The
classic globoid cell leukodystrophy (
Krabbe's disease) is caused by genetic defects in a lysosomal
enzyme,
galactosylceramidase. It is one of the two classic genetic leukodystrophies, together with
metachromatic leukodystrophy. The mode of inheritance is autosomal recessive. Typically, the disease occurs among infants and takes a rapidly fatal course, but rarer late-onset forms also exist. Clinical manifestations are exclusively neurologic with prominent white-matter signs. The pathology is unique, consisting of a rapid and nearly complete disappearance of myelin and myelin-forming cells--the oligodendrocytes in the central nervous system and the Schwann cells in the peripheral nervous system, reactive astroytic
gliosis, and infiltration of the unique and often multinucleated macrophages ("globoid cells") that contain strongly
periodic acid-Schiff (PAS)-positive materials. A normally insignificant but highly cytotoxic metabolite,
galactosylsphingosine (
psychosine), is also a substrate of
galactosylceramidase and is considered to play a critical role in the pathogenesis. The
galactosylceramidase gene has been cloned, and a large number of disease-causing mutations have been identified. Equivalent genetic
galactosylceramidase deficiency occurs in several mammalian species, such as mouse, dog, and monkey. Recently, deficiency of one of the
sphingolipid activator proteins,
saposin A, was demonstrated to cause a late-onset, slowly progressive
globoid cell leukodystrophy at least in the mouse, with all of the phenotypic consequences of impaired degradation of
galactosylceramidase substrates. Human
globoid cell leukodystrophy owing to
saposin A deficiency might be anticipated and should be suspected in human patients with a late-onset leukodystrophy with normal
galactosylceramidase activity when other possibilities are also excluded. The only serious attempt at treating human patients is
bone marrow transplantation, which can provide significant alleviation of symptoms, particularly in those patients with later-onset, more slowly progressive
globoid cell leukodystrophy.