Clinical, pathological and biochemical phenotype of globoid cell leukodystrophy (Krabbe disease) has several unique characteristics that are sometimes contrary to the conventional concept of genetic lysosomal disease. It was demonstrated early that galactosylceramide has unusual capacity to elicit a globoid cell-like reaction when implanted into the brain. Then, thirty years ago a hypothesis was introduced to explain the pathogenetic mechanism underlying the rapid and complete loss of myelin and myelinating cells. It postulated that galactosylsphingosine (psychosine), which is highly cytotoxic and also cannot be degraded due to the underlying genetic defect, is responsible for the very rapid loss of the oligodendrocytes and the consequent paradoxical analytical finding-lack of accumulation of the primary substrate, galactosylceramide, in patients’ brain. It took nearly ten years before the actual accumulation of psychosine was demonstrated in human Krabbe patients and also in the brain of mouse and dog models of the disease. During the intervening years, the psychosine hypothesis has been generally accepted as a critical pathogenetic mechanism in classical infantile globoid cell leukodystrophy. However, a more recent experimental mouse model due to genetic defect in saposin A, an in vivo galactosylceramidase activator protein, introduced new elements in our understanding of the disease process. Not only has it established the second gene, genetic defect of which can cause globoid cell leukodystrophy but it has indicated potential decoupling of the two previously postulated pathogenetic mechanisms, galactosylceramide for the globoid cell reaction and psychosine for loss of myelinating cells. Pathogenetic significance of participation of the major histocompatibility complexes and other immune mechanisms, inflammatory processes as suggested by activation of many cytokines, and possible interactions with sex hormones remain to be further explored.

(Communicated by Tamio YAMAKAWA, M. J. A., Jan. 14, 2003)