Abstract:

Objective To investigate the significance of elevated blood 3-hydroxyisovalerylcarnitine (C5OH) in the diagnosis of inherited metabolic diseases (IMD) and to explore the disease spectrum and genetic characteristics of children with abnormal C5OH in the population of northern China. Methods The data of IMD screening and diagnosis in hospitalized children from November 2012 to October 2021 were retrospectively analyzed, including tandem mass spectrometry (MS/MS) screening of blood metabolites, gas chromatography-mass spectrometry (GC-MS) analysis of urine metabolites and high-throughput sequencing analysis of gene variations. The blood and urine metabolic spectrum and gene variation spectrum of children with abnormal C5OH were analyzed. Results Among 53119 hospitalized children aged 0 to 7 years who underwent MS/MS screening for IMD, 48 (0.090%) children with increased C5OH were detected. Combined with urine GC-MS analysis, 9 (0.017%) children obtained biochemical diagnosis of IMD which verified by gene analysis. Of the 4 children with multiple carboxylase deficiency (MCD), 2 had HLCS gene variation and were confirmed as holocarboxylase synthetase deficiency, while the other 2 had BTD gene variation and were confirmed as biotinidase deficiency. ACAT1 variation was detected in 2 children with β-ketothiolase deficiency, and HMGCL variation was detected in 1 child with 3-hydroxy-3-methyl-glutaricacidemia. In 2 children with suspected MCD or 3-methylcrotonyl coenzyme A carboxylase deficiency that were not classified by biochemical diagnosis, HLCS variation was detected in 1 child, and BTD variation was detected in the other child, and MCD was finally diagnosed. The false positive rate of C5OH detection was 0.073% and the positive predictive value was 18.75%. The false positive rate of C5OH combined with other indicators (C4OH, C3 and C5:1) was 0.009%, and the positive predictive value was 58.33%. There was no false positive in the analysis of C5OH combined with urinary GC-MS, and the positive predictive value was 100%. Conclusions MCD is the main disease type in children with increased C5OH. For C5OH-related IMD, MS/MS combined with GC-MS metabolic analysis has high diagnostic efficiency and clinical value of guiding intervention in advance.

Key words: hydroxyisovalerylcarnitine, tandem mass spectrometry, metabolic spectrum, gene variation spectrum