Pathophysiology
MPS II is caused by a deficiency in the iduronate-2-sulfatase enzyme (IDS, EC 3.1.6.13), which catalyzes GAG breakdown by the removal of sulfate groups.1,2,4 In MPS II, GAGs accumulate in the tissues of multiple organ systems along with increased excretion of their breakdown products, heparan and dermatan, in the urine.2,4 Enzyme deficiency is most often due to protein misfolding, decreased production or decreased catalytic activity, rather than a complete lack of enzyme. Over 580 variants have been identified and are distributed over the entire IDS gene as small and large deletions, missense, nonsense and splicing variants, with about 25% of variants arising de novo.7 MPS II is also characterized by clinical heterogeneity, and due to its rarity, there is a poor understanding of the correlation between genotype and phenotype.7,8 However, the disease is often described as having two main phenotypes: severe, which is more common and caused by deletions or rearrangements that abolish iduronate-2-sulfatase (I2S) transcription; and attenuated, which lack cognitive impairment and developmental regression.2,8