title: Acid Ceramidase Deficiency is characterized by a unique plasma cytokine and ceramide profile that is altered by therapy.
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.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto M5G 1L7, Canada.
authors.forename: Shaalee
authors.initials: S
authors.lastname: Dworski
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425-5040, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Lu
authors.affiliation: Medical Genetics and Pediatrics, University of Calgary, Alberta Children's Hospital, Calgary T3B 6A8, Canada.
authors.forename: Aneal
authors.initials: A
authors.lastname: Khan
authors.affiliation: Department of Genetics, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke J1G 2E8, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Maranda
authors.affiliation: Department of Medical Genetics, McGill University, Montréal H3A 0G4, Canada; Department of Pediatrics, McGill University, Montréal H3A 0G4, Canada.
authors.forename: John J
authors.initials: JJ
authors.lastname: Mitchell
authors.affiliation: Pediatric Department, University Milano Bicocca, San Gerardo Hospital, Monza 20126, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.affiliation: G. Gaslini Children's Hospital, Genoa 16148, Italy.
authors.forename: Maja
authors.initials: M
authors.lastname: Di Rocco
authors.affiliation: German Center for Paediatric and Adolescent Rheumatology, Garmisch-Partenkirchen 82467, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Hugle
authors.affiliation: Division of Hematology and Immunology, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshimitsu
authors.affiliation: Pediatric Rheumatology, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Magnusson
authors.affiliation: Pediatric Rheumatology, Dokuz Eylul University, Izmir 35210, Turkey.
authors.forename: Balahan
authors.initials: B
authors.lastname: Makay
authors.affiliation: Gastroenterology and Metabolic Diseases, Dokuz Eylul University, Izmir 35210, Turkey.
authors.forename: Nur
authors.initials: N
authors.lastname: Arslan
authors.affiliation: Metabolic Diseases, University of Cordoba, Cordoba 14002, Argentina.
authors.forename: Norberto
authors.initials: N
authors.lastname: Guelbert
authors.affiliation: Department of Paediatric Oncology and Haematology, Medical University of Greifswald, Greifswald 17475, Germany.
authors.forename: Karoline
authors.initials: K
authors.lastname: Ehlert
authors.affiliation: Department of Paediatric Oncology and Haematology, Goethe University, Frankfurt 60323, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jarisch
authors.affiliation: Pediatric Rheumatology, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom.
authors.forename: Janet
authors.initials: J
authors.lastname: Gardner-Medwin
authors.affiliation: Pediatric Rheumatology, Notre Dame De Secours University Hospital, Byblos, Lebanon.
authors.forename: Rawane
authors.initials: R
authors.lastname: Dagher
authors.affiliation: Pediatric Rheumatology, Federal University of Sao Paulo, Sao Paulo 04023-900, Brazil.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Terreri
authors.affiliation: Neurogenetics, Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo 04023-900, Brazil.
authors.forename: Charles Marques
authors.initials: CM
authors.lastname: Lorenco
authors.affiliation: Pediatric Rheumatology, Bernard & Millie Duker Children's Hospital, Albany Medical Center, Albany, NY 12208, USA.
authors.forename: Lilianna
authors.initials: L
authors.lastname: Barillas-Arias
authors.affiliation: Metabolic Diseases, Children's National Health System, Washington, DC 20010, USA.
authors.forename: Pranoot
authors.initials: P
authors.lastname: Tanpaiboon
authors.affiliation: Plexcera Therapeutics, New York, NY 10029-6574, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Solyom
authors.affiliation: Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425-5040, USA.
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Xingxuan
authors.initials: X
authors.lastname: He
authors.affiliation: Plexcera Therapeutics, New York, NY 10029-6574, USA; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Schuchman
authors.affiliation: Laboratoire de Biochimie Métabolique, Institut Fédératif de Biologie, CHU Purpan, and INSERM UMR1037 CRCT, Toulouse 31037 Cedex 1, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto M5G 1L7, Canada; University Health Network, Toronto M5G 1L7, Canada; Medical College of Wisconsin, Milwaukee, WI 53226, USA. Electronic address: jmedin@mcw.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Medin
mesh_terms: D000818:Animals; D001171:Arthritis, Juvenile / Q000097:blood; D016026:Bone Marrow Transplantation; D002518:Ceramides / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D055577:Farber Lipogranulomatosis / Q000097:blood* / Q000628:therapy; D005260:Female; D006596:Hexosaminidases / Q000097:blood; D006801:Humans; D008297:Male; D051379:Mice
chemical_list: D002518:Ceramides; D016207:Cytokines; D006596:Hexosaminidases; C086400:chitotriosidase
keywords: Ceramides; Chemokines; Cytokines; IP-10; Juvenile Idiopathic Arthritis; MCP-1