Ahmad Alodaib1, 2, Areeg El-Gharbawy1, Yu Leng Phua1, Melanie Gillingham3, Jerry Vockley1, 4 and Steven F. Dobrowolski5
1Department of Pediatrics, Division of Medical Genetics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
2Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, 12713, Saudi Arabia
3Department of Molecular and Medical Genetics, Graduate Programs in Human Nutrition, Oregon Health & Science University, Portland, OR 97239, USA
4Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15213, USA
5Department of Pathology, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA
Background: Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is a fatty acid oxidation defect with variable presentations. Current therapy utilizes medium chain triglycerides (MCT). Triheptanoin (C7) is an experimental anaplerotic agent providing odd chain fatty acid metabolized to both acetyl-CoA and propionyl-CoA. Metabolomics and transcriptomics were applied to blood samples from VLCAD patient treated with C7 or MCT to assess impact upon the TCA cycle and other pathways.
Methods: Plasma from 11 VLCAD patients was assessed by metabolomics (Metabolon Inc) with 6 were treated with C7. Analyte profiles from alternatively treated patients were compared to a reference cohort to generate analyte specific Z-scores that were considered significant when ≥ +/- 2. Transcriptome assessment of cDNA libraries from patient and matched control WBCs was performed with an Illumina NextSeq 500.
Results: Metabolomics identified 871 analytes in energy and lipid pathways that were highly represented. Patients managed with C7 were replete in TCA intermediates where MCT showed a paucity of some TCA analytes. Propionylglycine was highly represented in C7 treated patients and virtually absent in MCT treated patients. Patients managed with C7 showed over-representation of unique odd chain sphingomyelins, phosphatidylcholine, and phosphatidylethanolamines. Transcriptome data identified TCA cycle and complex lipid pathways genes with higher representation in the C7.
Conclusion: Broad-based metabolomics is a powerful platform to assess alternative treatment strategies and their pathophysiological mechanisms. The findings in this study provide further evidence that in VLCAD affected patients, C7 has superior anaplerotic effects on the TCA cycle compared to MCT. Interestingly, C7 also impacts complex lipid representation (sphingomyelins, phosphatidylcholine, and phosphatidylethanolamines) suggesting the pathogenesis of VLCAD deficiency and/or its treatment may involve these pathways.