The primary goal of this proposal is to identify and characterize metabolic disorders from post-mortem tissue and fluids obtained from children classified as sudden infant death syndrome (SIDS), in an attempt to improve the understanding of its pathogenesis. The clinical, epidemiologic, and post-mortem autopsy findings commonly encountered in SIDS are nearly indistinguishable from those observed in various genetic disorders of amino acid and fat metabolism. Findings resulting from a preliminary study of post-mortem urine from 13 cases of SIDS include significant evidence in 6 cases for the existence of defective lipid metabolism. In some cases, the evidence points to new genetic disorders involving the oxidation of only unsaturated long-chain fats. These observations have led to the testable hyothesis that acute metabolic failure associated with inherited biochemical disorders is responsible for the sudden death of many children classified as SIDS. This hypothesis will be examined by a collaborative study in which the clinical, epidemiologic, and autopsy information on SIDS cases will be integrated with mass spectrometric analyses of urine, liver, and cerebrospinal fluid obtained at autopsy. The techniques to be applied include gas-chromatography mass spectrometry of organic acids and volatile free acids, radioenzymatic assay of urinary carnitine, and fast atom bombardment mass spectrometry for identification of specific acylcarnitines reflecting biochemical disorders. These are the best available methods for the recognition and diagnosis of many inherited metabolic diseases and are applicable to post-mortem urine and tissue samples owing to the chemical and biochemical stability of the diagnostic metabolites. Skin biopsies will be obtained post-mortem and fibroblast cultures will be available for enzyme assay and assessment of the integrity of fatty acid oxidation. These studies will be done only in those cases where there is mass spectrometric evidence of metabolic derangement in post-mortem fluid and tissue. These techniques should facilitate accomplishing the following objectives: 1. identification of known or suspected inherited biochemical disorders playing a part in the pathogenesis of SIDS, 2. Prevention: recognition and treatment of affected siblings or newborns with metabolic disorders in families with SIDS, 3. identification and characterization of suspected new genetic defects related to impaired oxidation of unsaturated fatty acids associated with SIDS.
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