Metachromatic leukodystrophy: recent research developments.

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulfatase A, causing the storage of the sphingolipid sulfatide. The disease is characterized by a progressive demyelination, which results in severe, finally lethal, neurologic symptoms. Genetically, the disease is heterogeneous, most mutant alleles are private, and only three have a frequency worth mentioning. An arylsulfatase A-deficient knockout mouse displays some of the disease features seen in patients but does not show the widespread demyelination characteristic of the disease. Nevertheless, this animal model was used to investigate the therapeutic potential of bone marrow stem cell-based gene therapy. Although treated animals show considerable arylsulfatase A activity in many tissues, including the brain, the effect on sulfatide storage was disappointing. Only in the kidney and liver of animals with very high enzyme levels was lipid storage positively affected. In particular, no effect was seen in the brain. These results suggest that bone marrow stem cell-based gene therapy could be of limited value in the treatment of this disease. The pathogenesis of the disease is poorly understood. It is not yet known how sulfatide storage negatively affects the metabolism of the oligodendrocyte. The amount and distribution of various proteins in the myelin of arylsulfatase A-deficient mice were investigated. It was shown that the myelin protein, myelin and lymphocyte protein (MAL), is reduced in deficient animals and that the myelin protein proteolipid displays an altered distribution within the myelin membranes. Possibly, these alterations contribute to the development of demyelination in this disease.