title: Biochemical pathogenesis of genetic leukodystrophies: comparison of metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe's disease).
abstract: Among the genetic leukodystrophies known to occur in man, the fundamental genetic defects have been clarified in two disorders, metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe's disease). Nevertheless, the biochemical sequences with which the underlying genetic defects lead to the clinical and pathological features of the diseases and to disruption of the normal brain function are not well understood. Comparison of the two classical leukodystrophies provides us an opportunity to consider the biochemical pathogenesis of these disorders, some common between them and others apparently unique. That both metachromatic leukodystrophy and globoid cell leukodystrophy manifest themselves almost exclusively as diseases of the myelin sheath is relatively easy to understand because both are caused by genetic abnormalities in the metabolism of the characteristic constituents of myelin, sulfatide and galactosylceramide. The presence of the abnormal and characteristic globoid cells in the white matter of Krabbe's disease patients appears to be due to a unique property of galactosylceramide in that, when present in free form in the brain, it elicits infiltration of macrophages which transform themselves to globoid-like cells. No other lipids, including sulfatide, are known to induce similar tissue reactions. The most conspicuous difference between the two diseases is the presence or absence of abnormal accumulation of the substrates, the degradation of which is genetically blocked in the respective diseases. In metachromatic leukodystrophy, sulfatide accumulates to abnormally high levels, as logically expected for a "lysosomal storage disease". In Krabbe's disease, on the other hand, galactosylceramide is always much less than normal despite the genetic block in its catabolic pathway. This paradoxical finding can be explained by the "psychosine hypothesis".(ABSTRACT TRUNCATED AT 250 WORDS)
mesh_terms: D001921:Brain / Q000201:enzymology; D002553:Cerebroside-Sulfatase / Q000172:deficiency; D002648:Child; D002549:Diffuse Cerebral Sclerosis of Schilder / Q000201:enzymology; D005698:Galactosylceramidase / Q000172:deficiency; D005699:Galactosylceramides / Q000378:metabolism; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000201:enzymology* / Q000235:genetics; D007966:Leukodystrophy, Metachromatic / Q000201:enzymology* / Q000235:genetics; D009186:Myelin Sheath / Q000201:enzymology; D009836:Oligodendroglia / Q000201:enzymology; D011609:Psychosine / Q000378:metabolism; D013433:Sulfoglycosphingolipids / Q000378:metabolism
chemical_list: D005699:Galactosylceramides; D013433:Sulfoglycosphingolipids; D011609:Psychosine; D002553:Cerebroside-Sulfatase; D005698:Galactosylceramidase