| Summary: | The primary genetic defect underlying Krabbe disease or globoid cell leukodystrophy is considered to be a deficiency of galactosylceramide-beta-galactosidase. In the present study of the brains from 18 patients who had died from Krabbe disease at 7-37 months of age, the concentration of galactosylceramide of cerebral and cerebellar white matter was severely reduced to 10-20% of that in age-matched controls. The lowest values were found in the most long-standing cases. Lactosylceramide was reduced to about 50% of normal, while globotriaosylceramide, blobotetraosylceramide and III3-alpha-fucosylneolactotetraosylceramide were increased 10 to 100-fold. Two glycosphingolipids, which have never before been isolated from normal human brains were now isolated and characterized: galactosylsphingosine (psychosine) and galactosyl beta 1 leads to 4 galactosylceramide. We were unable to identify galactosylsphingosine in normal human brains with certainty. We estimate its concentration in the cerebral white matter in Krabbe disease to be increased at least 100-fold (higher than normal). Psychosine was isolated also from the cerebral cortex in Psychosine was isolated also from the cerebral cortex in Krabbe disease after derivatization to the N-acetyl form. Its concentration there was 1 nmol/g tissue compared with 6-10 nmol/g in the white matter. All the neutral glycosphingolipids were isolated and their structure proved by the quantitative determination of their components, degradation by acid and specific glycohydrolases and permethylation and gas-liquid chromatographic-mass spectrometric assay of the methylated sugars. The paradoxical findings of a severely reduced concentration of galactosylceramide and a primary deficiency of cerebroside-beta-galactosidase can be explained by the present finding of the accumulation of galactosylsphingosine in the brains from patients who had died from Krabbe disease. The enzyme has a broad specificity and it normally also degrades galactosylsphingosine. Because of competitive inhibition by the accumulated galactosylceramide its lysosomal hydrolysis will be blocked. The concentration of psychosine will steadily increase and reach toxic levels and kill the oligodendroglial cells. This results in an arrest of the galactosylceramide biosynthesis. Therefore, we feel that galactosylsphingosine and not galactosylceramide is the primary storage substance in the brain in Krabbe disease that the disease is a psychosine lipidosis.
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