METACHROMATIC LEUKODYSTROPHY - MOLECULAR-GENETICS AND AN ANIMAL-MODEL

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder cau sed by the deficiency of arylsulphatase A (ASA; EC 3.1.6.8). Deficienc y of this enzyme causes intralysosomal storage of the sphingolipid cer ebroside sulphate. This lipid is abundant in myelin and it may thus no t be surprising that storage mainly affects oligodendrocytes. Patients suffer from a progressive demyelination causing various neurological symptoms. The disease is fatal and treatment is not available. The hum an ASA gene has been cloned and more than 40 mutations have been analy sed: that cause metachromatic leukodystrophy. Few of these alleles are frequent among patients, whereas most mutant alleles have only been f ound in single families. Since MLD has only been described in humans a nd no naturally occurring animal model has been described, ASA-deficie nt mice have been generated by homologous recombination. The ASA knock out mice are unable to degrade sulphatide and store the lipid intralys osomally. The pattern of lipid storage in neuronal and nonneuronal tis sues resembles that described for patients. In the nervous system, lip id storage is found in oligodendrocytes, astroytes and some neurons. A nimals display an astrogliosis and a decreased average axonal diameter ; Purkinje cells and Bergmann glia of the cerebellum are morphological ly aberrant. Demyelination is seen in the acoustic ganglion and occurs between the ages of 6 and 12 months. The animals are deaf at this age and display various neuromotor abnormalities. However, compared to hu mans the mice have a surprisingly mild phenotype, since they have a no rmal life span and do not develop widespread demyelination. ASA-defici ent mice have been transplanted with bone marrow, which was transduced with a retroviral vector expressing arylsulphatase A. The majority of transplanted animals display sustained expression of arylsulphatase A from the retroviral construct up to 5 months after transplantation. H owever, preliminary data suggest that this therapeutic approach does n ot reduce storage material.