-age infants: why simple rules for complicated decisions should be avoided. Semin Perinatol 2014;38:317. 8. Janvier A, Lorenz JM, Lantos JD. Antenatal counselling for parents facing an extremely preterm birth: limitations of the medical evidence. Acta Paediatr 2012;101:800-4. 9. Boss RD, Hutton N, Sulpar LJ, West AM, Donohue PK. Values parents apply to decision-making regarding delivery room resuscitation for high-risk newborns. Pediatrics 2008;122:5839. 10. Grobman WA, Kavanaugh K, Moro T, DeRegnier RA, Savage T. Providing advice to parents for women at acutely high risk of periviable delivery. Obstet Gynecol 2010;115:904-9.
Newborn Screening for Spinal Muscular Atrophy and Lysosomal Storage Disorders Takes Advantage of Novel Therapies
I
tional SMN2, was approved by FDA after phase 3 trials showed n 2 reports in this volume of The Journal, the progress, and significant clinical motor neuron improvements (eg, imcomplexity, of newborn screening (NBS) is on full view. proved head control, sitting, standing, respiratory health). One report, from Chien et al,1 describes the successful pilot Because the pathology of SMA causes motor of NBS for spinal muscular atrophy (SMA) See related articles, neuron death, early recognition and treatcoming just in time to take advantage of a pgs 130 and 124 ment is essential to spare neurons and lessen novel intrathecal gene therapy for SMA, neurodegeneration. The current SMA NBS pilot study proves nusinersen (SPINRAZA; Biogen, Research Triangle Park, North that this is possible. Carolina), recently approved by the Food and Drug AdminChien et al1 adapted reverse transcription polymerase chain istration (FDA). A second paper on NBS, from Burton et al,2 offers results of the first 15 months of NBS for 5 lysosomal reaction genetic sequencing of SMN1 from dried blood spots storage disorders (LSDs). Both reports demonstrate remarkand confirmed mutations by multiplex-ligation probe ampliable progress in detecting severe degenerative infantile and jufication on 120 267 newborns referred between November 2014 venile disorders that previously were diagnosed principally on and September 2016 to the National Taiwan University Hosclinical disease symptoms after disease onset. New methods were pital Newborn Screening Center. Rapid turnaround of results necessary for the elucidation of these disorders: for SMA, screen(3 days for 98% of samples), low cost per sample, and low rates ing relying on a DNA-based NBS method, and in LSD screenof unsatisfactory samples with positive predictive value of 100% ing, necessitating the development of a rapid and reliable made this method feasible for population screening. Seven pamultienzyme assay. tients were detected (screening program incidence 1:17 181 live For patients with SMA, until recently no effective therapy births), of whom 3 were symptomatic during the follow-up has been available, lessening the urgency of early diagnosis. period. Symptoms of type 1 SMA typically begin during the first few Burton et al2 report on the initial 15 months of NBS for 5 LSDs (Pompe, Fabry, Gaucher, mucopolysaccharidosis I [MPSmonths after birth, and patients progress to respiratory failure I], and Niemann-Pick diseases) in Illinois. Each condition has and death by age 2 years. an FDA-approved enzyme-replacement therapy (ERT), and 2 Patients with SMA have deletions or mutations in both copies (Fabry, Gaucher) have oral small molecule therapies. The conof the SMN1 gene and a decreased number of functional copies ditions are heterogeneous clinically but can be detected by a of SMN2.3 Although still not understood fully, greater numbers of SMN2 correlate with a milder phenotype. In December 2016, multiplex enzyme assay in dried blood spots. Some patients a novel intrathecal drug, nusinersen, which up-regulates funcmay be symptomatic in the early months of life (eg, infantile Pompe), and ERT is lifesaving. Others may present in early years (eg, MPS I), whereas others may present later in life (eg, Fabry, ERT Enzyme-replacement therapy Gaucher). Presentation of Gaucher disease also may occur in FDA Food and Drug Administration early months in severe cases and in the juvenile years or adultLSD Lysosomal storage disorder MPS-I Mucopolysaccharidosis I hood for some patients with Pompe disease. In addition, infants NBS Newborn screening with MPS I typically develop progressive neurologic regresSMA Spinal muscular atrophy sion for which hematopoietic stem cell transplantation is 9
THE JOURNAL OF PEDIATRICS • www.jpeds.com effective only before significant neurodegeneration has occurred. A reliable NBS test offers a diagnosis that allows therapy to be instituted before the occurrence of irrevocable pathology. Prediction of prognosis and age of onset from enzyme or molecular data is difficult in many cases, necessitating ongoing monitoring by specialists. In 219 793 infants screened in Illinois for LSDs since November 2014, Burton et al identified 28 affected individuals with one of the LSDs. Molecular confirmation was complicated in some cases by variants of unknown significance in the affected gene. The authors conclude that the benefits of early diagnosis led to early treatment options in 3 of 28 cases: 1 patient with severe MPS I who had hematopoietic stem cell transplantation/ERT and 2 patients with infantile-onset Pompe disease who received ERT. The other 25 cases were asymptomatic and continue to be followed for early signs of disease before initiating therapy. A large number of pseudodeficiency cases were identified for Pompe (15), MPS I (30), and Fabry (16) disease. The Fabry cases were all carriers of p.A143T variant, for which clinical significance currently is unclear. The authors thoughtfully discuss the benefits of this NBS protocol and the potential for psychological damage. In addition, in cases of unknown penetrance and prognosis, the appropriateness of testing other at-risk family members is called into question. The difficulty and cost (financially and otherwise) of following asymptomatic patients over many years is difficult for all concerned. NBS relies on the logic that metabolic or molecular aberrations relative to normal can diagnose accurately affected individuals before symptoms appear. This logic does not apply equally to all diseases, as both NBS studies makes clear. Patients appear to fall along a spectrum of affectedness that
Volume 190 cannot clearly be understood solely by enzyme levels and DNAbased studies. Advances that better allow prediction of likely symptomatic cases will enhance the NBS for these complex diseases and others. Until then, voices continue to call out for additional disease screening in the unaffected newborn. Advocates of whole-exome/genome screening in newborns, testing that is not far into the future, have much to learn from current NBS protocols. ■ Hans C. Andersson, MD Hayward Genetics Center Tulane University Medical School New Orleans, Louisiana Reprint requests: Hans C. Andersson, MD, Hayward Genetics Center, Tulane University Medical School, 1403 Tulane Ave, New Orleans, LA 70112. E-mail: [email protected]
The author serves as an Editorial Board member for The Journal of Pediatrics. The author declares no conflict of interest.
References 1. Chien Y-H, Chiang SC, Weng WC, Lee NC, Lin CJ, Hsieh WS, et al. Presymptomatic diagnosis of spinal muscular atrophy through newborn screening. J Pediatr 2017;190:124-9. 2. Burton B, Charrow J, Hoganson GE, Waggoner D, Tinkle B, Braddock SR, et al. Newborn screening for lysosomal storage disorders in Illinois: the initial 15-month experience. J Pediatr 2017;190:130-5. 3. Talbot K, Tizzano EF The clinical landscape for SMA in a new therapeutic era. Gene Ther, in press.
Searching for the Best Oral Treatment for Hypoglycemic Newborns feeding was attempted either by direct breastfeeding, exn this volume of The Journal, Harris et al1 report the impact pressed breast milk, formula, or a combination of these based of 40% dextrose gel and different types of feeding on maternal preference. For 54 episodes, infants did not receive (breastfeeding, expressed breast milk, formula, and no any feeding, because of the maternal desire feeding) on subsequent glucose concentraSee related article, p 136 to breastfeed only, but inability to express tions in hypoglycemic infants <48 hours of breast milk. The response to treatment with age. The analysis included 295 episodes of hybuccal gel (dextrose or placebo) and feeding was assessed by poglycemia, defined as a glucose concentration <46.8 mg/dL, measuring the glucose concentration 30 minutes after the gel from 227 infants. Most of these infants were screened for low was administered or in some cases after a longer duration so glucose concentrations because they had at least one of the folas not to interrupt feeding. lowing risk factors: infant of a diabetic mother, late preterm The mean increase in glucose concentration for all hypobirth at 35-36 weeks’ gestation, small for gestational age (<10th glycemic episodes was 11.7 mg/dL. Infants who received percentile or <2500 g), and/or large for gestational age (>90th dextrose gel had a 3.0 mg/dL larger increase in glucose conpercentile or >4500 g). In addition, 10 infants had low glucose concentrations after hypothermia or poor feeding. Episodes occurred at a median age of 4.5 hours (range 0.4-47.2 hours) with a median glucose concentration of 41.4 mg/dL (range 16.2P.R. is a member of the data safety and monitoring board for a National Institutes of 45.0 mg/dL). The subjects in this study were recruited from Health sponsored trial by Xeris Pharmaceuticals. The other authors declare no the Sugar Babies Study2 and were randomized to 40% dexconflicts of interest. trose or placebo buccal gel as part of the treatment regimen 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights reserved. https://doi.org10.1016/j.jpeds.2017.08.025 for low glucose concentrations. After subjects received the gel,
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References 1. Rysavy MA, Li L, Bell EF, Das A, Hintz SR, Stoll BJ, et al. Betweenhospital variation in treatment and outcomes in extremely preterm infants. N Engl J Med 2015;372:1801-11. 2. Inoue H, Ochiai M, Yasuoka K, Tanaka K, Kurata H, Fujiyoshi J, et al. Early mortality and morbidity in infants with birth weight ≤500g in Japan. J Pediatr 2017;190:112-7. 3. Schmidt B, Roberts RS, Davis PG, Doyle LW, Asztalos EV, Opie G, et al. Prediction of late death or disability at age 5 years using a count of 3 neonatal morbidities in very low birth weight infants. J Pediatr 2015;167:9826.e2. 4. Marlow N, Wolke D, Bracewell MA, Samara M. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9-19. 5. Doyle LW, Cheong JL, Burnett A, Roberts G, Lee KJ, Anderson PJ. Biological and social influences on outcomes of extreme-preterm/lowbirth weight adolescents. Pediatrics 2015;136:e1513-20.
•
November 2017
6. James J, Munson D, DeMauro SB, Langer JC, Dworetz AR, Natarajan G. Outcomes of preterm infants following discussions about withdrawal or withholding of life support. J Pediatr 2017;190:11823. 7. Dupont-Thibodeau A, Barrington KJ, Farlow B, Janvier A. End-of-life decisions for extremely low-gestational-age infants: why simple rules for complicated decisions should be avoided. Semin Perinatol 2014;38:317. 8. Janvier A, Lorenz JM, Lantos JD. Antenatal counselling for parents facing an extremely preterm birth: limitations of the medical evidence. Acta Paediatr 2012;101:800-4. 9. Boss RD, Hutton N, Sulpar LJ, West AM, Donohue PK. Values parents apply to decision-making regarding delivery room resuscitation for high-risk newborns. Pediatrics 2008;122:5839. 10. Grobman WA, Kavanaugh K, Moro T, DeRegnier RA, Savage T. Providing advice to parents for women at acutely high risk of periviable delivery. Obstet Gynecol 2010;115:904-9.
Newborn Screening for Spinal Muscular Atrophy and Lysosomal Storage Disorders Takes Advantage of Novel Therapies
I
tional SMN2, was approved by FDA after phase 3 trials showed n 2 reports in this volume of The Journal, the progress, and significant clinical motor neuron improvements (eg, imcomplexity, of newborn screening (NBS) is on full view. proved head control, sitting, standing, respiratory health). One report, from Chien et al,1 describes the successful pilot Because the pathology of SMA causes motor of NBS for spinal muscular atrophy (SMA) See related articles, neuron death, early recognition and treatcoming just in time to take advantage of a pgs 130 and 124 ment is essential to spare neurons and lessen novel intrathecal gene therapy for SMA, neurodegeneration. The current SMA NBS pilot study proves nusinersen (SPINRAZA; Biogen, Research Triangle Park, North that this is possible. Carolina), recently approved by the Food and Drug AdminChien et al1 adapted reverse transcription polymerase chain istration (FDA). A second paper on NBS, from Burton et al,2 offers results of the first 15 months of NBS for 5 lysosomal reaction genetic sequencing of SMN1 from dried blood spots storage disorders (LSDs). Both reports demonstrate remarkand confirmed mutations by multiplex-ligation probe ampliable progress in detecting severe degenerative infantile and jufication on 120 267 newborns referred between November 2014 venile disorders that previously were diagnosed principally on and September 2016 to the National Taiwan University Hosclinical disease symptoms after disease onset. New methods were pital Newborn Screening Center. Rapid turnaround of results necessary for the elucidation of these disorders: for SMA, screen(3 days for 98% of samples), low cost per sample, and low rates ing relying on a DNA-based NBS method, and in LSD screenof unsatisfactory samples with positive predictive value of 100% ing, necessitating the development of a rapid and reliable made this method feasible for population screening. Seven pamultienzyme assay. tients were detected (screening program incidence 1:17 181 live For patients with SMA, until recently no effective therapy births), of whom 3 were symptomatic during the follow-up has been available, lessening the urgency of early diagnosis. period. Symptoms of type 1 SMA typically begin during the first few Burton et al2 report on the initial 15 months of NBS for 5 LSDs (Pompe, Fabry, Gaucher, mucopolysaccharidosis I [MPSmonths after birth, and patients progress to respiratory failure I], and Niemann-Pick diseases) in Illinois. Each condition has and death by age 2 years. an FDA-approved enzyme-replacement therapy (ERT), and 2 Patients with SMA have deletions or mutations in both copies (Fabry, Gaucher) have oral small molecule therapies. The conof the SMN1 gene and a decreased number of functional copies ditions are heterogeneous clinically but can be detected by a of SMN2.3 Although still not understood fully, greater numbers of SMN2 correlate with a milder phenotype. In December 2016, multiplex enzyme assay in dried blood spots. Some patients a novel intrathecal drug, nusinersen, which up-regulates funcmay be symptomatic in the early months of life (eg, infantile Pompe), and ERT is lifesaving. Others may present in early years (eg, MPS I), whereas others may present later in life (eg, Fabry, ERT Enzyme-replacement therapy Gaucher). Presentation of Gaucher disease also may occur in FDA Food and Drug Administration early months in severe cases and in the juvenile years or adultLSD Lysosomal storage disorder MPS-I Mucopolysaccharidosis I hood for some patients with Pompe disease. In addition, infants NBS Newborn screening with MPS I typically develop progressive neurologic regresSMA Spinal muscular atrophy sion for which hematopoietic stem cell transplantation is 9
THE JOURNAL OF PEDIATRICS • www.jpeds.com effective only before significant neurodegeneration has occurred. A reliable NBS test offers a diagnosis that allows therapy to be instituted before the occurrence of irrevocable pathology. Prediction of prognosis and age of onset from enzyme or molecular data is difficult in many cases, necessitating ongoing monitoring by specialists. In 219 793 infants screened in Illinois for LSDs since November 2014, Burton et al identified 28 affected individuals with one of the LSDs. Molecular confirmation was complicated in some cases by variants of unknown significance in the affected gene. The authors conclude that the benefits of early diagnosis led to early treatment options in 3 of 28 cases: 1 patient with severe MPS I who had hematopoietic stem cell transplantation/ERT and 2 patients with infantile-onset Pompe disease who received ERT. The other 25 cases were asymptomatic and continue to be followed for early signs of disease before initiating therapy. A large number of pseudodeficiency cases were identified for Pompe (15), MPS I (30), and Fabry (16) disease. The Fabry cases were all carriers of p.A143T variant, for which clinical significance currently is unclear. The authors thoughtfully discuss the benefits of this NBS protocol and the potential for psychological damage. In addition, in cases of unknown penetrance and prognosis, the appropriateness of testing other at-risk family members is called into question. The difficulty and cost (financially and otherwise) of following asymptomatic patients over many years is difficult for all concerned. NBS relies on the logic that metabolic or molecular aberrations relative to normal can diagnose accurately affected individuals before symptoms appear. This logic does not apply equally to all diseases, as both NBS studies makes clear. Patients appear to fall along a spectrum of affectedness that
Volume 190 cannot clearly be understood solely by enzyme levels and DNAbased studies. Advances that better allow prediction of likely symptomatic cases will enhance the NBS for these complex diseases and others. Until then, voices continue to call out for additional disease screening in the unaffected newborn. Advocates of whole-exome/genome screening in newborns, testing that is not far into the future, have much to learn from current NBS protocols. ■ Hans C. Andersson, MD Hayward Genetics Center Tulane University Medical School New Orleans, Louisiana Reprint requests: Hans C. Andersson, MD, Hayward Genetics Center, Tulane University Medical School, 1403 Tulane Ave, New Orleans, LA 70112. E-mail: [email protected]
The author serves as an Editorial Board member for The Journal of Pediatrics. The author declares no conflict of interest.
References 1. Chien Y-H, Chiang SC, Weng WC, Lee NC, Lin CJ, Hsieh WS, et al. Presymptomatic diagnosis of spinal muscular atrophy through newborn screening. J Pediatr 2017;190:124-9. 2. Burton B, Charrow J, Hoganson GE, Waggoner D, Tinkle B, Braddock SR, et al. Newborn screening for lysosomal storage disorders in Illinois: the initial 15-month experience. J Pediatr 2017;190:130-5. 3. Talbot K, Tizzano EF The clinical landscape for SMA in a new therapeutic era. Gene Ther, in press.
Searching for the Best Oral Treatment for Hypoglycemic Newborns feeding was attempted either by direct breastfeeding, exn this volume of The Journal, Harris et al1 report the impact pressed breast milk, formula, or a combination of these based of 40% dextrose gel and different types of feeding on maternal preference. For 54 episodes, infants did not receive (breastfeeding, expressed breast milk, formula, and no any feeding, because of the maternal desire feeding) on subsequent glucose concentraSee related article, p 136 to breastfeed only, but inability to express tions in hypoglycemic infants <48 hours of breast milk. The response to treatment with age. The analysis included 295 episodes of hybuccal gel (dextrose or placebo) and feeding was assessed by poglycemia, defined as a glucose concentration <46.8 mg/dL, measuring the glucose concentration 30 minutes after the gel from 227 infants. Most of these infants were screened for low was administered or in some cases after a longer duration so glucose concentrations because they had at least one of the folas not to interrupt feeding. lowing risk factors: infant of a diabetic mother, late preterm The mean increase in glucose concentration for all hypobirth at 35-36 weeks’ gestation, small for gestational age (<10th glycemic episodes was 11.7 mg/dL. Infants who received percentile or <2500 g), and/or large for gestational age (>90th dextrose gel had a 3.0 mg/dL larger increase in glucose conpercentile or >4500 g). In addition, 10 infants had low glucose concentrations after hypothermia or poor feeding. Episodes occurred at a median age of 4.5 hours (range 0.4-47.2 hours) with a median glucose concentration of 41.4 mg/dL (range 16.2P.R. is a member of the data safety and monitoring board for a National Institutes of 45.0 mg/dL). The subjects in this study were recruited from Health sponsored trial by Xeris Pharmaceuticals. The other authors declare no the Sugar Babies Study2 and were randomized to 40% dexconflicts of interest. trose or placebo buccal gel as part of the treatment regimen 0022-3476/$ - see front matter. © 2017 Elsevier Inc. All rights reserved. https://doi.org10.1016/j.jpeds.2017.08.025 for low glucose concentrations. After subjects received the gel,
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