Metachromatic leukodystrophy: genetics, pathogenesis and therapeutic options.

UNLABELLED Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulphatase A (ASA). This leads to storage of the membrane lipid sulphatide, which is abundant in myelin. A pathological hallmark of the disease is demyelination, causing various and ultimately lethal neurological symptoms. Today more than 110 mutations in the ASA gene have been identified, of which only three are frequent. Patients homozygous for alleles, which do not allow for the synthesis of functional ASA always suffer from the severe form of the disease, whereas alleles allowing the expression of residual enzyme activity are associated with the later onset juvenile or adult forms of metachromatic leukodystrophy. In addition, there are other as yet unknown genetic or epigenetic factors modifying the phenotype substantially. ASA-deficient mice have been generated as a model of metachromatic leukodystrophy. These mice store sulphatide and show progressive neurological symptoms, but do not demyelinate. This animal model was recently improved using a transgenic approach, which generated mice in which sulphatide synthesis in myelin-producing cells is enhanced. This new animal model reflects the pathological characteristics of the human disease. ASA-deficient mice have been used in various therapeutic trials involving enzyme replacement, haematopoietic stem-cell-based gene therapy and direct injections of ASA-expressing viral vectors into the brain. These animal studies have paved the way for future clinical studies of enzyme replacement and gene therapy. CONCLUSION For many years this devastating disorder was considered untreatable and the outlook for patients was poor. Within a comparatively short period of time since the ASA gene was cloned in 1989, genetic and biochemical studies and data generated from newly developed animal models have led to the first clinical trials. It is hoped that these developments will prove beneficial for patients.