Doctors use newborn screening tests to catch serious health problems early, including a rare vitamin B12 disorder called CblC deficiency. However, standard screening tests sometimes miss milder cases of this disease. Researchers in Italy found that by adding an extra test that measures a substance called methylmalonic acid, they could catch three babies who would have been missed by regular screening. These babies had normal results on the first test but showed warning signs in the second test. Early detection and treatment with vitamin B12 injections helped these babies develop normally. This study shows that adding this extra test could help doctors find and treat more babies with mild forms of this condition before serious problems develop.

The Quick Take

  • What they studied: Whether standard newborn screening tests catch all babies with a rare vitamin B12 processing disorder, or if some mild cases are being missed
  • Who participated: Nine newborns diagnosed with CblC deficiency (a vitamin B12 metabolism disorder) identified through newborn screening in the Lazio region of Italy
  • Key finding: Three out of nine babies had completely normal results on the standard screening test but showed elevated levels of methylmalonic acid (a warning sign) on a second, more detailed test. This extra test caught mild cases that the standard test would have missed.
  • What it means for you: If you live in an area that uses this enhanced screening approach, more babies with mild vitamin B12 disorders may be caught early and treated before problems develop. However, this is a rare condition, so it affects very few families. Talk to your doctor about what screening tests your newborn receives.

The Research Details

Researchers reviewed data from a newborn screening center in Italy that tested nine babies confirmed to have CblC deficiency. They looked at what the screening tests showed for each baby, comparing the standard markers (called C3 and related measurements) with a second-tier test that measures methylmalonic acid (MMA). The study examined whether babies with normal standard test results still showed warning signs in the more detailed MMA test.

The screening process works in two stages: first, doctors test dried blood spots from newborns using standard markers. If those look abnormal, babies get a second test. The researchers found that some babies had completely normal first-stage results but still had elevated MMA in the second test, indicating they had the mild form of the disease.

This approach is important because it shows that adding one more measurement to the screening process can catch cases that would otherwise be missed. The babies who were caught early received vitamin B12 treatment (hydroxocobalamin) immediately, which helped prevent serious complications.

Standard newborn screening tests are designed to catch the most common and severe forms of diseases. However, milder versions of conditions can slip through the cracks, leading to delayed diagnosis and treatment. By understanding which additional tests can improve detection, doctors can prevent serious health problems in babies who might otherwise go undiagnosed. This is especially important for vitamin B12 disorders because early treatment is very effective at preventing brain damage and developmental problems.

This study is a case report describing nine babies with confirmed diagnoses, which is a smaller type of study. The strength of this research is that all nine babies had confirmed CblC deficiency, so the findings are reliable for these specific cases. However, because it’s based on cases from one screening center in Italy, the results may not apply everywhere. The study doesn’t compare different screening methods head-to-head, but rather shows what happened when one center used an additional test. The fact that three babies were caught by the extra test suggests the approach works, but larger studies would be needed to know how often this happens in other places.

What the Results Show

All nine babies with confirmed CblC deficiency were initially flagged by abnormal results in the standard screening markers (C3 levels or related ratios) combined with elevated methylmalonic acid. This means the combination of tests worked to catch all nine cases.

The most important finding was that three of these nine babies had completely normal C3 levels and ratios on their second screening test. However, these same three babies still showed elevated methylmalonic acid levels above the normal cut-off (above 2 µmol/L, which is a standard measurement). Without the methylmalonic acid test, these three babies would have been considered normal and sent home without diagnosis or treatment.

All nine babies received early treatment with hydroxocobalamin (a form of vitamin B12) as soon as they were diagnosed. Based on follow-up observations, all babies showed normal brain and developmental outcomes, suggesting that early detection and treatment prevented serious complications.

The study demonstrates that measuring methylmalonic acid as a second-tier test, even when standard markers return to normal, can identify mild cases of CblC deficiency that would otherwise be missed.

The research highlights that CblC deficiency exists on a spectrum from mild to severe. The three babies with normal C3 but elevated MMA represent the milder end of this spectrum. These mild cases are particularly easy to miss because they don’t show the typical warning signs that doctors usually look for. The fact that all nine babies achieved normal development with early treatment suggests that catching the disease before symptoms appear is crucial for good outcomes.

Previous research has shown that standard newborn screening catches most cases of CblC deficiency, but some mild cases are missed. This study confirms those concerns and provides a practical solution: adding methylmalonic acid testing as a routine second-tier test. The approach aligns with current recommendations from screening experts who suggest that second-tier testing can improve detection of rare metabolic disorders. This research adds to growing evidence that one-size-fits-all screening may not catch every baby who needs help.

This study describes only nine babies from one screening center in Italy, so the results may not apply everywhere. The study doesn’t compare what would happen without the methylmalonic acid test, so we can’t say for certain how many cases are missed in other places. The research is also limited to babies who were already identified as having CblC deficiency—it doesn’t tell us how many babies in the general population might have mild forms that are still being missed. Additionally, the follow-up period for developmental outcomes, while encouraging, may not be long enough to detect all possible long-term effects. Different countries and regions use different screening approaches, so this finding may be more or less relevant depending on where you live.

The Bottom Line

If you are a healthcare provider or work in newborn screening: Consider adding methylmalonic acid testing as a routine second-tier test, especially when standard markers are borderline or when clinical suspicion is high. This approach appears to improve detection of mild CblC deficiency. (Confidence: Moderate—based on a small case series from one center)

If you are a parent: Ask your healthcare provider what newborn screening tests your baby receives and whether methylmalonic acid testing is included. If your baby is diagnosed with CblC deficiency, early treatment with vitamin B12 is very effective and can prevent serious complications.

This finding is most important for: newborn screening programs and laboratories that design screening protocols; pediatricians and genetic specialists who care for newborns; and parents of babies born in regions where enhanced screening is available. This is less relevant for families in areas that already use comprehensive screening that includes methylmalonic acid testing. The condition is rare (CblC deficiency is the most common vitamin B12 metabolism disorder, but still affects only a small number of babies), so most families won’t be directly affected, but early detection can be life-changing for those who are.

Babies identified through newborn screening can begin treatment within days of diagnosis. The benefits of early treatment appear quickly, with babies showing improved metabolic control within weeks. Based on the follow-up data presented, normal development appears to continue when treatment is started early. However, long-term follow-up studies over many years would provide more complete information about outcomes.

Want to Apply This Research?

  • If your baby has been diagnosed with CblC deficiency: Track vitamin B12 injection dates and dosages, methylmalonic acid levels from blood tests (measured in µmol/L), and developmental milestones (first smile, rolling over, sitting up, walking, talking) to monitor treatment effectiveness and development over time.
  • Work with your healthcare team to: Set reminders for scheduled vitamin B12 injections (hydroxocobalamin), schedule regular blood tests to monitor methylmalonic acid levels, and keep detailed notes on your baby’s development and any concerns to discuss with your doctor.
  • Create a long-term tracking system that records: dates and results of methylmalonic acid tests, vitamin B12 treatment dates and doses, developmental progress compared to age-appropriate milestones, and any symptoms or concerns. Share this information regularly with your healthcare provider to ensure treatment is working effectively and your baby is developing normally.

This research describes a rare vitamin B12 metabolism disorder and screening approaches used in one Italian screening center. The findings are not a substitute for professional medical advice. If you have concerns about your baby’s newborn screening results or development, consult with your pediatrician or a genetic specialist immediately. Newborn screening protocols vary by location and healthcare system. The treatment and monitoring recommendations in this study should only be implemented under the guidance of qualified healthcare professionals. This article is for educational purposes and should not be used to diagnose or treat any medical condition.