Studies of pathogenesis in Farber disease-cloning of the DNA and study of signal transduction system

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Farber disease is a rare autosomal recessive sphingolipidosis caused by a deficiency of acid ceramidase, a lysosomal enzyme that normally catalyzes the hydrolysis of ceramide to sphingosine and free fatty acids.The disease is clinically characterized by swollen joints with limitation of movements, disseminated subcutaneous nodules, particularly in the joints and over pressured points, hoarseness, and progressive cachexia.Recently the mode of ceramide action and the regulation of its production have attracted great attention impart due to the emerging role of ceramide as an intracellular effector molecule in apoptosis.It is possible that at least some of the pathologic events in Farber disease are related to second messenger functions.We have recently diagnosed two patients with type II Farber disease due to the reduced enzymatic activity of ceramidase and accumulation of ceramide after feeding of radiolabelled serin.cDNA analysis of these patients disclosed V369I/V97E and homogygous mutation of V96 del, respectively.These mutations were confirmed in expression studies in COS I cells.Increased secreations of cytokins including IL-2, -6, and TNF- alpha, not detected in skin fibroblasts from control and Farber disease, and ceramide did not induced cytokin productions.The removed nodules showed increased level of ceramide and macrophage infiltrations.However, immunostainig of Fas, bcl-2, and IL-6 showed negative.Tunel method did not show significant positive staining and no DNA ladder was not detected in extracted DNA from nodules.These evidence suggest that apoptosis did not occur in the nodules.