We aim to define the pathogenesis and molecular basis of Metachromatic Leukodystrophy (MLD) and of Farber's lipogranulomatosis (ceramide deficiency), and to study animal analogues of the spingolipidoses in order to contribute to the development of effective therapy. To help define the pathogenesis of MLD, we will study the levels of all the sulfated lipids which have recently been identified as substrates of arylsulfatase A in MLD myelin and other subcellular fractions. Studies will be made of inhibitors of arylsulfatase A, with the aim of identifying or synthesizing compounds which inhibit this enzyme without causing other severe toxic effects. The effects of increased concentrations of sulfated lipids on the structure, composition, and stability of myelin will be studied in the developing nervous system of the tadpole, either by injection of these substances or of inhibitors of arylsulfatase A. We hope to define the molecular basis of four forms of MLD by attempts to isolate and characterize the mutant arylsulfatase A from each type. Studies of Farber's disease will focus on determining the normal distributions and characteristics of acid and alkaline ceramidases and their changes in Farber's disease. We will examine if there is a relationship between Farber's disease, multicentric reticulohistiocytosis, and juvenile rheumatoid arthritis and we will attempt to produce an animal model of this disease. In collaboration with veterinary pathologists, we will attempt to define biochemical basis of certain genetic neurological disorders in animals, and to help evaluate the effects of enzyme replacement therapy in cats with GM1 gangliosidosis.