- Email: [email protected]
Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience
ORIGINAL ARTICLES Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience Barbara K. Burton, MD1,2, George E. Hoganson, MD3, Julie Fleischer, MD4, Dorothy K. Grange, MD5, Stephen R. Braddock, MD6,7, Rachel Hickey, MS, LCGC1, Lauren Hitchins, DNP, CPNP, AGN-BC1,2, Daniel Groepper, CGC4, Katherine M. Christensen, MS, CGC6,7, Amelia Kirby, MD6,7, Conny Moody, MBA8, Heather Shryock8, Laura Ashbaugh, RN, BSN8, Rong Shao, PhD9, and Khaja Basheeruddin, PhD9 Objectives To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois.
Study design Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. Results One case of MPS II and 14 infants with pseudodeficiency for I2S were identified. Conclusions Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois. (J Pediatr 2019;-:1-3).
M
ucopolysaccharidosis type II (MPS II) or Hunter syndrome is a progressive, multisystemic X-linked lysosomal storage disorder with an estimated incidence between 1 in 100 000 to 170 000 births.1,2 The disorder results from a deficiency of iduronate-2-sulfatase (I2S) activity leading to accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate within the lysosomes. This results in cell and organ dysfunction and a shortened life expectancy. Approximately two-thirds of patients with MPS II have the severe or neuronopathic form of the disorder with cognitive impairment and one-third have the attenuated or non-neuronopathic form of the disorder with variable somatic involvement but no cognitive involvement. Enzyme replacement therapy (idursulfase) was approved by the US Food and Drug Administration in 2006 and is effective in prolonging survival3 and in stabilizing or improving some of the somatic manifestations of the disorder.4 Hematopoietic stem cell transplantation has been performed in some cases and may provide some cognitive benefit, although experience is limited.5,6 Symptoms of MPS II are typically observed as early as 2 years of age, but diagnosis is often significantly delayed because many of the early signs and symptoms occur commonly in the unaffected pediatric population.7 Experience with other lysosomal storage disorders has revealed that earlier treatment, including treatment prior to the onset of clinical symptoms, is typically associated with improved outcomes.8,9 Although there is limited experience in the presymptomatic treatment of MPS II, early treatment has been shown to be safe10-12 and based on the progressive nature of the disease, is likely to be beneficial. A pilot newborn screening program for MPS II has been ongoing in Taiwan since 2015 and has resulted in the diagnosis of the disorder in a number of affected infants, some of whom are now receiving treatment.13,14 Illinois became the first state in the US to implement population-based newborn screening in December 2017. In this report, we describe the experience in screening 162 000 infants during the first year of the screening program.
Methods Testing was performed in the Newborn Screening Laboratory of the Illinois Department of Public Health using the same dried blood spot samples submitted for the other newborn screening disorders. I2S was assayed in the presence of substrate (PerkinElmer, Waltham, Massachusetts) and internal standard in the presence of buffer and salts. Assays were run simultaneously with assays for 6 other lysosomal disorders. Using a multichannel pipette, 30 uL of 6-plex cocktail was added to one of the wells of one microtiter plate and 30 uL of the I2S cocktail
GAGs I2S MPS II
Glycosaminoglycans Iduronate-2-sulfatase Mucopolysaccharidosis type II
From the 1Ann and Robert H. Lurie Children’s Hospital of Chicago; 2Northwestern University Feinberg School of Medicine; 3University of Illinois College of Medicine, Chicago, IL; 4Southern Illinois University, Springfield, IL; 5 Washington University School of Medicine; 6Saint Louis University; 7SSM Health Cardinal Glennon Children’s Medical Center, St. Louis, MO; 8Office of Health Promotion, Illinois Department of Public Health, Springfield, IL; and 9Newborn Screening Laboratory, Illinois Department of Public Health, Chicago, IL Funding and disclosure information is available at www. jpeds.com. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.07.053
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
was added to the wells of the duplicate plate. The plates were sealed and shaken (875 rpm) on a rotator at 37 C for 17 hours, after which enzyme reactions were quenched by adding 100 uL acetonitrile using prewetted tips on a multichannel pipette for the 6-plex microtiter plate and 200 uL acetonitrile for the 1-plex microtiter plate. A 100 uL aliquot was transferred from the samples in the 1-plex plate to the corresponding samples in the 6-plex plate. The products and internal standards for all 7 enzymes were quantitated as previously described.15 A positive screen for MPS II was defined as I2S activity less than or equal to 10% of the daily median. Immediate referral to a designated consultant for diagnostic testing was recommended for infants with a positive result. Samples with I2S activity greater than 10% but less than or equal to 13% of the daily median were classified as borderline, and a second filter paper specimen was requested. If the result on the second sample was again borderline or positive, the infant was referred for diagnostic testing. Diagnostic testing was performed at commercial laboratories with the choice of laboratory determined by the consultant evaluating the patient.
Results A total of 162 000 infants were screened between December 11, 2017 and December 31, 2018. A total of 14 infants had a positive screening test result, and 2 other infants had a borderline result. All 16 of these infants were male. In the case of 1 borderline result, the I2S activity on the second sample was normal and no further testing or evaluation was conducted. In the second borderline case, the repeat sample also yielded a borderline result so the infant was referred for diagnostic testing. In total, therefore, 15 infants were seen for diagnostic evaluation. One positive diagnosis of MPS II was established. In this infant, no I2S activity was detected in the newborn screening specimen. The follow-up assay of plasma I2S yielded a result of 3.13 nmol/4 hour/mL (normal: >155 nmol/ 4 hour/mL; affected 0-15 nmol/4 hour/mL). Total urine GAGs were elevated at 128.19 mg/mmol creatinine (normal: 0-53 mg/mmol) with significant elevations of dermatan and heparan sulfate. Sequencing of the IDS gene revealed a known pathogenic mutation c.1403G>A (p.R468Q). The infant had no abnormal findings on physical examination. Subsequent to his evaluation, it was learned that he had an affected family member with MPS II. Review of medical records indicated that this family member had a neuronopathic phenotype, and the same mutation as observed in the patient. Hematopoietic stem cell transplantation was considered but not pursued. The infant was started on enzyme replacement therapy at 6 weeks of age. The remaining 14 infants referred for diagnostic evaluation were found to have I2S pseudodeficiency (Table). All had decreased levels of I2S on follow-up testing, either in plasma or in a dried blood spot, although only 1 had 2
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enzyme activity in the clearly affected range (patient 6). All except 1 patient had total urine GAGs within the normal range. Patient 12, who had 2 borderline newborn screening results, had mildly elevated total urine GAGs of 62.2 mg/ mmol creatinine (normal: <53 mg/mmol creatinine), although it was commented that it was a dilute specimen. In this infant, both the dermatan and heparan sulfate levels in a dried blood spot were normal. Several other infants with normal total GAGs in urine had minor elevations of dermatan and/or heparan sulfate. Of the 14 infants, 11 had sequencing of the IDS gene and a variant was identified in 10 of the 11. Five of these were novel variants seen in only a single infant and another novel variant was seen in 3 infants, 2 of whom are related. Two other infants had a variant previously reported in the Taiwanese population although neither of these infants were of Asian descent. One infant had low enzyme activity but no variant in the IDS gene. Five of the infants with pseudodeficiency were white, non-Hispanic, 2 were Hispanic, 5 were black, and 2 were Asian (1 Chinese and 1 Filipino). Testing of the mother for the IDS variant was performed in 11 of the 14 cases of pseudodeficiency and in each of these cases, the mother was found to be a carrier of the variant. In 3 of the infants with presumed pseudodeficiency (patients 3, 12, and 13), the clinically unaffected maternal grandfather was identified to have the same variant present in the infant as well as similar biochemical findings.
Discussion Interest in newborn screening for lysosomal disorders has been steadily increasing as new treatments for these disorders have been developed in the past decade. In the case of MPS II, current treatment options include enzyme
Table. Results of follow-up testing in infants with I2S pseudodeficiency Case number
Dried blood spots I2S (% daily median)
Diagnostic 12S (reference range)
IDS sequence variant c.863T>C, p.I288T None c.554C>G, p.P185R Not done c.778C>T, p.P260S c.1055A>G, p.D352G Not done c.684A>G, p.P228P; c.851C>T, p.P284L c.1499C>T, p.T500I c.1055A>G, p.D352G c.1499C>T, T500I c.674A>G, p.Y225C c.785T>A, p.V262E c.1055A>G, p.D352G
1 2 3 4 5 6 7 8
10 9 4 6 10 2 10 7
31.1* (³155) 50.9* (³155) 30.4* (³155) 61.6* (³155) 60.51* (³155) 5.32* (³155) 137.7* (³155) 22.56* (³155)
9 10 11 12 13 14
10 3 No value 12, 11 3 1
100.1* (³155) <1.5† (>1.5) <1.5† (>1.5) 1.5† (>1.5) <1.5† (>1.5) <1.5† (>1.5)
*Values expressed as nmol/4 hour/mL in plasma; performed at Greenwood Genetic Center. Affected range: <15 nmol/4 hour/mL. †Values expressed as nmol/hour/mL in dried blood spots; performed at Mayo Medical Laboratories. Affected range: <1.5 nmol/hour/mL.
Burton et al
- 2019 replacement therapy, which treats the somatic aspects of the disorder, and hematopoietic stem cell transplantation, which may offer cognitive benefit. Numerous other treatments, targeting both somatic and central nervous system disease, are in clinical trials or preclinical development. Newborn screening for MPS II prevents the diagnostic odyssey and delayed diagnosis experienced by many families who have a child with this disorder and will likely lead to improved clinical outcomes. Although the benefits of presymptomatic enzyme replacement therapy or transplant have not yet been well-documented due to the small number of affected infants diagnosed prior to clinical recognition, analogy with other lysosomal disorders would suggest that this will likely be beneficial because many of the findings of the disorder are likely to be more amenable to prevention than to reversal. Indeed, even in the absence of new therapeutic developments or evidence of the efficacy of early treatment in preventing clinical symptoms, knowledge of the diagnosis is likely to improve outcome through recommended surveillance for disease complications and recognition of the anesthetic risks associated with the disorder. Patients with MPS II typically undergo multiple surgical procedures in the early years of life, often prior to recognition of the diagnosis.16 Because airway narrowing and postoperative complications are common, it is essential that such surgery be performed in a facility equipped to manage a difficult airway. Pseudodeficiency has been documented for many other lysosomal enzymes and, based on both the Taiwanese experience and our findings, is clearly an issue with I2S as well. The incidence of pseudodeficiency in the population cannot be accurately determined from our data alone but it is clearly more common than true deficiency. In contrast to iduronidase pseudodeficiency in mucopolysaccharidosis type I (MPS I), which is primarily observed in the African American population, I2S pseudodeficiency does not appear to be confined to any particular racial or ethnic group. Although several recurrent alleles were encountered in our series, a number of novel variants were also observed. In addition to having normal total urine GAGs, most of the patients with presumed pseudodeficiency also had I2S activity slightly higher than that observed in patients with confirmed MPS II. The rate of screen positive or borderline results in this series (16 of 162 000 or 0.01%) is comparable with that reported by Scott et al from Washington State, who tested 60 000 anonymized newborn screening specimens and also found a screen positive rate of 0.01% using a cut-off of 10% of the daily mean.17 This low rate of positive samples should be easily manageable by any newborn screening follow-up program. Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into a statewide newborn screening program. Among 162 000 infants screened, a single case of MPS II and 14 infants with I2S pseudodeficiency were identified. n
ORIGINAL ARTICLES We thank Vera Shively, MS, Ann and Robert H. Lurie Children’s Hospital of Chicago, for expert editorial assistance. Submitted for publication May 24, 2019; last revision received Jun 28, 2019; accepted Jul 23, 2019. Reprint Requests: Barbara K. Burton, MD, Ann and Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Ave, Box 59, Chicago, IL 60611. E-mail: [email protected]
References 1. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A 2003;123A:310-3. 2. Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7. 3. Burton BK, Jego V, Miki J, Jones SA. Survival in idursulfase-treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 2017;40:867-74. 4. Muenzer J, Giugliani R, Scarpa M, Tylki-Szymanska A, Jego V, Beck M. Clinical outcomes in idursulfase-treated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). Orphanet J Rare Dis 2017;12:161. 5. Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, et al. Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: a nationwide survey in Japan. Mol Genet Metab 2012;107:513-20. 6. Selvanathan A, Ellaway C, Wilson C, Owens P, Shaw PJ, Bhattacharya K. Effectiveness of early hematopoietic stem cell transplantation in preventing neurocognitive decline in mucopolysaccharidosis type II: a case series. JIMD Rep 2018;41:81-9. 7. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr 2012;171:631-9. 8. Yang CF, Yang CC, Liao HC, Huang LY, Chiang CC, Ho HC, et al. Very early treatment for infantile-onset Pompe disease contributes to better outcomes. J Pediatr 2016;169:174-80. 9. Gabrielli O, Clarke LA, Ficcadenti A, Santoro L, Sampini L, Volpi N, et al. 12 year follow up of enzyme-replacement therapy in two siblings with attenuated mucopolysaccharidosis type I: the important role of early treatment. BMC Med Genet 2016;17:19. 10. Lampe C, Atherton A, Burton BK, Descartes M, Giugliani R, Horovitz DD, et al. Enzyme replacement therapy in mucopolysaccharidosis II patients under 1 year of age. JIMD Rep 2014;14:99-113. 11. Tylki-Szymanska A, Jurecka A, Zuber Z, Rozdzynska A, Marucha J, Czartoryska B. Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up. Acta Paediatr 2012;101:e42-7. 12. Tajima G, Sakura N, Kosuga M, Okuyama T, Kobayashi M. Effects of idursulfase enzyme replacement therapy for Mucopolysaccharidosis type II when started in early infancy: comparison in two siblings. Mol Genet Metab 2013;108:172-7. 13. Chuang C-K, Lin H-Y, Wang T-J, Huang YH, Chang MJ, Liao HC, et al. Status of newborn screening and follow up investigations for mucopolysaccharidoses I and II in Taiwan. Orphanet J Rare Dis 2018;13:84. 14. Chan MJ, Liao HC, Gelb MH, Chuang CK, Liu MY, Chen HJ, et al. Taiwan national newborn screening program by tandem mass spectrometry for mucopolysaccharidoses types I, II and VI. J Pediatr 2019;205:176-82. 15. Burton BK, 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. 16. Mendelsohn N, Harmatz P, Bodamer O, Burton BK, Giugliani R, Jones SA, et al. Importance of surgical history in diagnosing mucopolysaccharidosis type II (Hunter syndrome): data from the Hunter Outcome Survey. Genet Med 2010;12:816-22. 17. Scott CR, Elliott S, Loyola L, Huang J-Y, Wu Z, Feng J, et al. A high performance assay for the detection of MPS disorders, MLD, and CTX, from newborn blood spots. Mol Genet Metab 2018;123:S127.
Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience
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Appendix Supported by Shire Human Genetic Therapies Inc, Lexington, MA (a member of the Takeda group of companies) (IIR-USA-002083 [to B.B.]. Shire was not involved in the study design, collection, analysis, interpretation of the data, the writing of the report, or the decision to submit the paper for publication. B.B. has received consulting fees, clinical trial funding, personal fees, grants, from
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Takeda (Shire); personal fees from Biomarin; personal fees from Sanofi Genzyme; personal fees from Alexion; personal fees from Ultragenyx; other from Sangamo; personal fees from JCR Pharma; personal fees from Chiesi; personal fees from Moderna; personal fees from Horizon Pharma; and personal fees from Denali. G.H. has received grants from the Illinois Department of Public Health. L.H. has received personal fees from Shire/Takeda and personal fees from Sanofi Genzyme. The other authors declare no conflicts of interest.
Burton et al
Study design Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. Results One case of MPS II and 14 infants with pseudodeficiency for I2S were identified. Conclusions Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois. (J Pediatr 2019;-:1-3).
M
ucopolysaccharidosis type II (MPS II) or Hunter syndrome is a progressive, multisystemic X-linked lysosomal storage disorder with an estimated incidence between 1 in 100 000 to 170 000 births.1,2 The disorder results from a deficiency of iduronate-2-sulfatase (I2S) activity leading to accumulation of the glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate within the lysosomes. This results in cell and organ dysfunction and a shortened life expectancy. Approximately two-thirds of patients with MPS II have the severe or neuronopathic form of the disorder with cognitive impairment and one-third have the attenuated or non-neuronopathic form of the disorder with variable somatic involvement but no cognitive involvement. Enzyme replacement therapy (idursulfase) was approved by the US Food and Drug Administration in 2006 and is effective in prolonging survival3 and in stabilizing or improving some of the somatic manifestations of the disorder.4 Hematopoietic stem cell transplantation has been performed in some cases and may provide some cognitive benefit, although experience is limited.5,6 Symptoms of MPS II are typically observed as early as 2 years of age, but diagnosis is often significantly delayed because many of the early signs and symptoms occur commonly in the unaffected pediatric population.7 Experience with other lysosomal storage disorders has revealed that earlier treatment, including treatment prior to the onset of clinical symptoms, is typically associated with improved outcomes.8,9 Although there is limited experience in the presymptomatic treatment of MPS II, early treatment has been shown to be safe10-12 and based on the progressive nature of the disease, is likely to be beneficial. A pilot newborn screening program for MPS II has been ongoing in Taiwan since 2015 and has resulted in the diagnosis of the disorder in a number of affected infants, some of whom are now receiving treatment.13,14 Illinois became the first state in the US to implement population-based newborn screening in December 2017. In this report, we describe the experience in screening 162 000 infants during the first year of the screening program.
Methods Testing was performed in the Newborn Screening Laboratory of the Illinois Department of Public Health using the same dried blood spot samples submitted for the other newborn screening disorders. I2S was assayed in the presence of substrate (PerkinElmer, Waltham, Massachusetts) and internal standard in the presence of buffer and salts. Assays were run simultaneously with assays for 6 other lysosomal disorders. Using a multichannel pipette, 30 uL of 6-plex cocktail was added to one of the wells of one microtiter plate and 30 uL of the I2S cocktail
GAGs I2S MPS II
Glycosaminoglycans Iduronate-2-sulfatase Mucopolysaccharidosis type II
From the 1Ann and Robert H. Lurie Children’s Hospital of Chicago; 2Northwestern University Feinberg School of Medicine; 3University of Illinois College of Medicine, Chicago, IL; 4Southern Illinois University, Springfield, IL; 5 Washington University School of Medicine; 6Saint Louis University; 7SSM Health Cardinal Glennon Children’s Medical Center, St. Louis, MO; 8Office of Health Promotion, Illinois Department of Public Health, Springfield, IL; and 9Newborn Screening Laboratory, Illinois Department of Public Health, Chicago, IL Funding and disclosure information is available at www. jpeds.com. 0022-3476/$ - see front matter. ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jpeds.2019.07.053
1
THE JOURNAL OF PEDIATRICS
www.jpeds.com
was added to the wells of the duplicate plate. The plates were sealed and shaken (875 rpm) on a rotator at 37 C for 17 hours, after which enzyme reactions were quenched by adding 100 uL acetonitrile using prewetted tips on a multichannel pipette for the 6-plex microtiter plate and 200 uL acetonitrile for the 1-plex microtiter plate. A 100 uL aliquot was transferred from the samples in the 1-plex plate to the corresponding samples in the 6-plex plate. The products and internal standards for all 7 enzymes were quantitated as previously described.15 A positive screen for MPS II was defined as I2S activity less than or equal to 10% of the daily median. Immediate referral to a designated consultant for diagnostic testing was recommended for infants with a positive result. Samples with I2S activity greater than 10% but less than or equal to 13% of the daily median were classified as borderline, and a second filter paper specimen was requested. If the result on the second sample was again borderline or positive, the infant was referred for diagnostic testing. Diagnostic testing was performed at commercial laboratories with the choice of laboratory determined by the consultant evaluating the patient.
Results A total of 162 000 infants were screened between December 11, 2017 and December 31, 2018. A total of 14 infants had a positive screening test result, and 2 other infants had a borderline result. All 16 of these infants were male. In the case of 1 borderline result, the I2S activity on the second sample was normal and no further testing or evaluation was conducted. In the second borderline case, the repeat sample also yielded a borderline result so the infant was referred for diagnostic testing. In total, therefore, 15 infants were seen for diagnostic evaluation. One positive diagnosis of MPS II was established. In this infant, no I2S activity was detected in the newborn screening specimen. The follow-up assay of plasma I2S yielded a result of 3.13 nmol/4 hour/mL (normal: >155 nmol/ 4 hour/mL; affected 0-15 nmol/4 hour/mL). Total urine GAGs were elevated at 128.19 mg/mmol creatinine (normal: 0-53 mg/mmol) with significant elevations of dermatan and heparan sulfate. Sequencing of the IDS gene revealed a known pathogenic mutation c.1403G>A (p.R468Q). The infant had no abnormal findings on physical examination. Subsequent to his evaluation, it was learned that he had an affected family member with MPS II. Review of medical records indicated that this family member had a neuronopathic phenotype, and the same mutation as observed in the patient. Hematopoietic stem cell transplantation was considered but not pursued. The infant was started on enzyme replacement therapy at 6 weeks of age. The remaining 14 infants referred for diagnostic evaluation were found to have I2S pseudodeficiency (Table). All had decreased levels of I2S on follow-up testing, either in plasma or in a dried blood spot, although only 1 had 2
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enzyme activity in the clearly affected range (patient 6). All except 1 patient had total urine GAGs within the normal range. Patient 12, who had 2 borderline newborn screening results, had mildly elevated total urine GAGs of 62.2 mg/ mmol creatinine (normal: <53 mg/mmol creatinine), although it was commented that it was a dilute specimen. In this infant, both the dermatan and heparan sulfate levels in a dried blood spot were normal. Several other infants with normal total GAGs in urine had minor elevations of dermatan and/or heparan sulfate. Of the 14 infants, 11 had sequencing of the IDS gene and a variant was identified in 10 of the 11. Five of these were novel variants seen in only a single infant and another novel variant was seen in 3 infants, 2 of whom are related. Two other infants had a variant previously reported in the Taiwanese population although neither of these infants were of Asian descent. One infant had low enzyme activity but no variant in the IDS gene. Five of the infants with pseudodeficiency were white, non-Hispanic, 2 were Hispanic, 5 were black, and 2 were Asian (1 Chinese and 1 Filipino). Testing of the mother for the IDS variant was performed in 11 of the 14 cases of pseudodeficiency and in each of these cases, the mother was found to be a carrier of the variant. In 3 of the infants with presumed pseudodeficiency (patients 3, 12, and 13), the clinically unaffected maternal grandfather was identified to have the same variant present in the infant as well as similar biochemical findings.
Discussion Interest in newborn screening for lysosomal disorders has been steadily increasing as new treatments for these disorders have been developed in the past decade. In the case of MPS II, current treatment options include enzyme
Table. Results of follow-up testing in infants with I2S pseudodeficiency Case number
Dried blood spots I2S (% daily median)
Diagnostic 12S (reference range)
IDS sequence variant c.863T>C, p.I288T None c.554C>G, p.P185R Not done c.778C>T, p.P260S c.1055A>G, p.D352G Not done c.684A>G, p.P228P; c.851C>T, p.P284L c.1499C>T, p.T500I c.1055A>G, p.D352G c.1499C>T, T500I c.674A>G, p.Y225C c.785T>A, p.V262E c.1055A>G, p.D352G
1 2 3 4 5 6 7 8
10 9 4 6 10 2 10 7
31.1* (³155) 50.9* (³155) 30.4* (³155) 61.6* (³155) 60.51* (³155) 5.32* (³155) 137.7* (³155) 22.56* (³155)
9 10 11 12 13 14
10 3 No value 12, 11 3 1
100.1* (³155) <1.5† (>1.5) <1.5† (>1.5) 1.5† (>1.5) <1.5† (>1.5) <1.5† (>1.5)
*Values expressed as nmol/4 hour/mL in plasma; performed at Greenwood Genetic Center. Affected range: <15 nmol/4 hour/mL. †Values expressed as nmol/hour/mL in dried blood spots; performed at Mayo Medical Laboratories. Affected range: <1.5 nmol/hour/mL.
Burton et al
- 2019 replacement therapy, which treats the somatic aspects of the disorder, and hematopoietic stem cell transplantation, which may offer cognitive benefit. Numerous other treatments, targeting both somatic and central nervous system disease, are in clinical trials or preclinical development. Newborn screening for MPS II prevents the diagnostic odyssey and delayed diagnosis experienced by many families who have a child with this disorder and will likely lead to improved clinical outcomes. Although the benefits of presymptomatic enzyme replacement therapy or transplant have not yet been well-documented due to the small number of affected infants diagnosed prior to clinical recognition, analogy with other lysosomal disorders would suggest that this will likely be beneficial because many of the findings of the disorder are likely to be more amenable to prevention than to reversal. Indeed, even in the absence of new therapeutic developments or evidence of the efficacy of early treatment in preventing clinical symptoms, knowledge of the diagnosis is likely to improve outcome through recommended surveillance for disease complications and recognition of the anesthetic risks associated with the disorder. Patients with MPS II typically undergo multiple surgical procedures in the early years of life, often prior to recognition of the diagnosis.16 Because airway narrowing and postoperative complications are common, it is essential that such surgery be performed in a facility equipped to manage a difficult airway. Pseudodeficiency has been documented for many other lysosomal enzymes and, based on both the Taiwanese experience and our findings, is clearly an issue with I2S as well. The incidence of pseudodeficiency in the population cannot be accurately determined from our data alone but it is clearly more common than true deficiency. In contrast to iduronidase pseudodeficiency in mucopolysaccharidosis type I (MPS I), which is primarily observed in the African American population, I2S pseudodeficiency does not appear to be confined to any particular racial or ethnic group. Although several recurrent alleles were encountered in our series, a number of novel variants were also observed. In addition to having normal total urine GAGs, most of the patients with presumed pseudodeficiency also had I2S activity slightly higher than that observed in patients with confirmed MPS II. The rate of screen positive or borderline results in this series (16 of 162 000 or 0.01%) is comparable with that reported by Scott et al from Washington State, who tested 60 000 anonymized newborn screening specimens and also found a screen positive rate of 0.01% using a cut-off of 10% of the daily mean.17 This low rate of positive samples should be easily manageable by any newborn screening follow-up program. Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into a statewide newborn screening program. Among 162 000 infants screened, a single case of MPS II and 14 infants with I2S pseudodeficiency were identified. n
ORIGINAL ARTICLES We thank Vera Shively, MS, Ann and Robert H. Lurie Children’s Hospital of Chicago, for expert editorial assistance. Submitted for publication May 24, 2019; last revision received Jun 28, 2019; accepted Jul 23, 2019. Reprint Requests: Barbara K. Burton, MD, Ann and Robert H. Lurie Children’s Hospital of Chicago, 225 E. Chicago Ave, Box 59, Chicago, IL 60611. E-mail: [email protected]
References 1. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in Western Australia. Am J Med Genet A 2003;123A:310-3. 2. Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, et al. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7. 3. Burton BK, Jego V, Miki J, Jones SA. Survival in idursulfase-treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). J Inherit Metab Dis 2017;40:867-74. 4. Muenzer J, Giugliani R, Scarpa M, Tylki-Szymanska A, Jego V, Beck M. Clinical outcomes in idursulfase-treated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS). Orphanet J Rare Dis 2017;12:161. 5. Tanaka A, Okuyama T, Suzuki Y, Sakai N, Takakura H, Sawada T, et al. Long-term efficacy of hematopoietic stem cell transplantation on brain involvement in patients with mucopolysaccharidosis type II: a nationwide survey in Japan. Mol Genet Metab 2012;107:513-20. 6. Selvanathan A, Ellaway C, Wilson C, Owens P, Shaw PJ, Bhattacharya K. Effectiveness of early hematopoietic stem cell transplantation in preventing neurocognitive decline in mucopolysaccharidosis type II: a case series. JIMD Rep 2018;41:81-9. 7. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical considerations and common pitfalls. Eur J Pediatr 2012;171:631-9. 8. Yang CF, Yang CC, Liao HC, Huang LY, Chiang CC, Ho HC, et al. Very early treatment for infantile-onset Pompe disease contributes to better outcomes. J Pediatr 2016;169:174-80. 9. Gabrielli O, Clarke LA, Ficcadenti A, Santoro L, Sampini L, Volpi N, et al. 12 year follow up of enzyme-replacement therapy in two siblings with attenuated mucopolysaccharidosis type I: the important role of early treatment. BMC Med Genet 2016;17:19. 10. Lampe C, Atherton A, Burton BK, Descartes M, Giugliani R, Horovitz DD, et al. Enzyme replacement therapy in mucopolysaccharidosis II patients under 1 year of age. JIMD Rep 2014;14:99-113. 11. Tylki-Szymanska A, Jurecka A, Zuber Z, Rozdzynska A, Marucha J, Czartoryska B. Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up. Acta Paediatr 2012;101:e42-7. 12. Tajima G, Sakura N, Kosuga M, Okuyama T, Kobayashi M. Effects of idursulfase enzyme replacement therapy for Mucopolysaccharidosis type II when started in early infancy: comparison in two siblings. Mol Genet Metab 2013;108:172-7. 13. Chuang C-K, Lin H-Y, Wang T-J, Huang YH, Chang MJ, Liao HC, et al. Status of newborn screening and follow up investigations for mucopolysaccharidoses I and II in Taiwan. Orphanet J Rare Dis 2018;13:84. 14. Chan MJ, Liao HC, Gelb MH, Chuang CK, Liu MY, Chen HJ, et al. Taiwan national newborn screening program by tandem mass spectrometry for mucopolysaccharidoses types I, II and VI. J Pediatr 2019;205:176-82. 15. Burton BK, 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. 16. Mendelsohn N, Harmatz P, Bodamer O, Burton BK, Giugliani R, Jones SA, et al. Importance of surgical history in diagnosing mucopolysaccharidosis type II (Hunter syndrome): data from the Hunter Outcome Survey. Genet Med 2010;12:816-22. 17. Scott CR, Elliott S, Loyola L, Huang J-Y, Wu Z, Feng J, et al. A high performance assay for the detection of MPS disorders, MLD, and CTX, from newborn blood spots. Mol Genet Metab 2018;123:S127.
Population-Based Newborn Screening for Mucopolysaccharidosis Type II in Illinois: The First Year Experience
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Appendix Supported by Shire Human Genetic Therapies Inc, Lexington, MA (a member of the Takeda group of companies) (IIR-USA-002083 [to B.B.]. Shire was not involved in the study design, collection, analysis, interpretation of the data, the writing of the report, or the decision to submit the paper for publication. B.B. has received consulting fees, clinical trial funding, personal fees, grants, from
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Takeda (Shire); personal fees from Biomarin; personal fees from Sanofi Genzyme; personal fees from Alexion; personal fees from Ultragenyx; other from Sangamo; personal fees from JCR Pharma; personal fees from Chiesi; personal fees from Moderna; personal fees from Horizon Pharma; and personal fees from Denali. G.H. has received grants from the Illinois Department of Public Health. L.H. has received personal fees from Shire/Takeda and personal fees from Sanofi Genzyme. The other authors declare no conflicts of interest.
Burton et al