scholarly journals Newborn Screening for Mucopolysaccharidosis I: Moving Forward Learning from Experience

2020 ◽  
Vol 6 (4) ◽  
pp. 91
Author(s):  
Lorne A. Clarke ◽  
Patricia Dickson ◽  
N. Matthew Ellinwood ◽  
Terri L. Klein
Keyword(s):  
Newborn Screening ◽  
Predictive Value ◽  
Learning From Experience ◽  
Mucopolysaccharidosis I ◽  
Screening Programs ◽  
Screening Protocol ◽  
Second Tier ◽  
Mps I ◽  
Recent Evaluation

There have been significant advances allowing for the integration of mucopolysaccharidosis I into newborn screening programs. Initial experiences using a single-tier approach for this disorder have highlighted shortcomings that require immediate remediation. The recent evaluation of a second-tier biomarker integrated into the MPS I newborn screening protocol has been demonstrated to greatly improve the precision and predictive value of newborn screening for this disorder. This commentary urges newborn screening programs to learn from these experiences and improve newborn screening for mucopolysaccharidosis I and future mucopolysaccharidoses newborn screening programs by implementation of a second-tier biomarker analyte.

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 Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985–2019)

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Hsiang-Yu Lin ◽  
Chung-Lin Lee ◽  
Chia-Ying Chang ◽  
Pao Chin Chiu ◽  
Yin-Hsiu Chien ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Newborn Screening ◽  
Metabolic Diseases ◽  
Therapeutic Interventions ◽  
Multiple Sources ◽  
Taiwanese Population ◽  
Screening Programs ◽  
Different Types ◽  
Mps I ◽  
Diagnostic Age

Abstract Background Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs. Methods An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated. Results Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p < 0.01). Pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively introduced in Taiwan from 2016, and 48% (16/33) of MPS patients diagnosed between 2016 and 2019 were diagnosed by one of these screening programs, with a median diagnostic age at 0.2 years. For patients born between 2016 and 2019, up to 94% (16/17) were diagnosed with MPS via the newborn screening programs. At the time of this study, 81 patients had passed away with a median age at death of 15.6 years. Age at diagnosis was positively correlated with life expectancy (p < 0.01). Life expectancy also significantly increased between 1985 and 2019, however this increase was gradual (p < 0.01). Conclusions The life expectancy of Taiwanese patients with MPS has improved in recent decades and patients are being diagnosed earlier. Because of the progressive nature of the disease, early diagnosis by newborn screening programs and timely implementation of early therapeutic interventions may lead to better clinical outcomes.

scholarly journals Impact of Newborn Screening on Clinical Presentation of Congenital Adrenal Hyperplasia

Medicina ◽  
2021 ◽  
Vol 57 (10) ◽  
pp. 1035
Author(s):  
Rūta Navardauskaitė ◽  
Kornelija Banevičiūtė ◽  
Jurgita Songailienė ◽  
Kristina Grigalionienė ◽  
Darius Čereškevičius ◽  
...  
Keyword(s):  
Positive Predictive Value ◽  
Congenital Adrenal Hyperplasia ◽  
Newborn Screening ◽  
Sensitivity And Specificity ◽  
Serum Potassium ◽  
Predictive Value ◽  
Clinical Presentation ◽  
Adrenal Hyperplasia ◽  
Salt Wasting ◽  
Screening Programs

Background and Objectives: The main reason for Newborn screening (NBS) for congenital adrenal hyperplasia (CAH) is to prevent adrenal insufficiency that can lead to life-threatening conditions. On the other hand, screening programs are not always sensitive and effective enough to detect the disease. We aimed to evaluate impact of the national NBS on the clinical presentation of patients with CAH in Lithuania. Materials and Methods: A retrospective study was performed on data of 88 patients with CAH from 1989 to 2020. Patients with confirmed CAH were divided into two groups: (1) 75 patients diagnosed before NBS: 52 cases with salt-wasting (SW), 21 with simple virilising (SV) and two with non-classical (NC) form; (2) 13 patients diagnosed with NBS: 12 cases with SW and 1 case with SV form. For the evaluation of NBS effectiveness, data of only male infants with salt-wasting CAH were analysed (n = 36, 25 unscreened and nine screened). Data on gestational age, birth weight, weight, symptoms, and laboratory tests (serum potassium and sodium levels) on the day of diagnosis, were analysed. Results: A total of 158,486 neonates were screened for CAH from 2015 to 2020 in Lithuania and CAH was confirmed in 13 patients (12 SW, one–SV form), no false negative cases were found. The sensitivity and specificity of NBS program for classical CAH forms were 100%; however, positive predictive value was only 4%. There were no significant differences between unscreened and screened male infant groups in terms of age at diagnosis, serum potassium, and serum sodium levels. Significant differences were found in weight at diagnosis between the groups (−1.67 ± 1.12 SDS versus 0.046 ± 1.01 SDS of unscreened and screened patients respectively, p = 0.001). Conclusions: The sensitivity and specificity of NBS for CAH program were 100%, but positive predictive value—only 4%. Weight loss was significantly lower and the weight SDS at diagnosis was significantly higher in the group of screened patients.

scholarly journals Measurement of 17-Hydroxyprogesterone by LCMSMS Improves Newborn Screening for CAH Due to 21-Hydroxylase Deficiency in New Zealand

2020 ◽  
Vol 6 (1) ◽  
pp. 6 ◽  
Author(s):  
Mark R. de Hora ◽  
Natasha L. Heather ◽  
Tejal Patel ◽  
Lauren G. Bresnahan ◽  
Dianne Webster ◽  
...  
Keyword(s):  
New Zealand ◽  
Positive Predictive Value ◽  
Newborn Screening ◽  
Predictive Value ◽  
False Positive ◽  
Screening Tests ◽  
Hydroxylase Deficiency ◽  
Second Tier ◽  
17 Hydroxyprogesterone ◽  
21 Hydroxylase Deficiency

The positive predictive value of newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency was <2% in New Zealand. This is despite a bloodspot second-tier immunoassay method for 17-hydroxyprogesterone measurement with an additional solvent extract step to reduce the number of false positive screening tests. We developed a liquid chromatography tandem mass spectrometry (LCMSMS) method to measure 17-hydroxyprogesterone in bloodspots to replace our current second-tier immunoassay method. The method was assessed using reference material and residual samples with a positive newborn screening result. Correlation with the second-tier immunoassay was determined and the method was implemented. Newborn screening performance was assessed by comparing screening metrics 2 years before and 2 years after LCMSMS implementation. Screening data analysis demonstrated the number of false positive screening tests was reduced from 172 to 40 in the 2 years after LCMSMS implementation. The positive predictive value of screening significantly increased from 1.71% to 11.1% (X2 test, p < 0.0001). LCMSMS analysis of 17OHP as a second-tier test significantly improves screening specificity for CAH due to 21-hydroxylase deficiency in New Zealand.

Birthweight or Gestational Age Adjusted Second Tier LCMSMS Cut-offs Improve Newborn Screening for CAH in New Zealand

2021 ◽  
Author(s):  
Mark R de Hora ◽  
Natasha L Heather ◽  
Dianne Webster ◽  
Benjamin B Albert ◽  
Paul L Hofman
Keyword(s):  
New Zealand ◽  
Positive Predictive Value ◽  
Newborn Screening ◽  
Gestational Age ◽  
Predictive Value ◽  
False Positive ◽  
Age Groups ◽  
Screening Tests ◽  
Ratio Measurement ◽  
Second Tier

Abstract Context The positive predictive value of newborn screening for CAH in New Zealand is approximately 10%. The use of a second tier liquid chromatography tandem mass spectrometry bloodspot steroid profile test with birthweight or gestational age adjusted screening cut-offs may result in further screening improvements. Methods Three years of newborn screening data with additional second tier steroid metabolites was evaluated (n=167672 births). Data from babies with a negative screening test and confirmed CAH cases were compared. First and second-tier steroid measurements were correlated with both birthweight and with gestational age. Analysis of variance was used to determine birthweight and gestational age groups. Screening cut-offs were determined and applied retrospectively to model screening performance. Results First tier immunoassay data correlated better with gestational age than with birthweight but there was no difference with second tier steroid measurements. Four distinct birthweight and gestational age groups were established for 17-hydroxyprogesterone and a steroid ratio measurement. Application of 97.5 th percentile second tier birthweight or gestational age adjusted cut-offs would result in 10 positive tests over the period of the study with 8 true positive screens and 2 false positive tests. The positive predictive value of screening would be increased from 10.8% to 80%. Conclusions The use of either birthweight or gestational age adjusted cut-offs for second tier screening tests can significantly reduce the false positive rate of newborn screening for congenital adrenal hyperplasia in New Zealand without loss in screening sensitivity.

scholarly journals Diagnosis of Classic Homocystinuria in Two Boys Presenting with Acute Cerebral Venous Thrombosis and Neurologic Dysfunction after Normal Newborn Screening

2021 ◽  
Vol 7 (3) ◽  
pp. 48
Author(s):  
Alexander Asamoah ◽  
Sainan Wei ◽  
Kelly E. Jackson ◽  
Joseph H. Hersh ◽  
Harvey Levy
Keyword(s):  
Magnetic Resonance ◽  
Newborn Screening ◽  
Metabolic Disorders ◽  
False Negative ◽  
Screening Programs ◽  
Neurologic Dysfunction ◽  
Organ Systems ◽  
Newborn Screen ◽  
Total Homocysteine ◽  
Second Tier

Homocystinuria, caused by cystathionine β-synthase deficiency, is a rare inherited disorder involving metabolism of methionine. Impaired synthesis of cystathionine leads to accumulation of homocysteine that affects several organ systems leading to abnormalities in the skeletal, cardiovascular, ophthalmic and central nervous systems. We report a 14-month-old and a 7-year-old boy who presented with neurologic dysfunction and were found to have cerebral venous sinus thromboses on brain magnetic resonance imaging (MRI)/magnetic resonance venogram (MRV) and metabolic and hypercoagulable work-up were consistent with classic homocystinuria. The 14-month-old boy had normal newborn screening. The 7-year-old boy initially had an abnormal newborn screen for homocystinuria but second tier test that consisted of total homocysteine was normal, so his newborn screen was reported as normal. With the advent of expanded newborn screening many treatable metabolic disorders are detected before affected infants and children become symptomatic. Methionine is the primary target in newborn screening for homocystinuria and total homocysteine is a secondary target. Screening is usually performed after 24–48 h of life in most states in the US and some states perform a second screen as a policy on all tested newborns or based on when the initial newborn screen was performed. This is done in hopes of detecting infants who may have been missed on their first screen. In the United Kingdom, NBS using dried blood spot is performed at 5 to 8 days after birth. It is universally known that methionine is a poor target and newborn screening laboratories have used different cutoffs for a positive screen. Reducing the methionine cutoff increases the sensitivity but not necessarily the specificity of the test and increasing the cutoff will miss babies who may have HCU whose levels may not be high enough to be detected at their age of ascertainment. It is not clear whether adjusting methionine level to decrease the false negative rates combined with total homocysteine as a second-tier test can be used effectively and feasibly to detect newborns with HCU. Between December 2005 and December 2020, 827,083 newborns were screened in Kentucky by MS/MS. Kentucky NBS program uses the postanalytical tools offered by the Collaborative Laboratory Integrated Reports (CLIR) project which considers gestational age and birthweight. One case of classical homocystinuria was detected and two were missed on first and second tier tests respectively. The newborn that had confirmed classical homocystinuria was one of twenty-three newborns that were referred for second tier test because of elevated methionine (cutoff is >60 µmol/L) and/or Met/Phe ratio (cutoff is >1.0); all 23 dried blood spots had elevated total homocysteine. One of the subjects of this case report had a normal methionine on initial screen and the other had a normal second-tier total homocysteine level. The performance of methionine and total homocysteine as screening analytes for homocystinuria suggest that it may be time for newborn screening programs to consider adopting next generation sequencing (NGS) platforms as alternate modality of metabolic newborn screening. Because of cost considerations, newborn screening programs may not want to adopt NGS, but the downstream healthcare cost incurred due to missed cases and the associated morbidity of affected persons far exceed costs to newborn screen programs. Since NGS is becoming more widely available and inexpensive, it may be feasible to change testing algorithms to use Newborn Metabolic NGS as the primary mode of testing on dry blood specimens with confirmation with biochemical testing. Some commercial laboratories have Newborn Screening Metabolic gene panel that includes all metabolic disorders on the most comprehensive newborn screening panel in addition to many other conditions that are not on the panel. A more targeted NGS panel can be designed that may not cost much and eventually help avoid the pitfalls associated with delayed diagnosis and cost of screening.

scholarly journals Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985-2019)

2020 ◽  
Author(s):  
Hsiang-Yu Lin ◽  
Chung-Lin Lee ◽  
Chia-Ying Chang ◽  
Pao Chin Chiu ◽  
Yin-Hsiu Chien ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Newborn Screening ◽  
Metabolic Diseases ◽  
Therapeutic Interventions ◽  
Multiple Sources ◽  
Taiwanese Population ◽  
Screening Programs ◽  
Different Types ◽  
Mps I ◽  
Diagnostic Age

Abstract Background Mucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs.Methods An epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated.Results Between 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p<0.01). Pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively introduced in Taiwan from 2016, and 48% (16/33) of MPS patients diagnosed between 2016 and 2019 were diagnosed by one of these screening programs, with a median diagnostic age at 0.2 years. For patients born between 2016 and 2019, up to 94% (16/17) were diagnosed with MPS via the newborn screening programs. At the time of this study, 81 patients had passed away with a median age at death of 15.6 years. Age at diagnosis was positively correlated with life expectancy (p<0.01). Life expectancy also significantly increased between 1985 and 2019, however this increase was gradual (p<0.01).Conclusions The life expectancy of Taiwanese patients with MPS has improved in recent decades and patients are being diagnosed earlier. Because of the progressive nature of the disease, early diagnosis by newborn screening programs and timely implementation of early therapeutic interventions may lead to better clinical outcomes.

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 Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I

2020 ◽  
Vol 6 (3) ◽  
pp. 69 ◽  
Author(s):  
Zackary M. Herbst ◽  
Leslie Urdaneta ◽  
Terri Klein ◽  
Maria Fuller ◽  
Michael H. Gelb
Keyword(s):  
False Positive ◽  
Reference Range ◽  
Severe Disease ◽  
False Positive Rate ◽  
Dried Blood Spots ◽  
Mucopolysaccharidosis I ◽  
Blood Spots ◽  
Positive Rate ◽  
Second Tier ◽  
Mps I

All newborn screening (NBS) for mucopolysaccharidosis-I (MPS-I) is carried out by the measurement of α-iduronidase (IDUA) enzymatic activity in dried blood spots (DBS). The majority of low enzyme results are due to pseudodeficiencies, and studies from the Mayo Clinic have shown that the false positive rate can be greatly reduced by including a second-tier analysis of glycosaminoglycans (GAGs) in DBS as part of NBS. In the present study, we obtained newborn DBS from 13 patients with severe MPS-I and 2 with attenuated phenotypes. These samples were submitted to four different GAG mass spectrometry analyses in a comparative study: (1) internal disaccharide; (2) endogenous disaccharide; (3) Sensi-Pro; (4) Sensi-Pro Lite (a variation of Sensi-Pro with a simplified workflow). Patients with attenuated MPS-I show less GAG elevation than those with severe disease, and all MPS-I patients were separated from the reference range using all four methods. The minimal differential factor (lowest GAG marker level in MPS-I samples divided by highest level in the reference range of 30 random newborns) was about two for internal disaccharide, Sensi-Pro, and Sensi-Pro Lite methods. The endogenous disaccharide was clearly the best method with a minimal differential of 16-fold. This study supports use of second-tier GAG analysis of newborn DBS, especially the endogenous disaccharide method, as part of NBS to reduce the false positive rate.

scholarly journals Survival and diagnostic age of 175 Taiwanese patients with mucopolysaccharidoses (1985-2019)

2020 ◽  
Author(s):  
Hsiang-Yu Lin ◽  
Chung-Lin Lee ◽  
Chia-Ying Chang ◽  
Pao Chin Chiu ◽  
Yin-Hsiu Chien ◽  
...  
Keyword(s):  
Life Expectancy ◽  
Newborn Screening ◽  
Metabolic Diseases ◽  
Therapeutic Interventions ◽  
Multiple Sources ◽  
Taiwanese Population ◽  
Screening Programs ◽  
Different Types ◽  
Mps I ◽  
Diagnostic Age

Abstract BackgroundMucopolysaccharidoses (MPSs) are a group of inherited metabolic diseases, which are characterized by the accumulation of glycosaminoglycans, and eventually lead to the progressive damage of various tissues and organs.MethodsAn epidemiological study of MPS in Taiwan was performed using multiple sources. The survival and diagnostic age for different types of MPS between 1985 and 2019 were evaluated.ResultsBetween 1985 and 2019, there were 175 patients diagnosed with MPS disorders in the Taiwanese population, with a median diagnostic age of 3.9 years. There were 21 (12%), 78 (45%), 33 (19%), 32 (18%) and 11 (6%) patients diagnosed with MPS I, II, III, IV and VI, respectively, with median diagnostic ages of 1.5, 3.8, 4.7, 4.5 and 3.7 years, respectively. Diagnosis of MPS patients was significantly earlier in recent decades (p<0.01). Pilot newborn screening programs for MPS I, II, VI, IVA, and IIIB were progressively introduced in Taiwan from 2016, and 48% (16/33) of MPS patients diagnosed between 2016 and 2019 were diagnosed by one of these screening programs, with a median diagnostic age at 0.2 years. For patients born between 2016 and 2019, up to 94% (16/17) were diagnosed with MPS via the newborn screening programs. At the time of this study, 81 patients had passed away with a median age at death of 15.6 years. Age at diagnosis was positively correlated with life expectancy (p<0.01). Life expectancy also significantly increased between 1985 and 2019, however this increase was gradual (p<0.01).ConclusionsThe life expectancy of Taiwanese patients with MPS has improved in recent decades and patients are being diagnosed earlier. Because of the progressive nature of the disease, early diagnosis by newborn screening programs and timely implementation of early therapeutic interventions may lead to better clinical outcomes.

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