14800-DvRappard

29 Metachromatic leukodystrophy: disease spectrum and approaches for treatment 2 INTRODUCTION In this review, the pathology, diagnosis and possible treatment of metachromatic leukodystrophy MLD (250100), a rare disorder with an estimated birth prevalence of 1.4- 1.8 per 100.000, 1 is described. At present no curative treatment is available for all types of MLD. This is an emerging field in which several clinical trials looking for a possible cure for this devastating disease are ongoing. Recently published data on patient care and treatment are discussed. Metachromatic leukodystrophy (MLD) is an autosomal recessive inherited lysosomal disorder caused by mutations in the ARSA gene located on chromosome 22q13.33, resulting in a deficiency of the enzyme arylsulfatase A (ASA). Some mutations result in pseudodeficiency alleles 2 that result in 10-15% of normal enzyme activity, which is sufficient tophysiologicallyhydrolyze sulfatides anddoes not lead todisease symptoms. 2 This implicates that sulfatide degradation can function normally in the presence of only 10-15% functional ASA enzyme; which is an important consideration for the development of treatment options for MLD. Mutations in PSAP, encoding prosaposin, an activator protein of ASA, also lead to MLD (249900 ), but are rare. 3 In multiple sulfatase deficiency (272200), caused by mutations in the sulfatase-modifying factor-1 gene ( SUMF1 ) 4 , the function of the whole family of sulfatase enzymes is affected, leading to symptoms of MLD in addition to features of various mucopolysaccharidoses. 5 ASA is essential for sulfatide metabolism through the hydrolysis of the 3-O ester bond of galactosyl and lactosyl sulfatides. 1 Its deficiency results in the accumulation of sulfatides into lysosomal storage deposits in the central and peripheral nervous system, which exhibit accumulation of sulfatides and metachromatic staining characteristics. 6 In the nervous system, sulfatides accumulates in the oligodendrocytes, Schwann cells, phagocytes, astrocytes and also neurons (figure 1). 3 Sulfatides are the most abundant sphingolipids in myelin, accounting for 4% of its composition. They have important functions in the maintenance of myelin. 2 Their accumulation leads to demyelination. It has been shown in vitro that sulfatide loading triggers inflammatory cytokines, which are thought to be involved in apoptosis. 7