Newborn screening for primary carnitine deficiency: Weighing benefits against harms

Primary carnitine deficiency (PCD) is an inherited error of metabolism which results in severely decreased blood carnitine levels caused by a poorly functioning carnitine transport protein (OCTN2). Low blood carnitine levels may cause low blood sugar or cardiac issues, which may be fatal. Treatment consists of carnitine suppletion. Since expansion of the Dutch newborn screening program (2007), PCD has been an incidental finding in children screened. During pregnancy, carnitine is passed on to the foetus through the placenta. Low blood carnitine levels in newborns can therefore also be caused by low carnitine levels in the mother, because she has PCD. Many individuals with PCD never develop any symptoms. It is therefore unclear whether all people identified with PCD through newborn screening (newborns as well as mothers) require treatment.

We researched new methods of screening for PCD. First we analysed neonatal day-to-day carnitine concentrations and found that carnitine concentrations depend on gestational age and weight for gestational age, and most particularly of age at sampling. These variables may be accounted for when interpreting carnitine concentrations from newborn screening results. Furthermore we evaluate the use of a ratio of urine free carnitine to plasma free carnitine (RatioU:P) as an early discriminative test in newborns referred by NBS for low free carnitine. This ratio is significantly higher in newborns with PCD than in those without PCD and it accurately discriminates between positive and false positive newborn referrals for PCD by NBS, without misidentifying true positive cases. This test can be applied as a first test in referred newborns and may allow early exclusion of PCD as a diagnosis, greatly reducing the harm and cost of follow-up diagnostics.

In our research, we investigate the clinical, genetic and biochemical characteristics of all individuals investigated due to low carnitine levels in newborn screening, and of those diagnosed with PCD prior to newborn screening. Our research shows there are two forms of the disease: a severe and a mild form. The severe form can result in coma, cardiac dysfunction or sudden death and is easily treated with carnitine suppletion. The mild form does not require treatment and should be considered benign. A novel method used to measure the function of the affected transport protein, makes it possible to distinguish the two forms of PCD.