Pervasive inflammatory activation in patients with deficiency in very-long-chain acyl-coA dehydrogenase (VLCADD)

Objectives: Very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a disorder of fatty acid oxidation. Symptoms are managed by dietary supplementation with medium-chain fatty acids that bypass the metabolic block. However, patients remain vulnerable to hospitalisations because of rhabdomyolysis, suggesting pathologic processes other than energy deficit. Since rhabdomyolysis is a self-destructive process that can signal inflammatory/immune cascades, we tested the hypothesis that inflammation is a physiologic dimension of VLCADD.

Methods: All subjects (n = 18) underwent informed consent/assent. Plasma cytokine and cytometry analyses were performed. A prospective case analysis was carried out on a patient with recurrent hospitalisation. Health data were extracted from patient medical records.

Results: Patients showed systemic upregulation of nine inflammatory mediators during symptomatic and asymptomatic periods. There was also overall abundance of immune cells with high intracellular expression of IFNγ, IL-6, MIP-1β (CCL4) and TNFα, and the transcription factors p65-NFκB and STAT1 linked to inflammatory pathways. A case analysis of a patient exhibited already elevated plasma cytokine levels during diagnosis in early infancy, evolving into sustained high systemic levels during recurrent rhabdomyolysis-related hospitalisations. There were corresponding activated leukocytes, with higher intracellular stores of inflammatory molecules in monocytes compared to T cells. Exposure of monocytes to long-chain free fatty acids recapitulated the cytokine signature of patients.

Conclusion: Pervasive plasma cytokine upregulation and pre-activated immune cells indicate chronic inflammatory state in VLCADD. Thus, there is rationale for practical implementation of clinical assessment of inflammation and/or translational testing, or adoption, of anti-inflammatory intervention(s) for personalised disease management.