scholarly journals Two-Tiered Newborn Screening with Post-Analytical Tools for Pompe Disease and Mucopolysaccharidosis Type I Results in Performance Improvement and Future Direction

2020 ◽  
Vol 6 (1) ◽  
pp. 2 ◽  
Author(s):  
Patricia L. Hall ◽  
Rossana Sanchez ◽  
Arthur F. Hagar ◽  
S. Caleb Jerris ◽  
Angela Wittenauer ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Pompe Disease ◽  
Late Onset ◽  
Screening Program ◽  
Molecular Testing ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Analytical Tools ◽  
Mps I

We conducted a pilot newborn screening (NBS) study for Pompe disease (PD) and mucopolysaccharidosis type I (MPS I) in the multiethnic population of Georgia. We screened 59,332 infants using a two-tier strategy of flow injection tandem mass spectrometry (FIA-MSMS) enzyme assays. The first tier of testing was a 2-plex assay measuring PD and MPS I enzyme activity, followed by a second-tier test with additional enzymes to improve specificity. Interpretation of results was performed using post-analytical tools created using Collaborative Laboratory Integrated Reports (CLIR). We identified a single case of infantile onset PD, two cases of late onset PD, and one pseudodeficiency. The positive predictive value (PPV) for PD screening during the study was 66.7%. No cases of MPS I were identified during the study period, but there were 2 confirmed cases of pseudodeficiency and 6 cases lost to follow up. The two-tier screening strategy was successful in reducing false positive results and allowed for the identification and early treatment of a case of infantile PD but the frequency of pseudodeficiency in MPS I is problematic. Molecular testing is required and should be covered by the screening program to avoid delays in case resolution.

scholarly journals Implementing Statewide Newborn Screening for New Disorders: U.S. Program Experiences

2020 ◽  
Vol 6 (2) ◽  
pp. 35 ◽  
Author(s):  
Yvonne Kellar-Guenther ◽  
Sarah McKasson ◽  
Kshea Hale ◽  
Sikha Singh ◽  
Marci K. Sontag ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Screening Program ◽  
Muscular Atrophy ◽  
Survival Curve ◽  
Type I ◽  
Mucopolysaccharidosis Type I ◽  
Newborn Screening Program ◽  
Mps I ◽  
Insight Into

Data were collected from 39 newborn screening (NBS) programs to provide insight into the time and factors required for implementing statewide screening for Pompe, Mucopolysaccharidosis type I (MPS I), adrenoleukodystrophy (ALD), and Spinal Muscular Atrophy (SMA). Newborn screening program readiness to screen statewide for a condition was assessed using four phases: (1) approval to screen; (2) laboratory, follow-up, and information technology capabilities; (3) education; and (4) implementation of statewide newborn screening. Seventeen states (43.6%) reached statewide implementation for at least one new disorder. Those states reported that it took 28 months to implement statewide screening for Pompe and MPS I, 30.5 months for ALD, and 20 months for SMA. Using survival curve analysis to account for states still in progress, the estimated median time to statewide screening increased to 75 months for Pompe and 66 months for MPS I. When looking at how long each readiness component took to complete, laboratory readiness was one of the lengthier processes, taking about 39 months. Collaboration with other NBS programs and hiring were the most frequently mentioned facilitators to implementing newborn screening. Staffing or inability to hire both laboratory and follow-up staff was the most frequently mentioned barrier.

scholarly journals Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

2020 ◽  
Vol 6 (1) ◽  
pp. 10 ◽  
Author(s):  
Dawn S. Peck ◽  
Jean M. Lacey ◽  
Amy L. White ◽  
Gisele Pino ◽  
April L. Studinski ◽  
...  
Keyword(s):  
Newborn Screening ◽  
False Positive ◽  
Dermatan Sulfate ◽  
False Positive Rate ◽  
False Negative ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Second Tier ◽  
Mps I

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

scholarly journals Report of Five Years of Experience in Neonatal Screening for Mucopolysaccharidosis Type I and Review of the Literature

2020 ◽  
Vol 6 (4) ◽  
pp. 85 ◽  
Author(s):  
Vincenza Gragnaniello ◽  
Daniela Gueraldi ◽  
Laura Rubert ◽  
Francesca Manzoni ◽  
Chiara Cazzorla ◽  
...  
Keyword(s):  
Early Diagnosis ◽  
Early Treatment ◽  
Molecular Testing ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Years Of Experience ◽  
Enzyme Replacement ◽  
Second Tier ◽  
Mps I

Mucopolysaccharidosis type I (MPS I) is a progressive lysosomal storage disease, with neurological and visceral involvement, in which early diagnosis through newborn screening (NBS) and early treatment can improve outcomes. We present our first 5 years of experience with laboratory and clinical management of NBS for MPS I. Since 2015, we have screened 160,011 newborns by measuring α-L-iduronidase (IDUA) activity and, since 2019, glycosaminoglycans (GAGs) in dried blood spot (DBS) as a second-tier test. Positive screening patients were referred to our clinic for confirmatory clinical and molecular testing. We found two patients affected by MPS I (incidence of 1:80,005). Before the introduction of second-tier testing, we found a high rate of false-positives due to pseudodeficiency. With GAG analysis in DBS as a second-tier test, no false-positive newborns were referred to our clinic. The confirmed patients were early treated with enzyme replacement therapy and bone-marrow transplantation. For both, the clinical outcome of the disease is in the normal range. Our experience confirms that NBS for MPS I is feasible and effective, along with the need to include GAG assay as a second-tier test. Follow-up of the two positive cases identified confirms the importance of early diagnosis through NBS and early treatment to improve the outcome of these patients.

scholarly journals A pilot newborn screening program for Mucopolysaccharidosis type I in Taiwan

2013 ◽  
Vol 8 (1) ◽  
pp. 147 ◽  
Author(s):  
Shuan-Pei Lin ◽  
Hsiang-Yu Lin ◽  
Tuen-Jen Wang ◽  
Chia-Ying Chang ◽  
Chia-Hui Lin ◽  
...  
Keyword(s):  
Newborn Screening ◽  
Screening Program ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Newborn Screening Program

scholarly journals The combined use of enzyme activity and metabolite assays as a strategy for newborn screening of mucopolysaccharidosis type I

2020 ◽  
Vol 58 (12) ◽  
pp. 2063-2072 ◽  
Author(s):  
Giulia Polo ◽  
Daniela Gueraldi ◽  
Antonella Giuliani ◽  
Laura Rubert ◽  
Chiara Cazzorla ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Newborn Screening ◽  
False Positives ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Hematopoietic Stem ◽  
Enzyme Replacement ◽  
Second Tier ◽  
Mps I

AbstractObjectivesMucopolysaccharidosis type I (MPS I) was added to our expanded screening panel in 2015. Since then, 127,869 newborns were screened by measuring α-L-iduronidase (IDUA) enzyme activity with liquid chromatography tandem mass spectrometry (LC-MS/MS). High false positives due to frequent pseudodeficiency alleles prompted us to develop a second-tier test to quantify glycosaminoglycan (GAG) levels in dried blood spot (DBS).MethodsHeparan-sulfate (HS) and dermatan-sulfate (DS) were measured with LC-MS/MS after methanolysis. DBSs were incubated with methanolic-HCl 3 N at 65 °C for 45 min. Chromatographic separation used an amide column with a gradient of acetonitrile and water with 10 mM ammonium acetate in a 9-min run. The method was validated for specificity, linearity, lower limit of quantification (LOQ), accuracy and precision.ResultsIntra- and inter-day coefficients of variation were <15% for both metabolites. Reference values in 40 healthy newborns were: HS mean 1.0 mg/L, 0–3.2; DS mean 1.5 mg/L, 0.5–2.7). The two confirmed newborn MPS I patients had elevated HS (4.9–10.4 mg/L, n.v. <3.2) and DS (7.4–8.8 mg/L, n.v. <2.7). Since its introduction in February 2019, the second-tier test reduced the recall rate from 0.046% to 0.006%. Among 127,869 specimens screened, the incidence was 1:63,935 live births. Both patients started enzyme replacement therapy (ERT) within 15 days of birth and one of them received allogenic hematopoietic stem cell transplantation (HSCT) at ht age of 6 months.ConclusionsGAGs in DBS increased the specificity of newborn screening for MPS I by reducing false-positives due to heterozygosity or pseudodeficiency. Early diagnosis and therapeutical approach has improved the outcome of our patients with MPS I.

scholarly journals Sexual behaviour in a murine model of mucopolysaccharidosis type I (MPS I)

PLoS ONE ◽  
2019 ◽  
Vol 14 (12) ◽  
pp. e0220429 ◽  
Author(s):  
Ana Barbosa Mendes ◽  
Cinthia Castro do Nascimento ◽  
Vânia D’Almeida
Keyword(s):  
Sexual Behaviour ◽  
Murine Model ◽  
Type I ◽  
Mucopolysaccharidosis Type ◽  
Mucopolysaccharidosis Type I ◽  
Mps I

scholarly journals Mucopolysaccharidosis type I - Clinical and genetic characteristics of Romanian patients

2020 ◽  
Vol 28 (3) ◽  
pp. 279-286
Author(s):  
Camelia Alkhzouz ◽  
Cecilia Lazea ◽  
Diana Miclea ◽  
Carmen Asavoaie ◽  
Ioana Nascu ◽  
...  
Keyword(s):  
Severe Form ◽  
The Other ◽  
Compound Heterozygous ◽  
Type I ◽  
Ophthalmological Examination ◽  
Mucopolysaccharidosis Type ◽  
Hurler Syndrome ◽  
Mucopolysaccharidosis Type I ◽  
Genetic Characteristics ◽  
Mps I

AbstractBackground: Mucopolysaccharidosis type I (MPS I) is an autosomal recessive lysosomal storage disorder caused by a deficiency of α-L-iduronidase (IDUA), which leads to the accumulation of partially digested glycosaminoglycans (dermatan sulfate and heparan sulfate) in the lysosomes and induces multisystemic alteration. Hurler (severe), Scheie (mild), and Hurler/Scheie (intermediate) syndromes are clinical subtypes of MPS-I. To date, more than 290 IDUA mutations have been reported. The purpose of this study was to present the clinical and genetic characteristics of Romanian MPS I syndrome patients and their genotype-phenotype correlation.Patients and methods: Seven patients (5 girls and 2 boys) with MPS type I, belonging to 4 unrelated families, aged 0,75-17.9 years, were enrolled. The study methods consisted in: clinical and standard auxological assessment, bone radiographs, joint ultrasonography, goniometry, neurological and psychological evaluation, hepatic and splenic ultrasonography, cardiological evaluation, otorhinolaryngology examination, ophthalmological examination, spirometry, α-L-iduronidase enzyme activity assay and molecular analysis.Results: The seven patients originated from 4 unrelated families, three patients with severe, two patients with intermediate and two with attenuated clinical phenotype. Each patient presented the classical picture of MPS type I picture, represented by: variable coarse facial features, arthropathy, hepatosplenomegaly, cardiac involvement, respiratory dysfunction and neurological impairment. Five patological variants, three point mutations (p.Q70 *, p.I238Q and p.K324R), two deletion c.1045_1047delGAC, c.46_57delTCGCTCCTG) and an insertion (c.1389 insC) were identified in both alleles of the ADUA gene in homozygous or heterozygous form. Two novel mutations (p.K324R and c.1389 insC) were reported. The p.Q70*(c.208C>T) variant was identified in 2 families with severe form of disease (Hurler syndrome) in homozygous status in one family and in compound heterozygous status in the other family.Conclusion: The p.Q70* missense variant was the most frequent, correlated in all the cases who presented it with severe form, Hurler syndrome, the other mutations being usually isolated and particular for each patient, associated in our patients with less severe MPS I phenotype, as Hurler-Scheie or Scheie syndrome. The results of this study indicated the mutational heterogeneity of the IDUA gene and the difficulty to indicate some correlation between the genotype and phenotype in MPS I patients.

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