Abstract
Some success in identifying acyl-CoA dehydrogenase (ACAD) deficiencies before they are symptomatic has been achieved through tandem mass spectrometry. However, there has been several challenges that need to be confronted, including excess false positives, the occasional false negatives and indicators selection. To select ideal indicators and evaluate their performance for identifying ACAD deficiencies, data from 352,119 newborn babies, containing 20 cases, were used in this retrospective study. A total of three new ratios, C4/C5DC+C6-OH, C8/C14:1, and C14:1/C16-OH, were selected from 43 metabolites. Around 903 ratios derived from pairwise combinations of all metabolites via multivariate logistic regression analysis were used. In the current study, the regression analysis was performed to identify short chain acyl-CoA dehydrogenase (SCAD) deficiency, medium chain acyl-CoA dehydrogenase (MCAD) deficiency, and very long chain acyl-CoA dehydrogenase (VLCAD) deficiency. In both model-building and testing data, the C4/C5DC+C6-OH, C8/C14:1 and C14:1/C16-OH were found to be better indicators for SCAD, MCAD and VLCAD deficiencies, respectively, compared to [C4, (C4, C4/C2)], [C8, (C6, C8, C8/C2, C4DC+C5-OH/C8:1)], and [C14:1, (C14:1, C14:1/C16, C14:1/C2)], respectively. In addition, 22 mutations, including 5 novel mutations and 17 reported mutations, in ACADS, ACADM, and ACADL genes were detected in 20 infants with ACAD deficiency by using high-thorough sequencing based on target capture. The pathogenic mutations of c.1031A > G in ACADS, c.449_452delCTGA in ACADM and c.1349G > A in ACADL were found to be hot spots in Suzhou patients with SCAD, MCAD, and VLCAD, respectively. In conclusion, we had identified three new ratios that could improve the performance for ACAD deficiencies compared to the used indicators. We considered to utilize C4/C5DC+C6-OH, C8/C14:1, and C14:1/C16-OH as primary indicators for SCAD, MCAD, and VLCAD deficiency, respectively, in further expanded newborn screening practice. In addition, the spectrum of mutations in Suzhou population enriches genetic data of Chinese patients with one of ACAD deficiencies.
Highlights
Acyl-CoA dehydrogenase (ACAD) deficiencies, are the most common fatty acid oxidation disorders (FAODs), and could be identified by monitoring acyl carnitines (AC) using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) (Gregersen et al, 2001; Yamada and Taketani, 2019)
Of 544,001 newborns born in Suzhou, China, from April 2014 to June 2018, 352,119 (64.7%) cases were referred to expanded newborn screening for inborn metabolic disorders by HPLC-MS/MS (TQD, Waters, USA)
A total of 352,119 newborns were tested by HPLC-MS/MS and 20 (1/17,606) infants were confirmed with one of ACAD deficiencies
Summary
Acyl-CoA dehydrogenase (ACAD) deficiencies, are the most common fatty acid oxidation disorders (FAODs), and could be identified by monitoring acyl carnitines (AC) using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) (Gregersen et al, 2001; Yamada and Taketani, 2019). Based on deficiency of specific acyl-CoA dehydrogenase, ACAD deficiencies are classified into VLCAD (OMIM number: 201470), MCAD (OMIM number: 201450), and SCAD deficiency (OMIM number: 609016). The introduction of HPLC-MS/MS in newborn screening (NBS) can identify infants with any one of the ACAD deficiencies before they are symptomatic, implement appropriate dietary interventions, and provide them with protocols for emergency situations
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