Metachromatic Leukodystrophy: Recent Research Developments

Abstract

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. (J Child Neurol 2003;18:591—594).

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References

von Figura K. , Gieselmann V. , Jaeken J. : Metachromatic leukodystrophy, in Scriver CR , Beaudet AL , Sly WS , Valle D (eds): The Metabolic and Molecular Bases of Inherited Disease, 8th ed. New York, McGraw-Hill, 2000, 2693—2740.

Kreysing J. , von Figura K. , Gieselmann V. : The structure of the arylsulfatase A gene. Eur J Biochem 1991;191:627—631.

Polten A. , Fluharty AL , Fluharty CB , et al: Molecular basis of different forms of metachromatic leukodystrophy . N Engl J Med 1991;324:18—22.

Barth ML , Fensom A. , Harris A. : Prevalence of common mutations in the arylsulphatase A gene in metachromatic leukodystrophy patients diagnosed in Britain. Hum Genet 1993;91:73—77.

Fluharty AL , Fluharty CB , von Figura K. , Gieselmann V. : Two new arylsulfatase A mutations in a juvenile metachromatic leukodystrophy patient. Am J Hum Genet 1991;49:1340—1350.

Tylky-Szymanska A. , Berger J. , Loschl B. , et al: Late juvenile metachromatic leukodystrophy in three patients with a similar clinical course and an identical mutation on one allele. Clin Genet 1996;50:281—292.

Gieselmann V. , Polten A. , Kreysing J. , von Figura K. : Arylsulfatase A pseudodeficiency: Loss of a polyadenylylation signal and a N-glycosylation site. Proc Natl Acad Sci U S A 1989;86:9436—9440.

Baldinger S. , Pierpont ME , Wenger DA : Pseudodeficiency of arylsulfatase A: A counseling dilemma. Clin Genet 1987;31:70—76.

Hess B. , Saftig P. , Hartmann D,et al: Phenotype of arylsulfatase A-deficient mice: Relationship to human metachromatic leukodystrophy. Proc Natl Acad Sci U S A 1996;93:14821—14826.

10.

D'Hooge R. , Coenen R. , Gieselmann V. , et al: Decline in brain stem auditory evoked potentials coincides with loss of spiral ganglion cells in arylsulfatase deficient mice. Brain Res 1999;847:352—356.

11.

D'Hooge R. , Hartmann D. , Manil J. , et al: Neuromotor alterations and cerebellar deficits in aged arylsulfatase A deficient mice. Neurosci Lett 1999;273:93—95.

12.

Consiglio A. , Quattrini A. , Martino S. , et al: In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: Correction of neuropathology and protection against learning impairments in affected mice. Nat Med 2001;7:310—316.

13.

Kornfeld S. : Structure and function of the mannose-6-phosphate/insulin like growth factor II receptors. Annu Rev Biochem 1992;61:307—330.

14.

Kennedy DW , Abkowitz JL : Kinetics of central nervous system microglial and macrophage engraftment: Analysis using a transgenic bone marrow transplantation model. Blood 1997;90:986—993.

15.

Matzner U. , Harzer K. , Learish RD , et al: Long-term expression and transfer of arylsulfatase A into brain of arylsulfatase A-deficient mice transplanted with bone marrow expressing the arylsulfatase A cDNA from a retroviral vector. Gene Ther 2000;14:1250—1257.

16.

Matzner U. , Habetha M. , Gieselmann V. : Retrovirally expressed human arylsulfatase A corrects the metabolic defect of arylsulfatase A-deficient mouse cells. Gene Ther 2000;7:805—812.

17.

Simons K. , Ikonen E. : Functional rafts in cell membranes. Nature 1997;387:569—572.

18.

Simons K. , Toomre D. : Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000;1:31—39.

19.

Kramer EM , Koch T. , Niehaus A. , Trotter J. : Oligodendrocytes direct glycosylphosphatidyl inositol anchored proteins to the myelin sheath in glycosphingolipid-rich complexes. J Biol Chem 1997;272: 8937—8945.

20.

Kramer EM , Klein C. , Koch T. , et al: Compartmentation of Fyn kinase with glycosylphosphatidyl-inositol-anchored molecules in oligodendrocytes facilitates kinase activation during myelination . J Biol Chem 1999;274:29042—29049.

21.

Frank M. : MAL, a proteolipid in glycosphingolipid enriched domains: Functional implications in myelin and beyond. Prog Neurobiol 2000;60:531—544.

22.

Anderson TJ , Schneider A. , Barrie JA , et al: Late-onset neurodegeneration in mice with increased dosage of the proteo protein gene. J Comp Neurol 1998;394:506—519.