Autisim, a clinical syndrome manifested by the inability to perform the higher cortical functions associated with communication, has many different ideologies. This grant is specifically designed to characterize the clinical, biochemical and genetic abnormalities associated with the recently described deficiency of adenylosuccinate lyase in certain autistic individuals. The establishment of a specific enzyme abnormality is a subgroup of autistic patients is a key step towards understanding the pathophysiology of the disease. The clinical correlates of adenylosuccinate lyase deficiency will be determined by screening several types of populations for a deficiency of this enzyme. Initial screening will be performed using a urine dipstick to sample and ship the urine followed by a Brattono-Marshall reaction to detect abnormally high concentrations of the succinylpurines found in patients with adenylosuccinate lyase deficiency. Tentative positives will be confirmed by high performance liquid chromatograhy analyses of urine samples followed by enzymatic assays of cytoplasmic extracts from fibroblasts. Finally, family members of affected patients will be studied to determine the inheritance of the enzyme deficiency and of the clinical symptoms. Fibroblast and lymphoblast lines derived from individuals with adenylosuccinate lyase deficiency will be utilized for in depth biochemical studies of purine synthesis, concentrations and excretions. The mutant enzyme will be evaluated by performing studies of kinetics, stability, pH optima, and other physical/chemical properties. Using antibodies directed against normal adenylosuccinate lyase enzyme, the quantity of cross-reacting material will be evaluated. The cDNA coding for adenylosuccinate lyase will be cloned and used to restriction map normal and mutant ASMP lyase genes. The probe will also be used to map the gene to its chromosomal location by in situ hybridization. 5-aminoimidazole-4-carboxamide-1-riboside will be used to try and correct the biochemical as well as the clinical manifestations of adenylosuccinate lyase deficiency. In vivo parameters such as the de novo synthesis of purines, the excretion of abnormal metabolites and clinical symptoms will be compared before and during therapy. These studies are designed to help define the pathophyisiology of symptoms. The combined clinical, biochemical, genetic and therapeutic studies will provide a comprehensive investigation of adenylosuccinate lyase deficiency.
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