Newborn Screening Follow-up: An Elevated C5 with a Normal Repeat
A newborn screening card collected at 36 hours of life reports an elevated C5 acylcarnitine (C5 1.2 micromol/L; cutoff 0.8). The infant is now 12 days old, exclusively breastfed, thriving (weight up 250 g), with no lethargy, vomiting, or hypoglycemia. A repeat dried blood spot at 12 days shows C5 0.5 micromol/L (within reference). Plasma acylcarnitine profile shows C5 0.4 micromol/L, free carnitine 18 micromol/L (low-normal), and no other abnormalities. Urine organic acids are normal. The family asks whether the first result was a 'false positive' and whether they can stop worrying.
1. How do you interpret the discordant results, and what is the appropriate follow-up?
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Interpretation: A mildly elevated C5 on the first card with a normal repeat and a normal plasma profile is most consistent with a false-positive or transient elevation, but it does not fully exclude a mild or intermittent disorder. C5 elevations can reflect isovaleryl-CoA dehydrogenase deficiency (isovaleric acidemia), 2-methylbutyryl-CoA dehydrogenase deficiency, pivalic acid exposure (some antibiotics and prodrugs), or maternal carnitine status. The low-normal free carnitine is a clue that carnitine status may be marginal; free carnitine can be low in breastfeeding infants and in some organic acidemias.
Follow-up:
- Confirm the infant is clinically well and feeding normally (she is).
- Repeat the plasma acylcarnitine and urine organic acids once more when well, and consider a repeat dried blood spot.
- Review medications and maternal diet for pivalate-containing compounds.
- If all repeat testing is normal and the infant remains well, the episode can be considered a resolved false positive, but document the plan and advise the family to report any future episodes of lethargy, poor feeding, or vomiting.
- If any repeat is abnormal, proceed to molecular testing (e.g., IVD, ACADSB) and metabolic referral.
Key point: a single normal repeat does not always close the case; integrate clinical status and repeat testing before declaring a false positive.
2. The family asks about the risk to future children and whether they should have prenatal testing. How do you counsel them?
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Counseling:
- At present there is no confirmed diagnosis, so there is no defined recurrence risk to quantify. The most likely explanation is a false-positive screen, in which case the recurrence risk is not increased.
- If a specific disorder were later confirmed (e.g., isovaleric acidemia, autosomal recessive), the recurrence risk would be 25% for each pregnancy, and carrier testing of parents and prenatal or preimplantation options could be discussed.
- Explain that newborn screening is a screening test, not a diagnostic test, and that false positives are common; the purpose of follow-up is to protect the child while avoiding unnecessary anxiety.
- Recommend that they keep the child's records and inform the pediatrician of the screening history, since a future illness could prompt re-evaluation.
Practical points: Do not order prenatal testing without a confirmed diagnosis and identified familial variants. Offer genetic counseling if a diagnosis is established. Reassure while maintaining a safety net: report lethargy, poor feeding, or vomiting promptly.