Mucopolysaccharidosis type II (MPS II; Hunter disease) is caused by deficiency of the enzyme iduronate-2-sulphatase (IDS) and patients present with a wide range of clinical signs and symptoms. The level of activity of IDS, however, does not allow prediction of phenotype. In our study of unrelated individuals with MPS II, alterations in the IDS gene could be identified in all 155 patients. Investigations in families in which the occurrence of MPS II was sporadic revealed mosaicism in the mothers of a small number of patients and a high frequency of de novo mutations occurring preferentially during male meiosis. Mutations identified in our patients include 27 large alterations and 128 small gene alterations (96 different alterations). These data further confirm the extreme heterogeneity of IDS gene alterations, as more than 330 have been reported to date. This genetic heterogeneity may explain the high degree of clinical heterogeneity in MPS II. Therefore, attempts have been made to establish genotype-phenotype correlations in order to provide an indication of the likely prognosis and a basis on which to evaluate treatment. To date, some progress has been made in predicting the clinical phenotype from the genotype although it remains difficult in a few individual cases. However, as the crystallographic 3D structure of IDS is yet to be determined, evaluation of the impact of mutations on IDS activity is often time consuming. Furthermore, if a given mutation is recurrent, some patients carrying the same change may present with different phenotypes, suggesting that factors other than the IDS gene (e.g. other genes, environmental factors) can modulate the clinical phenotype.

Conclusion: Although genotype-phenotype correlations may be difficult to establish, they will be of increasing importance for choosing the most appropriate therapy for an individual patient, as new therapeutic strategies may be targeted according to phenotype.