Mucopolysaccharidosis Type I Newborn Screening: Best Practices for Diagnosis and Management
2016; Elsevier BV; Volume: 182; Linguagem: Inglês
10.1016/j.jpeds.2016.11.036
ISSN1097-6833
AutoresL. Clarke, Andrea M. Atherton, Barbara K. Burton, Debra Day‐Salvatore, Paige Kaplan, Nancy D. Leslie, C. Ronald Scott, David W. Stockton, Janet A. Thomas, Joseph Muenzer,
Tópico(s)Carbohydrate Chemistry and Synthesis
ResumoThe mucopolysaccharidoses (MPS) are a group of rare progressive genetic disorders of glycosaminoglycan (GAG) metabolism caused by deficiency of enzymes responsible for lysosomal GAG degradation. The accumulation of partially degraded GAG and the resulting disturbance of cellular homeostasis leads to progressive cellular and tissue damage ultimately resulting in multiorgan system involvement.1Muenzer J. Overview of the mucopolysaccharidoses.Rheumatology. 2011; 50: v4-12Crossref PubMed Scopus (328) Google Scholar Mucopolysaccharidosis type 1 (MPS I) results from deficiency of the lysosomal enzyme α-L-iduronidase (IDUA) because of pathogenic variants in the IDUA gene.2Muenzer J. Wraith J.E. Clarke L.A. Mucopolysaccharidosis I: management and treatment guidelines.Pediatrics. 2009; 123: 19-29Crossref PubMed Scopus (343) Google Scholar MPS I presents clinically as a disease spectrum spanning early onset, progressive severe disease with cognitive impairment (Hurler syndrome), to later onset progressive disease with highly variable and later onset central nervous system (CNS) involvement (attenuated MPS I). Attenuated MPS I encompasses a spectrum previously referred to by the eponyms Hurler-Scheie and Scheie syndromes.1Muenzer J. Overview of the mucopolysaccharidoses.Rheumatology. 2011; 50: v4-12Crossref PubMed Scopus (328) Google Scholar Untreated patients with the most severe form of MPS I usually die in the first decade. In contrast, life expectancy for untreated patients with attenuated disease ranges from mortality in the second or third decade to full life expectancy, albeit with considerable morbidity. The birth incidence of MPS I is ~1 in 100 000 live births estimated from a number of population studies.3Moore D. Connock M.J. Wraith E. Lavery C. The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK.Orphanet J Rare Dis. 2008; 3: 24Crossref PubMed Scopus (120) Google Scholar Although the disease pathophysiology is not well understood, most of the clinical manifestations of MPS I are secondary deleterious effects because of disturbed GAG metabolism. Organs involved include the brain, musculoskeletal system, heart, lungs, and eyes. Many symptoms and complications are difficult or impossible to reverse. Thus, initiation of treatment early in the natural history of disease is thought to be a key factor in achieving optimal outcome.2Muenzer J. Wraith J.E. Clarke L.A. Mucopolysaccharidosis I: management and treatment guidelines.Pediatrics. 2009; 123: 19-29Crossref PubMed Scopus (343) Google Scholar Available disease modifying therapies include hematopoietic stem cell transplantation (HSCT) and enzyme replacement therapy (ERT) with laronidase.4de Ru M.H. Boelens J.J. Das A.M. Jones S.A. van der Lee J.H. Mahlaoui N. et al.Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure.Orphanet J Rare Dis. 2011; 6: 55-62Crossref PubMed Scopus (184) Google Scholar Because early intervention with HSCT has been demonstrated to stabilize neurocognitive function in MPS I,5Aldenhoven M. Wynn R.F. Orchard P.J. O'Meara A. Veys P. Fischer A. et al.Long-term outcome of Hurler syndrome patients after hematopoietic cell transplantation: an international multicenter study.Blood. 2015; 125: 2164-2172Crossref PubMed Scopus (218) Google Scholar, 6Kunin-Batson A.S. Shapiro E.G. Rudser K.D. Lavery C.A. Bjoraker K.J. Jones S.A. et al.Long-term cognitive and functional outcomes in children with mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) treated with hematopoietic cell transplantation.JIMD Rep. 2016; 29: 95-102Crossref PubMed Scopus (28) Google Scholar, 7Aldenhoven M. Jones S.A. Bonney D. Borrill R.E. Coussons M. Mercer J. et al.Hematopoietic cell transplantation for mucopolysaccharidosis patients is safe and effective: results after implementation of international guidelines.Biol Blood Marrow Transplant. 2015; 21: 1106-1109Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar it is currently recommended as standard for patients who are predicted to have severe disease.4de Ru M.H. Boelens J.J. Das A.M. Jones S.A. van der Lee J.H. Mahlaoui N. et al.Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure.Orphanet J Rare Dis. 2011; 6: 55-62Crossref PubMed Scopus (184) Google Scholar, 6Kunin-Batson A.S. Shapiro E.G. Rudser K.D. Lavery C.A. Bjoraker K.J. Jones S.A. et al.Long-term cognitive and functional outcomes in children with mucopolysaccharidosis (MPS)-IH (Hurler Syndrome) treated with hematopoietic cell transplantation.JIMD Rep. 2016; 29: 95-102Crossref PubMed Scopus (28) Google Scholar ERT with laronidase is used for treating nondirect CNS manifestations of MPS I. Clinical trials and follow-up studies of ERT in MPS I have demonstrated improvements in some somatic manifestations and functional outcomes in patients with attenuated MPS I.8Kakkis E.D. Muenzer J. Tiller G.E. Waber L. Belmont J. Passage M. et al.Enzyme-replacement therapy in mucopolysaccharidosis I.N Engl J Med. 2001; 344: 182-188Crossref PubMed Scopus (591) Google Scholar, 9Sifuentes M. Doroshow R. Hoft R. Mason G. Walot I. Diament M. et al.A follow-up study of MPS I patients treated with laronidase enzyme replacement therapy for 6 years.Mol Genet Metab. 2007; 90: 171-180Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 10Wraith J.E. The first 5 years of clinical experience with laronidase enzyme replacement therapy for mucopolysaccharidosis I.Expert Opin Pharmacother. 2005; 6: 489-506Crossref PubMed Scopus (127) Google Scholar, 11Wraith J.E. Clarke L.A. Beck M. Kolodny E.H. Pastores G.M. Muenzer J. et al.Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase).J Pediatr. 2004; 144: 581-588Abstract Full Text Full Text PDF PubMed Scopus (498) Google Scholar, 12Clarke L.A. Wraith J.E. Beck M. Kolodny E.H. Pastores G.M. Muenzer J. et al.Long-term efficacy and safety of laronidase in the treatment of mucopolysaccharidosis I.Pediatrics. 2009; 123: 229-240https://doi.org/10.1542/peds.2007-3847Crossref PubMed Scopus (287) Google Scholar, 13Shapiro E.G. Nestrasil I. Rudser K. Delaney K. Kovac V. Ahmed A. et al.Neurocognition across the spectrum of mucopolysaccharidosis type I: age, severity, and treatment.Mol Genet Metab. 2015; 116: 61-68Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar Laronidase has also been found to be useful in the peritransplant period for patients with severe MPS I.4de Ru M.H. Boelens J.J. Das A.M. Jones S.A. van der Lee J.H. Mahlaoui N. et al.Enzyme replacement therapy and/or hematopoietic stem cell transplantation at diagnosis in patients with mucopolysaccharidosis type I: results of a European consensus procedure.Orphanet J Rare Dis. 2011; 6: 55-62Crossref PubMed Scopus (184) Google Scholar, 14Ghosh A. Miller W. Orchard P.J. Jones S.A. Mercer J. Church H.J. et al.Enzyme replacement therapy prior to haematopoietic stem cell transplantation in Mucopolysaccharidosis Type I: 10 year combined experience of 2 centres.Mol Genet Metab. 2016; 117: 373-377Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar The use of ERT in the peritransplant period has been shown to be safe and has led to clinical improvements particularly in patients with significant cardiopulmonary disease before transplantation. In addition, ERT before transplantation has been reported to alleviate symptoms that may have influenced the conditioning regime or candidacy for transplantation of some patients.14Ghosh A. Miller W. Orchard P.J. Jones S.A. Mercer J. Church H.J. et al.Enzyme replacement therapy prior to haematopoietic stem cell transplantation in Mucopolysaccharidosis Type I: 10 year combined experience of 2 centres.Mol Genet Metab. 2016; 117: 373-377Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Because MPS I is a progressive disorder, the success of both HSCT and ERT depends on early initiation of treatment. Therefore, early identification of patients is critical. Because many of the early disease manifestations represent common childhood symptoms (eg, inguinal/umbilical hernia and recurrent upper respiratory tract infections), diagnosis based on early symptom recognition is challenging and has been met with limited success. Newborn screening (NBS) strategies should be more effective in this regard. MPS I NBS via determination of IDUA activity in dried blood spot (DBS)-derived samples is currently underway in the US15Hopkins P.V. Campbell C. Klug T. Rogers S. Raburn-Miller J. Kiesling J. Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri.J Pediatr. 2015; 166: 172-177Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 16Scott C.R. Elliott S. Buroker N. Thomas L.I. Keutzer J. Glass M. et al.Identification of infants at risk for developing Fabry, Pompe, or mucopolysaccharidosis-I from newborn blood spots by tandem mass spectrometry.J Pediatr. 2013; 163: 498-503Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar and in pilot programs in Taiwan,17Lin S.-P. Lin H.-Y. Wang T.-J. Chang C.-Y. Lin C.-H. Huang S.-F. et al.A pilot newborn screening program for Mucopolysaccharidosis type I in Taiwan.Orphanet J Rare Dis. 2013; 8: 147-154Crossref PubMed Scopus (63) Google Scholar Italy,18Paciotti S. Persichetti E. Pagliardini S. Deganuto M. Rosano C. Balducci C. et al.First pilot newborn screening for four lysosomal storage diseases in an Italian region: identification and analysis of a putative causative mutation in the GBA gene.Clin Chim Acta. 2012; 413: 1827-1831Crossref PubMed Scopus (42) Google Scholar Austria,19Matern D. Gavrilov D. Oglesbee D. Raymond K. Rinaldo P. Tortorelli S. Newborn screening for lysosomal storage disorders.Semin Perinatol. 2015; 39: 206-216Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar and Hungary.19Matern D. Gavrilov D. Oglesbee D. Raymond K. Rinaldo P. Tortorelli S. Newborn screening for lysosomal storage disorders.Semin Perinatol. 2015; 39: 206-216Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar The US Department of Health and Human Services recommended uniform screening panel20US Department of Health and Human Services Advisory committee on heritable disorders in newborns and children.http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendedpanel/index.htmlGoogle Scholar provides the list of core and secondary disorders that should be included in every NBS program. A proposal for MPS I NBS received a positive recommendation by the US Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children,21US Department of Health and Human Services Health Resources and Services Administration Nominate a condition.http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/nominatecondition/reviews/nominatedconditions.pdfGoogle Scholar and the US Secretary approved the addition of MPS I to the recommended uniform screening panel in February 2016. Given the wide clinical spectrum of MPS I and the differences in therapy based on subtype, the precise determination of where a patient fits in the broad spectrum of disease is essential. It is important to note that no currently available biochemical criteria can reliably distinguish phenotypes. Therefore, additional assessments including molecular analysis and skilled clinical assessments are required. Table I summarizes data obtained from the MPS I Registry highlighting the features observed in patients less than 2 years of age. It is important to note that many of the signs and symptoms considered characteristic of MPS I may not necessarily differentiate between attenuated and severe phenotypes, or may not be present in neonates.23de Ru M.H. Teunissen Q.G. van der Lee J.H. Beck M. Bodamer O.A. Clarke L.A. et al.Capturing phenotypic heterogeneity in MPS I: results of an international consensus procedure.Orphanet J Rare Dis. 2012; 7: 22-30Crossref PubMed Google Scholar A summary of the challenges in predicting MPS I disease severity in individuals detected by NBS is summarized in Table II.Table IAnalysis of symptom frequency in patients ≤2 years of age (from Pastores et al22Pastores G.M. Arn P. Beck M. Clarke J.T.R. Guffon N. Kaplan P. et al.The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with Mucopolysaccharidosis Type I.Mol Genet Metab. 2007; 91: 37-47Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar)Symptoms/complicationsPercentage of patients ≤2 y of age with symptomCoarse facies98Valvular disease95Corneal clouding90Hepatomegaly84Upper airway obstruction → OSA82Kyphosis gibbus75Joint contractures72Hernia70Dysostosis multiplex70Cognitive impairment60Enlarged tongue60Splenomegaly60Eustachian tube obstruction → otitis media55Hip dysplasia42Genu valgum38Reactive airway disease37Scoliosis35Carpal tunnel syndrome25Pes cavus18Glaucoma10Heart failure3Cor pulmonale2OSA, obstructive Sleep Apnea. Open table in a new tab Table IIChallenges in predicting disease severity following positive NBS for MPS I•No biochemical criteria reliably distinguish MPS I subtypes•Many signs and symptoms that establish an MPS I diagnosis in older patients do not differentiate between attenuated and severe phenotypes, or are not present in newborns•In the absence of 2 pathogenic IDUA variants previously reported to be associated with defined disease severity, genotype/phenotype correlation is complicated by the existence of private (reported only in single individuals with MPS I) missense mutations that can not be used to predict the phenotype•IDUA enzyme analysis is complicated by pseudo-deficiency because of:•Benign variants•Reduced in vitro enzyme activity in clinically unaffected individuals•Prevalence in African American population Open table in a new tab OSA, obstructive Sleep Apnea. The routine laboratory diagnostic IDUA enzyme assay cannot distinguish between the different phenotypes. Although many biomarkers of MPS have been reported, their ability to reliably distinguish MPS I subtypes, particularly in early infancy, has not been demonstrated.24Clarke L.A. Winchester B. Giugliani R. Tylki-Szymanska A. Amartino H. Biomarkers for the mucopolysaccharidoses: discovery and clinical utility.Mol Genet Metab. 2012; 106: 395-402Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Patients with Hurler syndrome, in general, have higher levels of urine GAG (uGAG) than patients with attenuated disease, but the precise threshold level that distinguishes these subtypes, particularly at early disease stages, is unknown. In sophisticated studies using cultured MPS I fibroblasts and evaluating enzyme kinetics, immunoquantification, and in vitro turnover studies, it was possible to correlate between the genotype, the biochemical phenotype, and clinical course.25Bunge S. Clements P.R. Byers S. Kleijer W.J. Brooks D.A. Hopwood J.J. Genotype-phenotype correlations in mucopolysaccharidosis type I using enzyme kinetics, immunoquantification and in vitro turnover studies.Biochim Biophys Acta. 1998; 1407: 249-256Crossref PubMed Scopus (68) Google Scholar This complex assay requires specific antibodies that make it difficult to reproduce in other laboratories. The analysis of oligosaccharides, derived from heparan sulfate and dermatan sulfate from MPS I fibroblasts and measured by electrospray tandem mass spectrometry, has also been shown to discriminate between patients with and without CNS pathology.26Fuller M. Brooks D.A. Evangelista M. Hein L.K. Hopwood J.J. Meikle P.J. Prediction of neuropathology in mucopolysaccharidosis I patients.Mol Genet Metab. 2005; 84: 18-24Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar These studies require long-term fibroblast cultures and mass spectrometry-based GAG assays. Kingma et al27Kingma S.D. Langereis E.J. De Klerk C.M. Zoetekouw L. Wagemans T. Ijlst L. et al.An algorithm to predict phenotypic severity in mucopolysaccharidosis type I in the first month of life.Orphanet J Rare Dis. 2013; 8: 99-109Crossref PubMed Scopus (29) Google Scholar developed an algorithm to predict clinical severity in MPS I based on genotyping and an optimized IDUA assay, however, this assay is not routinely available. In a preliminary proteomic study, the lysosomal protein β-galactosidase was elevated 3.6- to 5.7-fold in severe but not attenuated MPS I,28Heywood W.E. Camuzeaux S. Doykov I. Patel N. Preece R.-L. Footitt E. et al.Proteomic discovery and development of a multiplexed targeted MRM-LC-MS/MS assay for urine biomarkers of extracellular matrix disruption in Mucopolysaccharidoses I, II, and VI.Anal Chem. 2015; 87: 12238-12244Crossref PubMed Scopus (16) Google Scholar and 1 study has reported that serum heparin-cofactor II-thrombin complex levels can differentiate patients with severe MPS I from patients with attenuated MPS I.29Randall D.R. Colobong K.E. Hemmelgarn H. Sinclair G.B. Hetty E. Thomas A. et al.Heparin cofactor II-thrombin complex: a biomarker of MPS disease.Mol Genet Metab. 2008; 94: 456-461Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar Neither of these studies evaluated the utility of these biomarkers in the neonate or early infant, and, thus, their utility for use in NBS is limited. Over 200 IDUA pathogenic variants have been identified. Because MPS I is an autosomal recessive disorder, both pathogenic alleles are required to be identified to consider using genotype to predict phenotype. An analysis of pathogenic IDUA variants in patients with MPS I has shown clear genotype-phenotype correlations.30Terlato N.J. Cox G.F. Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.Genet Med. 2003; 5: 286-294Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar Homozygosity or compound heterozygosity for common nonsense mutations (eg, p.W402X and p.Q70X) predominated among patients with severe disease, whereas patients with attenuated disease have at least 1 allele that contains a missense or a splice site variant. Although 62% of patient genotypes included at least 1 nonsense allele, all patients with 2 nonsense alleles, whether homozygous or compound heterozygous, had severe disease. However, not all patients with severe disease had nonsense mutations. Up to 70% of pathogenic variants are recurrent and, thus, may be helpful in phenotype prediction. Although genotype-phenotype correlations have been established with some common variants, there are individuals and families with unique missense variants that cannot be used to predict the clinical phenotype.30Terlato N.J. Cox G.F. Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.Genet Med. 2003; 5: 286-294Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 31Li P. Wood T. Thompson J.N. Diversity of mutations and distribution of single nucleotide polymorphic alleles in the human alpha-L-iduronidase (IDUA) gene.Genet Med. 2002; 4: 420-426Crossref PubMed Scopus (29) Google Scholar, 32Beesley C.E. Meaney C.A. Greenland G. Adams V. Vellodi A. Young E.P. et al.Mutational analysis of 85 mucopolysaccharidosis type I families: frequency of known mutations, identification of 17 novel mutations and in vitro expression of missense mutations.Hum Genet. 2001; 109: 503-511Crossref PubMed Scopus (101) Google Scholar The presence of IDUA pseudodeficiency alleles (benign variants) complicates NBS screening for MPS I. Pseudodeficiency is decreased IDUA enzyme activity when measured using current artificial substrates with no evidence of altered GAG metabolism.33Thomas G. “Pseudodeficiencies” of lysosomal hydrolases.Am J Hum Genet. 1994; 54: 934-940PubMed Google Scholar, 34Whitley C.B. Gorlin R.J. Krivit W. A nonpathologic allele (IW) for low alpha-L-iduronidase enzyme activity vis-a-vis prenatal diagnosis of Hurler syndrome.Am J Med Genet. 1987; 28: 233-243Crossref PubMed Google Scholar, 35Aronovich E.L. Pan D. Whitley C.B. Molecular genetic defect underlying alpha-L-iduronidase pseudodeficiency.Am J Hum Genet. 1996; 58: 75-85PubMed Google Scholar IDUA pseudodeficiency alleles can result in decreased enzyme activity when found in the homozygous state or in the compound heterozygous state with another pseudodeficiency allele, a pathogenic variant, or a variant of unknown significance. The Missouri NBS program reported that of 46 infants with a positive NBS screen, 26 had leukocyte IDUA enzyme activity below normal levels but above levels identified in patients with confirmed severe MPS I.36Pollard L. Braddoc S. Christensen K. Boylan D. Heese B. Diagnostic follow-up of 47 infants with a positive newborn screen for Hurler syndrome: identification of four recurrent IDUA sequence changes that significantly reduce enzyme activity.in: APHL meeting, Anaheim, CA. Proceedings of the 2014 APHl newborn screening and genetic testing symposium, Anaheim, CA, October 27-30, 2014. 2014http://www.aphl.org/conferences/Documents/Follow-up-2.pdfGoogle Scholar Follow-up testing showed that uGAG levels in these infants were not indicative of severe MPS I, and no patient was homozygous or compound heterozygous for previously reported pathogenic variants. Four purported pseudodeficiency missense IDUA alleles were identified (p.A79T, p.H82Q, p.D223N, and p.V322E) of which p.A79T was prevalent in the African American population.36Pollard L. Braddoc S. Christensen K. Boylan D. Heese B. Diagnostic follow-up of 47 infants with a positive newborn screen for Hurler syndrome: identification of four recurrent IDUA sequence changes that significantly reduce enzyme activity.in: APHL meeting, Anaheim, CA. Proceedings of the 2014 APHl newborn screening and genetic testing symposium, Anaheim, CA, October 27-30, 2014. 2014http://www.aphl.org/conferences/Documents/Follow-up-2.pdfGoogle Scholar The common finding of pseudodeficiency in individuals detected by NBS complicates the interpretation of confirmatory results, however, this is resolved in most cases by DNA sequencing, which is now considered standard-of-care when the diagnosis of MPS I is being considered. An expert group of North American physicians, clinician scientists, and genetic counselors with experience in MPS I diagnosis, treatment, and management, as well as NBS, convened to review state-of-the-art practices for diagnosis of infants with MPS I identified through NBS programs. The expert group invited to this discussion were defined by virtue of their active participation in the development of diagnostics, clinical trials and/or ongoing clinical evaluation, management of patients with MPS, and participation in NBS programs. Current practice and evidence from both published information and personal experience was reviewed at a meeting in Salt Lake City in March of 2015. Literature review was performed by searching PUBMED with key words: Mucopolysaccharidosis I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, NBS, and lysosomal disorders; the bibliography was provided to attendees before the meeting date. The objective of this review was to develop an algorithm for addressing patient follow-up testing and monitoring given the wide clinical spectrum of MPS I and the different therapeutic recommendations based on disease subtype. Preliminary information on the algorithm developed was presented at the 2015 American Academy of Pediatrics Meeting.37Atherton A. Burton B. Day-Salvatore D. Clarke L. Kaplan P. Leslie N. et al.Guidelines for the diagnosis and management of infants with MPS I identified through newborn screening.https://aap.confex.com/aap/2015/webprogrampress/Paper31844.htmlDate: 2015Google Scholar Currently, NBS programs for MPS I begin with analysis of IDUA activity measured directly from the DBS. Available screening assays include fluorometric,15Hopkins P.V. Campbell C. Klug T. Rogers S. Raburn-Miller J. Kiesling J. Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri.J Pediatr. 2015; 166: 172-177Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 18Paciotti S. Persichetti E. Pagliardini S. Deganuto M. Rosano C. Balducci C. et al.First pilot newborn screening for four lysosomal storage diseases in an Italian region: identification and analysis of a putative causative mutation in the GBA gene.Clin Chim Acta. 2012; 413: 1827-1831Crossref PubMed Scopus (42) Google Scholar digital microfluidics,15Hopkins P.V. Campbell C. Klug T. Rogers S. Raburn-Miller J. Kiesling J. Lysosomal storage disorder screening implementation: findings from the first six months of full population pilot testing in Missouri.J Pediatr. 2015; 166: 172-177Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar and tandem mass spectrometry-based analyses.38Ombrone D. Malvagia S. Funghini S. Giocaliere E. Bona Della M.L. Forni G. et al.Screening of lysosomal storage disorders: application of the online trapping-and-cleanup liquid chromatography/mass spectrometry method for mucopolysaccharidosis I.Eur J Mass Spectrom (Chichester). 2013; 19: 497-503Crossref PubMed Scopus (5) Google Scholar, 39Chennamaneni N.K. Kumar A.B. Barcenas M. Spacil Z. Scott C.R. Turecek F. et al.Improved reagents for newborn screening of mucopolysaccharidosis types I, II, and VI by tandem mass spectrometry.Anal Chem. 2014; 86: 4508-4514Crossref PubMed Scopus (36) Google Scholar, 40Gucciardi A. Legnini E. Di Gangi I.M. Corbetta C. Tomanin R. Scarpa M. et al.A column-switching HPLC-MS/MS method for mucopolysaccharidosis type I analysis in a multiplex assay for the simultaneous newborn screening of six lysosomal storage disorders.Biomed Chromatogr. 2014; 28: 1131-1139Crossref PubMed Scopus (12) Google Scholar, 41Tomatsu S. Kubaski F. Sawamoto K. Mason R.W. Yasuda E. Shimada T. et al.Newborn screening and diagnosis of mucopolysaccharidoses: application of tandem mass spectrometry.Nihon Masu Sukuriningu Gakkai Shi. 2014; 24: 19-37PubMed Google Scholar MPS I screening may be included in multiplex assays that include screens for multiple lysosomal storage disorders in a single DBS sample.40Gucciardi A. Legnini E. Di Gangi I.M. Corbetta C. Tomanin R. Scarpa M. et al.A column-switching HPLC-MS/MS method for mucopolysaccharidosis type I analysis in a multiplex assay for the simultaneous newborn screening of six lysosomal storage disorders.Biomed Chromatogr. 2014; 28: 1131-1139Crossref PubMed Scopus (12) Google Scholar If IDUA levels are below established cut-off values, the process outlined in the algorithm in the Figure is proposed to confirm and delineate disease severity, and guide appropriate follow-up and treatment. The main concept underlying this algorithm is the critical importance of precisely defining the phenotype of the patient with particular emphasis on ensuring that patients with Hurler syndrome be identified and directed to transplantation programs. The approaches used for enzyme analysis from the NBS card uses artificial substrates and are similar to the methodology that is used for the diagnostic assay albeit with a much smaller sample volume. Because of the latter consideration, a repeat assay using a fresh blood sample is required after a positive NBS. The issue of pseudodeficiency relates to the use of the artificial substrates that are used to measure iduronidase enzyme activity. Both the NBS assays and the diagnostic assay use these artificial substrates and, thus, are not able to distinguish pseudodeficiency from true deficiency. The frequency of pseudodeficiency will be different in different populations; data to date suggests that the frequency is highest within the African American population. At this time, there does not appear to be straightforward means using the initial NBS card to definitively and accurately exclude a diagnosis of MPS I after the positive NBS result. Nevertheless, the seriousness of MPS I and the critical need for early treatment initiation particularly for individuals with Hurler syndrome necessitates the steps that follow. Confirmatory IDUA enzyme analysis (from fresh blood leukocytes, serum, or plasma) should be performed for all DBS-positive newborn samples, ideally arranged by a geneticist/metabolic disease team. A normal level of enzyme activity in the confirmatory assay is indicative of a false positive DBS assay thus excluding a diagnosis of MPS I. Following a positive confirmatory enzyme assay, all patients should be urgently assessed by a genetic/metabolic disease specialist for further clinical, molecular, and biochemical assessments. Because the turnaround time for the confirmatory enzyme analysis would be approximately 1 week and, if positive, the subsequent step of IDUA gene sequencing would have an approximate 3 weeks turnaround time, it is anticipated that screening programs would likely obtain both samples at the initial time of patient recall and not proceed to IDUA gene sequencing until IDUA deficiency is confirmed. It is anticipated that advances in sequencing technologies could result in a more rapid turnaround for this step. Because of the complex nature of the discussion, the initial patient recall should be communicated to the family and organized by a genetics/metabolic team that is well versed in this condition
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