Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria
Abstract
:1. Introduction
2. Materials and Methods
2.1. Newborn Screening
2.2. NGS2025 as Extension of the German National NBS Panel
2.3. Combined Multiple-Tier NBS Algorithm
2.4. Ethical Approval
2.5. Statistical Analysis
3. Results
3.1. Study Population
3.2. Suspected and Confirmed Diagnoses
3.3. Time to Treatment
3.4. Case A: Vitamin B6-Responsive CBS Deficiency
3.5. Case B: Vitamin B12-Responsive Methylmalonic Aciduria, CblA-Type
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
3-OH-PA | 3-Hydroxypropionic acid |
C2 | Acetyl carnitine |
C3 | Propionyl carnitine |
C3/C2 | Propionyl carnitine-acetyl carnitine ratio |
Cbl | Cobalamin |
CBS | Cystathionine beta-synthase |
DBS | Dried blood spot |
Hcy | Total homocysteine |
IMD | Inherited metabolic disease |
MCA | Methylcitrate |
Met | Methionine |
Met/Phe | Methionine-phenylalanine ratio |
MMA | Methylmalonic acid |
MS/MS | Tandem mass spectrometry |
MTHFR | Methylenetetrahydrofolate reductase |
MUT | Methylmalonyl-CoA mutase |
NBS | Newborn screening |
NGS2025 | Pilot panel “Newborn screening 2020/2025” |
Phe | Phenylalanine |
UKHD | Heidelberg University Hospital |
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Suspected Diagnosis (N) | Results of Confirmatory Tests | Confirmed Diagnosis (N) | Positive Predictive Value (PPV) | Estimated Birth Prevalences [1:X] | |||||
---|---|---|---|---|---|---|---|---|---|
Confirmation of the Initially Suspected Diagnosis | Confirmation of Another Diagnosis of the Algorithm | False Positives | For the Initially Suspected Diagnosis | For Any Diagnosis of the Algorithm | Study Cohort [95% CI] | Reports from Literature | |||
Propionic Acidemia (PA) | 43 | 3 | 2 (1× B12D, 1× MMA) | 38 | 4 | 0.07 | 0.12 | 137,177 [136,814–137,540] | 5000 (Saudi Arabia) [33]–150,000 [34,35] |
Methylmalonic Acidurias (MMA) | 19 | 4 | 5 (B12D) | 10 | 5 | 0.21 | 0.47 | 109,741 [109,451–110,032] | 50,000–200,000 [10,34,35] |
Isolated Remethylation Disorders | 54 | 3 | 26 (B12D) | 25 | 3 | 0.06 | 0.54 | 182,902 [182,419–183,387] | No valid data [20] |
Combined Remethylation Disorders | 3 | 1 | 2 (B12D) | 0 | 1 | 0.33 | 1 | 548,707 [547,256–550,161] | No valid data [20] |
Homocystinuria | 45 | 1 * | 6 * (B12D) | 39 | 1 * | 0.02 | 0.13 | 548,707 [547,256–550,161] | 1800 (Qatar) [36]–200,000 [37]–900,000 [30] |
Neonatal Vitamin B12 Deficiency (B12D) | 294 | 113 | 1 (PA) | 180 # | 153 * | 0.38 | 0.39 | 3586 § [3577–3596] | 2000 [11]–3600 [9,17,23]–30,000 [38] |
TOTAL | 458 | 125 * | 42 * | 292 | 166 | 0.27 | 0.36 | 3305 [3297–3314] |
Disease Name, Number (N) of Patients | Age at First NBS Report [days] | Age at Start of Therapy [days] | Age at Disease Confirmation [days] | Symptomatic at First NBS Report | Additional Information | ||
---|---|---|---|---|---|---|---|
Propionic Acidemia | |||||||
N = 4 | PA-1 | 7 | 8 | 8 | No | Suspected diagnosis: Vitamin B12 deficiency | |
PA-2 | 6 | 6 | 7 | Yes | Mild hyperammonemia, metabolic acidosis | ||
PA-3 | 0 | at birth # | 0 | No | High-risk screening (sibling of PA-2) | ||
PA-4 | 3 | at birth # | 3 | No | High-risk screening, pre-natal diagnosis | ||
Methylmalonic Acidurias | |||||||
N = 5 | MMA-1 | 15 | 15 | 16 | No | Partial vitamin B12-responsiveness, MUT-type | |
MMA-2 | 8 | 2 | 3 | Yes | Mild hyperammonemia | MUT-type | |
MMA-3 | 8 | 8 | 9 | Yes | Mild hyperammonemia, metabolic acidosis | MUT-type | |
MMA-4 | 3 | 3 | 4 | No | MUT-type | ||
MMA-5 * | 6 | 7 | 7 | No | Full vitamin B12-responsiveness, CblA-type | ||
Isolated Remethylation Disorders | |||||||
N = 3 | MTHFR-1 | 8 | 8 | 9 | No | High-risk screening | |
MTHFR-2 | 6 | 6 | 12 | No | |||
MTHFR-3 | 52 | 59 | 59 | Yes | Muscular hypotonia | Recall delayed due to IT-technical complications | |
Combined Remethylation Disorders | |||||||
N = 1 | CblC | 8 | 8 | 8 | Yes | Feeding difficulties, hypothermia | |
Homocystinuria | |||||||
N = 1 | CBS * | 9 | 30 | 30 (B12D)/ 102 (CBS) | No | Full vitamin B6-responsiveness, additional vitamin B12 deficiency | |
Neonatal Vitamin B12 Deficiency | |||||||
N = 153 | Median (range) | No | One patient was symptomatic (mild muscular hypotonia) at start of therapy (116 days) due to delayed confirmatory diagnostics despite tracking by NBS laboratory [17] | ||||
8.5 (5–52) | 31 (6–157) | 30 (6–145) | |||||
TOTAL | |||||||
N = 166 | Median (range) | N = 161 no N = 5 yes | |||||
8 (0–52) | 30 (0–157) | 29 (0–145) |
Age at Sampling: | 41 h | 12 d | 27 d | 74 d | 96 d | 102 d | ||
---|---|---|---|---|---|---|---|---|
Reference Values UKHD | ||||||||
DBS (NBS): | ||||||||
1st tier: | Met/Phe | 0.26–0.56 | 0.57 | 0.94 | ||||
Met [µmol/l] | 11–35 11–40 (ext #) | 33 | 37 | |||||
2nd tier: | Hcy [µmol/l] | 0.1–12 0–15 (ext #) | 15.3 | 20.5 | ||||
Confirmatory diagnostics: | ||||||||
Plasma: | ||||||||
Hcy [µmol/l] | 2–14 | 34 | 84 | 85 | 119 | |||
Met [µmol/l] | 15–35 | - * | 119 | 81 | 97 | |||
MMA [µmol/l] | 0–0.26 | 0.25 | 0.24 | 0.22 | n/a | |||
Vitamin B12 [pmol/l] | 160–670 | 136 | 959 | 497 | 576 | |||
Folic acid [nmol/l] | 4.5–21 | >45 | 36 | >45 | >45 | |||
Holo-Transcobalamin [µmol/l] | >60 | 47 | >150 | n/a | n/a | |||
Urine: | ||||||||
MMA [mmol/molCrea] | 0–10 | 6.7 | 2.5 | n/a | 6.1 | |||
Treatment (all oral): | ||||||||
Vitamin B12: | ||||||||
Folic acid: | ||||||||
Vitamin B6: |
Age at Sampling: | 40 h | 6 d | 8 d | ||
---|---|---|---|---|---|
Reference Values UKHD | |||||
DBS (NBS): | |||||
1st tier: | C3 [µmol/l] | 0−5.5 | 16.3 | 9.1 | 53.8 |
C3/2 | 0−0.22 | 0.38 | 0.39 | 1.4 | |
2nd tier: | MMA [µmol/l] | 0−2.35 | 466.3 | ||
3-OH-PA [µmol/l] | 0−77.5 | 109.5 | |||
MCA [µmol/l] | 0−0.34 | 7.8 | |||
Hcy [µmol/l] | 0.1−12 | 9.4 | |||
Confirmatory diagnostics: | |||||
Plasma: | |||||
Ammonium [µmol/l] | 12−53 | 27 | |||
Urine: | |||||
MMA [mmol/mol creatinine] | 0−18 | 5767 | |||
MCA [mmol/mol creatinine] | 0−9 | 68 | |||
MMA-stable isotope quantification [mmol/mol creatinine] | 0−10 | 8363 | |||
Treatment: | |||||
Carnitine: | |||||
Vitamin B12: |
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Share and Cite
Schnabel, E.; Kölker, S.; Gleich, F.; Feyh, P.; Hörster, F.; Haas, D.; Fang-Hoffmann, J.; Morath, M.; Gramer, G.; Röschinger, W.; et al. Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria. Nutrients 2023, 15, 3355. https://doi.org/10.3390/nu15153355
Schnabel E, Kölker S, Gleich F, Feyh P, Hörster F, Haas D, Fang-Hoffmann J, Morath M, Gramer G, Röschinger W, et al. Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria. Nutrients. 2023; 15(15):3355. https://doi.org/10.3390/nu15153355
Chicago/Turabian StyleSchnabel, Elena, Stefan Kölker, Florian Gleich, Patrik Feyh, Friederike Hörster, Dorothea Haas, Junmin Fang-Hoffmann, Marina Morath, Gwendolyn Gramer, Wulf Röschinger, and et al. 2023. "Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria" Nutrients 15, no. 15: 3355. https://doi.org/10.3390/nu15153355
APA StyleSchnabel, E., Kölker, S., Gleich, F., Feyh, P., Hörster, F., Haas, D., Fang-Hoffmann, J., Morath, M., Gramer, G., Röschinger, W., Garbade, S. F., Hoffmann, G. F., Okun, J. G., & Mütze, U. (2023). Combined Newborn Screening Allows Comprehensive Identification also of Attenuated Phenotypes for Methylmalonic Acidurias and Homocystinuria. Nutrients, 15(15), 3355. https://doi.org/10.3390/nu15153355