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

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.