Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS
Abstract
:1. Introduction
2. Materials and Methods
2.1. Studied Subjects
2.2. Routine Biochemical Screening
2.3. Second Tier Tests (2TT)
3. Results and Discussion
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Correction Statement
References
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Screened Disorders | OMIM | Cut-Offs and Ratios | |
---|---|---|---|
Amino Acid Disorders (AAD) | Phenylketonuria (PKU)/Hyperphenylalaninemia (HPhe) | 261600 | Phe (>150 μM) and Phe/Tyr (>1.5) |
Maple syrup urine disease (MSUD) | 248600 | XLeu (>270 μM) and Val (>285 μM) Val/Phe > 4, Xleu/Phe > 5 | |
Tyrosinemia type I (TYR1) | 276700 | Tyr (>210 μM) selects for 2TT (SA) | |
Tyrosinemia type II (TYR2) | 276600 | Tyr (>500 μM) selects for 2TT | |
Tyrosinemia type III (TYR3) | 276710 | Tyr (>500 μM) selects for 2TT | |
Homocystinuria (CBS deficiency) | 236200 | Met (>45 μM) selects for 2TT | |
Methionine adenosyltransferase deficiency (MATI/III deficiency) | 250850 | Met (>45 μM) selects for 2TT | |
Organic Acidurias (OA) | 3-Methyl crotonyl-CoA carboxylase deficiency (3-MCCD) | 210200 | C5OH (>1.0 μM) |
Isovaleric acidemia (IVA) | 243500 | C5 (>1.0 μM) selects for 2TT | |
Propionic acidemia (PA) | 606054 | C3 (>5.25 μM) or C3/C2 (>0.2) selects for 2TT | |
Methylmalonic acidemia (MMA Mut-/Mut0) | 251000 | C3 (>5.25 μM) or C3/C2 (>0.2) selects for 2TT | |
Malonic acidemia (MAL) | 248360 | C3DC (>0.35 μM) | |
Glutaric acidemia type I (GA1) | 231670 | C5DC (>0.2 μM) | |
3-Hydroxy-3-methylglutaryl CoA lyase deficiency (3HMGLD) | 246450 | C5OH (>1.0 μM) and C6DC (>0.07 μM) | |
Methylmalonic acidemia type CblA/B (MAHCA or CblA and MAHCB or CblB) | 251100 251110 | C3 (>5.25 μM) and C3/C2 (>0.2) selects for 2TT | |
Methylmalonic acidemia type CblC/D (MAHCC or CblC and MAHCD or CblD) | 277400 277410 | C3 (>5.25 μM) or C3/C2 (>0.2) selects for 2TT | |
Urea Cycle Disorders (UCD) | Citrullinaemia type I (CTLN1) | 215700 | Cit (>200 μM) |
Argininosuccinate lyase deficiency (ASL deficiency) | 207900 | ASA (>1 μM) | |
Arginase deficiency (ARG deficiency) | 207800 | Arg (>50 μM) and Arg/Orn (>1.0) | |
Fatty Acid Oxidation Disorders (FAOD) | Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) | 201450 | C8 (>0.3 μM) and C8/C10 (>2.5) |
Long-chain 3-OH acyl-CoA dehydrogenase deficiency (LCHADD)/Trifunctional Protein deficiency (TFP) | 609016 609015 | C16OH (>0.10 μM), C18:1OH (>0.07 μM), C18OH (>0.06 μM) and C16OH/C16 (>0.04) | |
Multiple acyl-CoA dehydrogenase deficiency (MADD) | 231680 | Multiple elevations from C4 to C18 acyl carnitines | |
Carnitine uptake defect (CUD) | 212140 | C0 (<6.8 μM) | |
Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) | 201475 | C14:1 (>0.46 μM), C14:2 (>0.17 μM) and C14:1/C12:1 (>6.0) | |
Short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (SCHADD) | 231530 | C4OH (>0.95 μM) | |
Carnitine palmitoyl-transferase I deficiency (CPTIA) | 255120 | C0/(C16 + C18) (>30) | |
Carnitine palmitoyl-transferase II deficiency (CPTII)/Carnitine-acylcarnitine translocase deficiency (CACT) | 255110 212138 | C0/(C16 + C18) (<3.0) |
Disorder | Primary Marker | Secondary Marker | Year of Implementation in the PNSP | References |
---|---|---|---|---|
Tyrosinemia | Tyrosine | SA | 2006 | [5] |
Propionic/methylmalonic acidurias | Propionylcarnitine (C3) | MMA, 3OHprop, PropGly | 2017 | [6,7] |
Cobalamin metabolism defects | Propionylcarnitine (C3) and ↓ methionine | MMA and tHcy | 2017 | [6,7] |
Classic homocystinuria | Methionine | tHcy | 2017 | [7] |
Isovaleric aciduria | Isovaleryl/2-methylbutyrylcarnitine (C5) | C5 and Piv-C5 | 2017 | [8] |
Condition | 2TT Results | ||||||
---|---|---|---|---|---|---|---|
MMA | PropGly | 3OHprop | tHcy | Isovalerylcarnitine | 2-Methylbutyrylcarnitine | SA | |
Propionic acidemia (PA) | N | ↑↑ | ↑↑ | N | |||
Methylmalonyl- CoA mutase deficiency (Mut0 /Mut-) | ↑↑ | N | N | N | |||
Cobalamin type A/B deficiency (CblA/B) | ↑ | N | N | N | |||
Cobalamin type C/D deficiency (CblC/D) | ↑ | N | N | ↑ | |||
Vitamin B12 deficiency (of maternal cause) a | N or ↑ | N | N | N or ↑ | |||
Homocystinuria | ↑↑ | ||||||
Methionine adenosyltransferase I/III deficiency | N or ↑ | ||||||
Isovaleric aciduria | ↑↑ | ||||||
2-Methylbutyrylglycinuria b | ↑ | ||||||
Tyrosinemia type I | ↑↑ |
Detected Disorders | Positive Cases | Birth Prevalence | Estimated Worldwide Birth Prevalence |
---|---|---|---|
Amino acid disorders | 231 | 1:7640 | 1:6803 a |
Phenylketonuria (PKU)/Hyperphenylalaninemia (HPhe) | 154 | 1:11,611 | 1:15,267 a |
Maple syrup urine disease (MSUD) | 19 | 1:92,886 | 1:81,967 a |
Tyrosinemia type I (TYR1) | 6 | 1:294,138 | 1:100,000 a |
Tyrosinemia type II (TYR2) | 2 | 1:882,415 | <1:1,000,000 b |
Tyrosinemia type III (TYR3) | 5 | 1:294,138 | <1:1,000,000 b |
Homocystinuria (CBS deficiency) | 4 | 1:441,208 | 1:243,902 a |
Methionine adenosyltransferase deficiency (MATI/III deficiency) | 41 | * | <1:1,000,000 b |
Urea cycle disorders | 26 | 1:67,878 | 1:34,364 a |
Citrullinemia type I (CTLN1) | 10 | 1:176,483 | 1:250,000 c |
Argininosuccinate lyase deficiency (ASL deficiency) | 9 | 1:196,092 | 1:220,000 c |
Arginase deficiency (ARG deficiency) | 7 | 1:252,119 | 1:35,700 d |
Organic acid disorders | 116 | 1:15,214 | 1:11,481 a |
3-Methyl crotonyl-CoA carboxylase deficiency (3-MCCD) | 39 | 1:45,252 | Unknown b |
Isovaleric acidemia (IVA) | 6 | 1:294,138 | 1:196,078 a |
Propionic acidemia (PA) | 4 | 1:441,208 | 1:93,457 a |
Methylmalonic acidemia (MMA Mut-/Mut 0) | 9 | 1:196,092 | <1:100,000 e |
Cobalamin metabolism deficiency (CblA, B, C, and D)/Vitamin B12 deficiency | 22 | 1:80,220 | <1:100,000 b |
Glutaric acidemia type 1 (GA 1) | 20 | 1:88,219 | 1:100,000 b |
3-Hydroxy-3-methylglutaryl CoA lyase deficiency (3HMGLD) | 11 | 1:160,439 | <1:1,000,000 b |
ß-Ketothiolase deficiency (BKTD) | 1 | ** | Approximately 250 cases reported worldwide f |
Holocarboxylase synthase deficiency (HLCS deficiency) | 2 | ** | 1:200,000 b |
Malonic acidemia (MAL) | 2 | 1:882,415 | <1:1,000,000 b |
Fatty acid oxidation disorders | 304 | 1:4819 | 1:15,360 a |
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) | 240 | 1:6603 | 1:17,301 a |
Long-chain 3-OH acyl-CoA dehydrogenase deficiency (LCHADD) | 16 | 1:110,302 | 1:250,000 b |
Mitochondrial trifunctional protein deficiency (MTPD) | 1 | 1:1,764,830 | Less than 100 cases reported worldwide b |
Short-chain 3-hydroxyacyl-CoA dehydrogenase Deficiency (SCHADD) | 2 | 1:882,415 | <1:1,000,000 b |
Multiple acyl-CoA dehydrogenase deficiency (MADD) | 12 | 1:147,069 | 1:200,000 b |
Brown–Vialetto–Van Laere Syndrome (BVVL) | 1 | ** | <1:1,000,000 b |
Carnitine uptake defect (CUD) | 11 | 1:160,439 | Unknown b |
Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) | 12 | 1:147,069 | Over 400 cases reported worldwide b |
Carnitine palmitoyl-transferase I (CPTIA) deficiency | 4 | 1:441,208 | <1:1,000,000 b |
Carnitine palmitoyl-transferase II (CPTII) deficiency | 3 | 1:588,277 | <1:1,000,000 b |
Carnitine-acylcarnitine translocase (CACT) deficiency | 2 | 1:882,415 | Approximately 60 cases reported worldwide b |
Total | 677 | 1:2607 | 1:1964 a |
Maternal Condition/Disorder | Number of Cases |
---|---|
Vitamin B12 deficiency | 27 |
3-MCCD | 18 |
CUD | 8 |
GA 1 | 5 |
MCADD | 1 |
Total | 59 |
Year | Number of FPs for IVA |
---|---|
2011 | 29 |
2012 | 33 |
2013 | 59 |
2014 | 35 |
2015 | 36 |
2016 1 | 5 |
2017 2 | 0 |
Parameters | Value |
---|---|
Number of screened neonates | 1,764,830 |
Global birth prevalence of IEM | 1:2607 |
False positives (FPs) | 2636 |
False negatives (FNs) | 8 |
Positive predictive value (PPV) | 21% |
False positive rate (%) | 0.15% |
Sensitivity (%) | 98.89% |
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Gonçalves, M.M.; Marcão, A.; Sousa, C.; Nogueira, C.; Fonseca, H.; Rocha, H.; Vilarinho, L. Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS. Int. J. Neonatal Screen. 2024, 10, 25. https://doi.org/10.3390/ijns10010025
Gonçalves MM, Marcão A, Sousa C, Nogueira C, Fonseca H, Rocha H, Vilarinho L. Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS. International Journal of Neonatal Screening. 2024; 10(1):25. https://doi.org/10.3390/ijns10010025
Chicago/Turabian StyleGonçalves, Maria Miguel, Ana Marcão, Carmen Sousa, Célia Nogueira, Helena Fonseca, Hugo Rocha, and Laura Vilarinho. 2024. "Portuguese Neonatal Screening Program: A Cohort Study of 18 Years Using MS/MS" International Journal of Neonatal Screening 10, no. 1: 25. https://doi.org/10.3390/ijns10010025