Acid ceramidase deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy

Dworski, S. et al. (2017) Acid ceramidase deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy. Biochimica et Biophysica Acta: Molecular Basis of Disease, 1863(2), pp. 386-394. (doi: 10.1016/j.bbadis.2016.11.031) (PMID:27915031)

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Abstract

Acid Ceramidase Deficiency (Farber disease, FD) is an ultra-rare Lysosomal Storage Disorder that is poorly understood and often misdiagnosed as Juvenile Idiopathic Arthritis (JIA). Hallmarks of FD are accumulation of ceramides, widespread macrophage infiltration, splenomegaly, and lymphocytosis. The cytokines involved in this abnormal hematopoietic state are unknown. There are dozens of ceramide species and derivatives, but the specific ones that accumulate in FD have not been investigated. We used a multiplex assay to analyze cytokines and mass spectrometry to analyze ceramides in plasma from patients and mice with FD, controls, Farber patients treated by hematopoietic stem cell transplantation (HSCT), JIA patients, and patients with Gaucher disease. KC, MIP-1α, and MCP-1 were sequentially upregulated in plasma from FD mice. MCP-1, IL-10, IL-6, IL-12, and VEGF levels were elevated in plasma from Farber patients but not in control or JIA patients. C16-Ceramide (C16-Cer) and dhC16-Cer were upregulated in plasma from FD mice. a-OH-C18-Cer, dhC12-Cer, dhC24:1-Cer, and C22:1-Cer-1P accumulated in plasma from patients with FD. Most cytokines and only a-OH-C18-Cer returned to baseline levels in HSCT-treated Farber patients. Sphingosines were not altered. Chitotriosidase activity was also relatively low. A unique cytokine and ceramide profile was seen in the plasma of Farber patients that was not observed in plasma from HSCT-treated Farber patients, JIA patients, or Gaucher patients. The cytokine profile can potentially be used to prevent misdiagnosis of Farber as JIA and to monitor the response to treatment. Further understanding of why these signaling molecules and lipids are elevated can lead to better understanding of the etiology and pathophysiology of FD and inform development of future treatments.

Item Type:Articles
Additional Information:This work was supported by the Rare Disease Foundation & BC Children's Hospital Foundation [Microgrant to J.A.M.]; the National Institutes of Health [1R21NS078191-01A1 to J.A.M., R01 DK54830 to E.H.S.]; Vaincre les Maladies Lysosomales [to T.L. and J.A.M.]; and Plexcera Therapeutics [to E.H.S.].
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Gardner-Medwin, Dr Janet
Authors: Dworski, S., Lu, P., Khan, A., Maranda, B., Mitchell, J. J., Parini, R., Di Rocco, M., Hugle, B., Yoshimitsu, M., Magnusson, B., Makay, B., Arslan, N., Guelbert, N., Ehlert, K., Jarisch, A., Gardner-Medwin, J., Dagher, R., Terreri, M. T., Lorenco, C. M., Barillas-Arias, L., Tanpaiboon, P., Solyom, A., Norris, J. S., He, X., Schuchman, E. H., Levade, T., and Medin, J. A.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Biochimica et Biophysica Acta: Molecular Basis of Disease
Publisher:Elsevier
ISSN:0925-4439
ISSN (Online):1879-260X
Published Online:01 December 2016

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