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Article

Milder Form of Cobalamin C Disease May Be Missed by Newborn Screening: The Importance of Methylmalonic Acid Assessment

by
Francesca Nardecchia
1,*,†,
Agnese De Giorgi
1,†,
Silvia Santagata
2,
Teresa Giovanniello
2,
Manuela Tolve
2,
Antonio Angeloni
3,
Vincenzo Leuzzi
1,
Francesco Pisani
1 and
Claudia Carducci
3
1
Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza University of Rome, Via dei Sabelli 108, 00141 Rome, Italy
2
Unit of Clinical Pathology, Policlinico Umberto I University Hospital, 00161 Rome, Italy
3
Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Neonatal Screen. 2025, 11(3), 77; https://doi.org/10.3390/ijns11030077 (registering DOI)
Submission received: 4 August 2025 / Revised: 26 August 2025 / Accepted: 5 September 2025 / Published: 12 September 2025
Versions Notes

Abstract

CblC deficiency is the most common intracellular disorder of vitamin B12 metabolism. Expanded newborn screening (NBS) plays a key role in early diagnosis, allowing timely treatment and preventing serious complications. However, traditional first-tier markers—such as propionylcarnitine (C3) and its ratios with other metabolites (e.g., methionine, carnitine, and acetylcarnitine)—have limited sensitivity, particularly for mild forms, leading to missed or delayed diagnoses. In this study, we analyzed data from the NBS Center of the Lazio region (Italy) and identified nine newborns with confirmed CblC deficiency. All were recalled due to abnormalities in C3 or related ratios, along with elevated methylmalonic acid (MMA) levels. Notably, three infants had completely normal C3 levels and ratios during the second screening test, yet they showed MMA levels above the cut-off value (2 µmol/L), enabling a diagnosis of otherwise undetectable mild CblC cases. Our center regularly measures MMA in dried blood spots, even when first-tier markers return to normal on the second sample. This approach allows for early diagnosis and immediate treatment with hydroxocobalamin in patients with mild CblC deficiency, resulting in early intervention, effective metabolic control, and, based on current follow-up, normal neurodevelopmental outcomes. Our findings highlight the essential role of second-tier MMA testing in improving the detection of mild CblC deficiency during NBS.
Keywords: newborn screening; CblC defect; propionylcarnitine; methylmalonic acid; second-tier test; late-onset newborn screening; CblC defect; propionylcarnitine; methylmalonic acid; second-tier test; late-onset

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MDPI and ACS Style

Nardecchia, F.; De Giorgi, A.; Santagata, S.; Giovanniello, T.; Tolve, M.; Angeloni, A.; Leuzzi, V.; Pisani, F.; Carducci, C. Milder Form of Cobalamin C Disease May Be Missed by Newborn Screening: The Importance of Methylmalonic Acid Assessment. Int. J. Neonatal Screen. 2025, 11, 77. https://doi.org/10.3390/ijns11030077

AMA Style

Nardecchia F, De Giorgi A, Santagata S, Giovanniello T, Tolve M, Angeloni A, Leuzzi V, Pisani F, Carducci C. Milder Form of Cobalamin C Disease May Be Missed by Newborn Screening: The Importance of Methylmalonic Acid Assessment. International Journal of Neonatal Screening. 2025; 11(3):77. https://doi.org/10.3390/ijns11030077

Chicago/Turabian Style

Nardecchia, Francesca, Agnese De Giorgi, Silvia Santagata, Teresa Giovanniello, Manuela Tolve, Antonio Angeloni, Vincenzo Leuzzi, Francesco Pisani, and Claudia Carducci. 2025. "Milder Form of Cobalamin C Disease May Be Missed by Newborn Screening: The Importance of Methylmalonic Acid Assessment" International Journal of Neonatal Screening 11, no. 3: 77. https://doi.org/10.3390/ijns11030077

APA Style

Nardecchia, F., De Giorgi, A., Santagata, S., Giovanniello, T., Tolve, M., Angeloni, A., Leuzzi, V., Pisani, F., & Carducci, C. (2025). Milder Form of Cobalamin C Disease May Be Missed by Newborn Screening: The Importance of Methylmalonic Acid Assessment. International Journal of Neonatal Screening, 11(3), 77. https://doi.org/10.3390/ijns11030077

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