Krabbe disease: Genetic aspects and progress toward therapy

Krabbe disease or globoid cell leukodystrophy is a disorder involving the w hite matter of the peripheral and central nervous systems. Mutations in the gene for the lysosomal enzyme galactocerebrosidase (GALC) result in. low e nzymatic activity and decreased ability to degrade galactolipids found almo st exclusively in myelin. The pathological changes observed, including the presence of globoid cells and decreased myelin, appear to result from the t oxic nature of psychosine and accumulation of galactosylceramide that canno t be degraded due to the GALC deficiency. Over 60 mutations have been ident ified in this gene. The great majority are disease-causing; however, a few are considered polymorphisms. While most patients present with symptoms wit hin the first 6 months of life, others present later in life including adul thood. Even patients with the same genotype can have very different clinica l presentations and course. The reason for this is not known. Treatment at this time is limited to hematopoietic stem cell transplantation that appear s to slow the progression of the disease and improve the magnetic resonance images. Studies using stem cells and viral vectors to transduce transplant able cells are under way in model systems. In culture, oligodendrocytes fro m the twitcher mouse model can assume a normal appearance after differentia tion if GALC activity is provided via viral transduction or uptake from don or cells. Therefore continued myelination. and/or remyelination in patients will require supplying GALC activity by transplanted cells or viral vector s to still functional endogenous oligodendrocytes or transplantation of nor mal oligodendrocytes or stem cells that can differentiate into oligodendroc ytes. Using the animal models these options can be explored. (C) 2000 Acade mic Press.