False positive cases of elevated tetradecenoyl carnitine in newborn mass screening showed significant loss of body weight

Abstract

Very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, a condition in which the body is unable to break down long-chain fatty acids properly, is the most common fatty acid oxidation disorder in Japan. Tandem mass spectrometry has been used in newborn screening (NBS), allowing the detection of patients with VLCAD deficiency even before symptoms manifest. However, tandem mass spectrometry has a high false positive rate. We investigated the clinical characteristics of patients with false positive results for tetradecenoyl acylcarnitine (C14:1). This case-control study used data collected between the 1st of January 2014 and the 31st of March 2019. The case group was defined as patients having levels of both C14:1 and C14:1/C2 ratio higher than cut-off levels in the first newborn mass screening, who were eventually diagnosed as false positives by attending doctors at Kobe University Hospital, Palmore Hospital, or Kakogawa Central City Hospital in Japan. The control group comprised 100 patients randomly selected from the three facilities. The false positive group included 17 cases, and the control group contained 300 patients. The demographics of each group did not show any significant differences in sex, body weight at birth, Cesarean section rate, complete breastfeeding rate, or the number of feedings per day. However, the change in body weight at the sampling day of NBS in the false positive and control groups was −10.2%, and − 4.6%, respectively, showing a statistically significant difference ( p < 0.01). In addition, body weight gain at the one-month medical checkup was 38.9 g/day in the false positive group and 44.1 g/day in the control group ( p < 0.05). An elevation of C14:1 carnitine has been reported in situations involving the catalysis of fatty acid. Therefore, patients with severe body weight loss might be associated with poor sucking or poor milk supply, which might cause a false positive elevation of C14:1 and C14:1/C2. In suspected VLCAD deficiency, attending doctors should pay attention to body weight changes recorded during newborn mass screening.

Biochemical Markers for the Diagnosis of Mitochondrial Fatty Acid Oxidation Diseases

“…In newborn screening, false positives have been reported in patients, following a loss of body weight and other circumstances of catalysis of fatty acids [ 86 ] and fasting [ 87 ]. Therefore, poor milk supply, poor sucking, and other causes of body weight loss should be reviewed in these situations.…”

Very Long-Chain Acyl-CoA Dehydrogenase Deficiency: High Incidence of Detected Patients With Expanded Newborn Screening Program

“…The primary marker is elevated C14:1 acylcarnitine (tetradecenoylcarnitine), together with other longchain acylcarnitines and disease-specific acylcarnitines ratios that can be calculated (C14, C14:2, C14:1/C2, C14:1/C16). As previously reported, MS/MS has a high false-positive rate and it is often difficult to differentiate between true positives, heterozygous carriers, and false positives (Spiekerkoetter, 2010;Bo et al, 2020). False positives can also occur due to insufficient breastfeeding, which might cause an elevation of C14:1 and C14:1/C2.…”

“…False positives can also occur due to insufficient breastfeeding, which might cause an elevation of C14:1 and C14:1/C2. That’s why it is suggested that in suspected VLCADD, attending doctors should pay attention to body weight changes recorded during newborn body mass screening ( Bo et al, 2020 ).…”

A Distinctive Metabolomics Profile and Potential Biomarkers for Very Long Acylcarnitine Dehydrogenase Deficiency (VLCADD) Diagnosis in Newborns

“…For example, some newborns with severe body weight loss were diagnosed with VLCADD in the first NBS results. However, they were false positive results, and the elevation of C14:1-carnitine was due to the increased catalytic process of fatty acids [ 24 ]. Also, it was found that the acylcarnitine profile used for VLCADD patients might be interfering with LCADD [ 25 ].…”