MOLECULAR-GENETICS OF METACHROMATIC LEUKODYSTROPHY

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A. The disease is characterized by a progressive demyelination that causes a variety of neurological sympt oms. Patients die within a few years after the age of onset. Clinicall y the disease is heterogeneous and according to the age of onset three different forms can be distinguished. The gene of arylsulphatase A ha s been cloned and several mutations causing metachromatic leukodystrop hy have been characterized. The distribution of these alleles among pa tients with different clinical forms of the disease has revealed a gen otype-phenotype correlation. A major determinant of the clinical pheno type is the residual enzyme activity that it associated with a particu lar genotype. Homozygosity for alleles that do not allow the synthesis of arylsulphatase A polypeptides causes the most severe form of disea se, whereas homozygosity for alleles that encode arylsulphatase A with low residual enzyme activity is found in the mild late-onset forms of disease. A substantial arylsulphatase A deficiency can also be found in healthy individuals at high frequency. This phenomenon has been ter med pseudodeficiency. It is often difficult to distinguish whether an arylsulphatase A deficiency is due to metachromatic leukodystrophy or harmless pseudodeficiency. The characterization of the mutations causi ng pseudodeficiency has allowed the detection of the pseudodeficiency allele in the DNA of probands and has thus improved the diagnosis and genetic counselling for metachromatic leukodystrophy.