Krabbe disease: Genetic aspects and progress toward therapy

被引:156
作者
Wenger, DA [1 ]
Rafi, MA
Luzi, P
Datto, J
Costantino-Ceccarini, E
机构
[1] Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurol, Philadelphia, PA 19107 USA
[2] CNR, Ctr Studio Cellule Germinali, Siena, Italy
关键词
Krabbe disease; globoid cell leukodystrophy; myelin; galactocerebrosidase; psychosine; galactosylceramide; oligodendrocyte; stem cells;
D O I
10.1006/mgme.2000.2990
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Krabbe disease or globoid cell leukodystrophy is a disorder involving the white matter of the peripheral and central nervous systems. Mutations in the gene for the lysosomal enzyme galactocerebrosidase (GALC) result in. low enzymatic activity and decreased ability to degrade galactolipids found almost exclusively in myelin. The pathological changes observed, including the presence of globoid cells and decreased myelin, appear to result from the toxic nature of psychosine and accumulation of galactosylceramide that cannot be degraded due to the GALC deficiency. Over 60 mutations have been identified in this gene. The great majority are disease-causing; however, a few are considered polymorphisms. While most patients present with symptoms within the first 6 months of life, others present later in life including adulthood. Even patients with the same genotype can have very different clinical presentations and course. The reason for this is not known. Treatment at this time is limited to hematopoietic stem cell transplantation that appears to slow the progression of the disease and improve the magnetic resonance images. Studies using stem cells and viral vectors to transduce transplantable cells are under way in model systems. In culture, oligodendrocytes from the twitcher mouse model can assume a normal appearance after differentiation if GALC activity is provided via viral transduction or uptake from donor cells. Therefore continued myelination. and/or remyelination in patients will require supplying GALC activity by transplanted cells or viral vectors to still functional endogenous oligodendrocytes or transplantation of normal oligodendrocytes or stem cells that can differentiate into oligodendrocytes. Using the animal models these options can be explored. (C) 2000 Academic Press.
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页码:1 / 9
页数:9
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