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However, the unambiguous diagnosis of true VLCADD patients may be challenging, and a high rate of false positive individuals identified by newborn screening undergo confirmation diagnostics. In this study, we show the outcome of enzyme testing in lymphocytes as a confirmatory tool in newborns identified by screening, and the correlation with molecular sequencing of the <jats:italic>ACADVL<\/jats:italic> gene. From April 2013 to March 2017, in 403 individuals with characteristic acylcarnitine profiles indicative of VLCADD, palmitoyl\u2010CoA oxidation was measured followed by molecular genetic analysis in most of the patients with residual activity (RA) &lt;50%. In almost 50% of the samples (209\/403) the RA was &gt;50%, one\u2010third of the individuals (125\/403) displayed a RA of 30\u201350% and 69\/403 individuals showed a residual activity of 0\u201330%. Sequencing of the <jats:italic>ACADVL<\/jats:italic> gene revealed that all individuals with activities below 24% were true VLCADD patients, individuals with residual activities between 24 and 27% carried either one or two mutations. Twenty new mutations could be identified and functionally classified based on their effect on enzyme function. Finally, we observed an up\u2010regulation of MCAD\u2010activity in many patients. However, this did not correlate with the degree of VLCAD RA. Although the likely clinical phenotype cannot be fully foreseen by genetic and functional tests as it depends on many factors, our data demonstrate the strength of this functional enzyme test in lymphocytes as a quick and reliable method for confirmation diagnostics of VLCADD.<\/jats:p>","DOI":"10.1007\/s10545-018-0245-5","type":"journal-article","created":{"date-parts":[[2018,9,7]],"date-time":"2018-09-07T08:17:27Z","timestamp":1536308247000},"page":"1169-1178","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["The diagnostic challenge in very\u2010long chain acyl\u2010CoA dehydrogenase deficiency (VLCADD)"],"prefix":"10.1002","volume":"41","author":[{"given":"Julia","family":"Hesse","sequence":"first","affiliation":[{"name":"Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine Medical Centre\u2010 University of Freiburg, Faculty of Medicine, University of Freiburg Freiburg 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