14800-DvRappard

12 Chapter 1 compound heterozygosity for 0 and R alleles usually causes the juvenile type, and patients with the adult type are mostly carrying two R alleles. 1 The involvement of the peripheral nervous system (PNS) varies depending on the genotype. In patients carrying at least one 0 allele (coinciding with rapid disease progression), the PNS is likely to be involved already at diagnosis, whereas in the adult type PNS involvement occurs late and is mild. 1 Cesani et al described the genotype-phenotype correlation in 432 patients that were published in the international literature up to 2015. They found the late-infantile form to be the most common disease variant (around 48%), followed by the juvenile (23%) and the adult (22%). 2 In our Dutch patient cohort however, the juvenile form is most prevalent (accounting for 61% of diagnosed cases between 2008 and 2017), followed by the late infantile (23%) and adult form (16%). PATHOPHYSIOLOGY OF MLD Sulfatide (3-O-sulfogalactosylceramide) is themost abundant sulfoglycolipid (Figure 1). 5 Sulfoglycolipids form a considerable fraction of glycolipids. These glycosphingolipids form an abundant component of cellular membranes in all eukaryotic cells. 5 Sulfatide is degraded in lysosomes, after a sphingolipid activator protein, saposin B, has extracted it from membranes to make it accessible for arylsulfatase A, which then hydrolyzes the sulfate group. 5 In the nervous system, sulfatides are mostly present in oligodendrocytes and Schwann cells. 5 Figure 1. Structure of sulfatide. Galactosylceramide, the precursor of sulfatide, and sulfatide are the two major glycosphingolipids of the myelin sheath and contribute to the stability, flexibility and compaction of myelin. 3 Sulfatide negatively regulates oligodendrocyte differentiation, has a function in the initiation of myelination and inhibits axonal outgrowth. 5,8 In MLD,