Abstract
BackgroundAlteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. Therefore, early diagnosis and intervention is critical. Most of the neonatal cases with acquired vitamin B12 deficiency have been detected by clinical symptoms and only few of them trough NBS programs. We aim to assess the usefulness of the second-tier test: methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) in our newborn screening program and explore the implications on the detection of cobalamin (vitamin B12) related disorders, both genetic and acquired conditions.MethodsA screening strategy using the usual primary markers followed by the analysis of MMA, MCA and Hcys as second tier-test in the first dried blood spot (DBS) was developed and evaluated.ResultsDuring the period 2015–2018 a total of 258,637 newborns were screened resulting in 130 newborns with acquired vitamin B12 deficiency (incidence 1:1989), 19 with genetic disorders (incidence 1:13,613) and 13 were false positive. No false negatives were notified. Concerning the second-tier test, the percentage of cases with MMA above the cut-off levels, both for genetic and acquired conditions was very similar (58% and 60%, respectively). Interestingly, the percentage of cases with increased levels of Hcys was higher in acquired conditions than in genetic disorders (87% and 47%, respectively). In contrast, MCA was high only in 5% of the acquired conditions versus in 53% of the genetic disorders, and it was always very high in all patients with propionic acidemia.ConclusionsWhen screening for methylmalonic acidemia and homocystinuria, differential diagnosis with acquired vitamin B12 deficiency should be done. The results of our strategy support the inclusion of this acquired condition in the NBS programs, as it is easily detectable and allows the adoption of corrective measures to avoid the consequences of its deficiency.
Highlights
Alteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage
In the period 2015–2018 a total of 258,637 newborns were screened (Fig. 2b), of which 9,889 showed alterations of primary markers (3.8%), disclosing 720 newborns with altered secondary markers, of which 91 presented clearly altered values on the first dried blood spot (DBS) resulting in 64 acquired vitamin B 12 deficiency, 16 were diagnosed with genetic defects and 7 were false positive
The current strategy resulted in 130 newborns with acquired vitamin B 12 deficiency among 258,637 newborns screened, 19 with genetic disorders and 13 were false positive
Summary
Alteration of vitamin B12 metabolism can be genetic or acquired, and can result in anemia, failure to thrive, developmental regression and even irreversible neurologic damage. We aim to assess the usefulness of the second-tier test: methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) in our newborn screening program and explore the implications on the detection of cobalamin (vitamin B12) related disorders, both genetic and acquired conditions. Methylmalonic acidemia, propionic acidemia and homocystinuria, including remethylation defects, are an extensive group of inherited genetic defects included in the expanded newborn screening (NBS) programs in several countries[1, 2]. Methylmalonic acid (MMA), methylcitric acid (MCA) and homocysteine (Hcys) are widely known biomarkers of genetic conditions leading isolated or combined methylmalonic acidemia and homocystinuria [3, 4], or propionic acidemia [5]. Elevations of MMA, Hcys and MCA can be the result of secondary alterations, such as acquired vitamin B12 (cobalamin) deficiency [6]. Any alteration of vitamin B12 metabolism, as well as alterations of its absorption, transport, or low intake could cause high levels of MMA and/ or Hcys and even MCA accumulation and low levels of Met
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