Infantile and fetal globoid cell leukodystrophy: analysis of galactosylceramide and galactosylsphingosine.

Galactosylceramide and galactosylsphingosine (psychosine) were assayed in tissues from infants and fetuses with globoid cell leukodystrophy (GLD). Galactosylceramide concentrations were not increased in nervous tissues or other organs. Using a sensitive assay method, we found galactosylsphingosine accumulations in GLD tissues, both infantile and fetal, which suggests that GLD is a generalized galactosylsphingosine storage disease. High galactosylsphingosine levels were observed in the brain, spinal cord, and sciatic nerve of infants with GLD and in the spinal cord of a fetus with GLD, where lesions characteristic to GLD were noted. In tissues without morphological changes, such as somatic organs and the brain in fetal GLD, galactosylsphingosine concentrations were low. These results suggest that a close relationship exists between galactosylsphingosine accumulation and the pathogenesis of GLD. The finding that galactosylsphingosine, but not galactosylceramide, accumulates in the tissue of GLD can be explained by our previous observation that galactosylceramide, but not galactosylsphingosine, is readily hydrolyzed by an intact galactosylceramidase II, which is genetically distinct from galactosylceramidase I.

The twitcher mouse: myelinogenesis in organotypic culture.

Myelinogenesis was followed in organotypic cultures of the spinal cord of the neurological mutant mouse, the Twitcher. As a clinically, pathologically and biochemically equivalent model of Krabbe disease this mutant is an important tool for investigating the nervous system. Normal initiation and development of myelination was observed. At 35 days in vitro (DIV) the Twitcher cultures exhibited blisters attached to the intact myelin sheath and bubbling of myelin suggestive of myelin breakdown. Myelin degeneration progressed thereafter. The Twitcher spinal cord survived in culture for more than two months, a period much longer than the life span of affected mice. In order to correlate pathological and biochemical changes, the activity of UDP-galactose:ceramide galactosyltransferase was quantitated in normal and Twitcher cultures. In both the Twitcher and the control groups the galactosyltransferase activity rapidly increased up to 20-25 DIV and then declined. The galactosyltransferase activity of the Twitcher tended to be lower than the controls even during the early myelination period. At 35 DIV the activity in the Twitcher was definitely lower than the controls, and at 52 DIV it was nearly negligible. The galactosyltransferase activity therefore correlated well with the morphologically observed early normal myelination and subsequent myelin degeneration.