14800-DvRappard

43 Metachromatic leukodystrophy: disease spectrum and approaches for treatment 2 cross the blood brain barrier, this type of therapy would not only be promising for MLD but also for several other lysosomal diseases. A combination of these approaches will hopefully lead to a satisfying treatment of patients suffering from MLD. Practice Points • The diagnosis of MLD cannot be always based on the level of ASA activity, but may need confirmation by mutation analysis or urinary sulfatide excretion due to the possibility of pseudodeficiency. • If clinical presentation and MRI suggest MLD, but ASA activity is normal, the measurement of sulfatide excretion in urine and mutation analysis of PSAP is necessary to come to a definite diagnosis. • A scoring system for brain abnormalities, in combination with clinical parameters, can be used to measure disease severity. Research agenda • A systematic evaluation of the effectiveness of HSCT • Longer follow up on the preliminary results of gene therapy and intracerebral enzyme replacement therapy Summary MLD is a severe storage disease caused by deficiency of the lysosomal enzyme arylsulfatase A, resulting in accumulation of sulfatides in the central and peripheral nervous system. A late-infantile, juvenile and adult onset type are distinguished based on the age of onset of the disease. The diagnosis of MLD is established through MRI and the detection of levels of ASA enzymatic activity in leukocytes, accompanied by mutation analysis and, in selected cases, measurement of sulfatide excretion in the urine. Brain MRI is characterized by widespread white matter changes with T2-hyperintense signal starting in the corpus callosum and periventricular and central white matter, but sparing subcortical fibers. There are several pitfalls in the diagnostic process: resemblance of the presenting symptoms of MLD to those found in Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy (CIDP) in young children, the pseudodeficiency alleles with no symptoms but low ASA activity, and patients with saposin B deficiency who are symptomatic with normal ASA activity. No curative treatment is available for all types of MLD. This review focuses on current therapeutic approaches as HSCT, but also on possible future therapies that are now being evaluated in clinical trials such as enzyme therapy and gene therapy. The preliminary results of the gene therapy trial