14800-DvRappard

11 General introduction 1 INTRODUCTION Metachromatic leukodystrophy (MLD; OMIM 250100) is an inherited lysosomal disorder, caused by recessivemutations in ARSA, located on chromosome 22q13.33 and encoding arylsulfatase A (ASA). The estimated birth prevalence of MLD is 1.4-1.8 per 100.000. 1 ASA is essential for sulfatide metabolism through the hydrolysis of the 3-O ester bond of galactosyl and lactosyl sulfatides. Deficiency of ASA results in accumulation of undegraded sulfatides in the lysosomes and membranes of all cell types, especially in myelinating cells, oligodendrocytes and Schwann cells. 2 This results in progressive demyelination of the central and peripheral nervous system (CNS and PNS). The disease is classified into a late-infantile, juvenile and adult onset type, based on the age of onset of presenting symptoms. GENETICS More than 150 ARSA mutations have been described to date. 3 The characterized mutations are divided into two groups: 0 alleles, which are associated with extreme low enzyme activity, and R alleles which have detectable residual activity. 1 The following mutations are the most common ones in Europe: c.465+1G>A (p.?) (0 allele and commonly found in the late-infantile type), c.542T>G (p.Ile181Ser) and c.1283C>T (p.Pro428Leu) (R allele, common adult variant). 2 The c.827C>T (p.Thr276Met) variant is frequently associated with the late-infantile type. Pseudodeficiency alleles are the result of the c.1055A>G, p.(Asn352Ser) (traditionally named c.1049A>G)) and the c.*96A>G variant and result in 10-15% of normal enzyme activity, which is sufficient to hydrolyze sulfatides and does not cause disease symptoms, even in a homozygous state. 4 The prosaposin gene ( PSAP ) is an activator protein of ASA, and mutations in this gene, though rare, also lead to MLD. 5 Multiple sulfatase deficiency (MSD) is characterized by deficiency of all sulfatase activities, caused by a mutation in the sulfatase modifying factor 1 ( SUMF1 ) gene, that encodes a protein involved in the post translational modification of sulfatases. 6 The phenotype of MSD is a combination of the different sulfatase defects. The neurodegenerative course of the disease is similar to MLD. In addition, hepatosplenomegaly, short stature, corneal clouding, ichthyosis and skeletal changes are common. 7 Even between patients sharing the same genotype, there is considerable clinical variability. Still, the amount of residual ASA does correlate with the subtype; homozygosity for 0 alleles is mainly prevalent in the late-infantile type, whereas