Genetics of metachromatic leukodystrophy

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by the deficiency of arylsulfatase A (ASA). The mode of inheritance is autosomal recessive. The disease occurs panethnically and its frequency is 1 in 40000. The deficiency of the enzyme causes the accumulation of its substrate cerebroside sulfate. Since this sphingolipid is mainly found in the myelin membranes the disease primarily affects the oligodendrocytes. Patients suffer from a progressive demyelination and die due to a variety of neurologic symptoms. Clinically the disease is heterogeneous. Depending on the age of onset a late infantile, juvenile and adult form can be distinguished. We have cloned the cDNA and gene of arylsulfatase A. Several disease causing mutations have been identified and a simple genotype phenotype correlation has been revealed. Currently we try to develop a mouse model of MLD via homologous recombination in embryonic stem cells. The model will allow to elucidate the pathogenesis of the disease and to test possible therapeutic approaches.