We propose biochemical and clinical studies in three groups of genetically determined disorders which are associated with mental retardation: Adrenoleukodystrophy, the sialidoses and genetically determined disorders of the urea cycle. Adrenoleukodystrophy is an X-linked disorder associated with the accumulation of very long chain fatty acids in the white matter of the nervous system and the adrenal cortex. We will search for the cause of this accumulation by a variety of approaches including the study of beta oxidation, with emphasis on peroxisomal oxidation, and by studies in cultured skin fibroblasts. We will conduct a therapeutic trial of dietary restriction of very long chain fatty acids. The sialidoses represent a newly recognized group of disorders, which may include four distinct subtypes. We will identify the nature of the accumulated sialoproteins and gangliosides, and purify and study the sialidases with the aid of newly synthesized substrates. Studies of genetically determined disorders of the urea cycle will focus on correlative behavioral and biochemical studies of heterozygotes, in follow-up of an observation that heterozygotes for ornithine transcarbamylase deficiency show slight but significant intellectual defects.
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