Abstract
A 3.5 year old Hispanic female presented with signs and symptoms concerning for MPS II (Hunter Syndrome). The diagnosis of MPS II was confirmed by enzyme and molecular testing. Genetic evaluation revealed undetectable plasma iduronate-2-sulfatase enzyme activity and an inversion between intron 7 of the IDS gene and a region near exon 3 of IDS-2. This inversion is the molecular cause for ~8% of cases of MPS II and often results in a severe phenotype. X-inactivation studies revealed an inactivation ratio of 100:0. Given the patient's undetectable enzyme level, in combination with a severe IDS gene mutation, classic features at time of presentation, and the significantly skewed X inactivation, there was concern that she was at high risk of developing high and sustained antibody titers to idursulfase which would limit her benefit from enzyme replacement therapy (ERT). Anti-drug neutralizing antibodies to idursulfase have been associated with reduced systemic exposure to idursulfase and poorer clinical outcomes. Therefore, the decision was made to concurrently treat the patient with immune tolerance induction therapy during the first month of treatment with idursulfase in order to decrease the risk of developing high sustained antibody titers. The immune tolerance induction protocol consisted of rituximab weekly for 4 weeks, methotrexate three times a week for 3 weeks and monthly IVIG through B-cell and immunoglobulin recovery. Immune tolerance induction was initiated concurrently with the start of ERT. The patient had no significant adverse effects related to undergoing immune tolerance induction therapy and two and half years later is doing well with significantly reduced urine glycosaminoglycans and very low anti-drug antibody titers. This immune tolerance induction protocol could be considered for other patients with MPS II as well as patients with other lysosomal storage disorders who are starting on enzyme replacement therapy and are at high risk of developing neutralizing anti-drug antibodies.
Highlights
Mucopolysaccharidosis type II (MPS II; OMIM # 309900), known as Hunter syndrome, is a rare, X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2-sulfatase, encoded by the IDS gene [1,2,3]
We describe to our knowledge the first female patient with MPS II with zero IDS gene activity due to skewed X-inactivation to safely undergo concurrent immune tolerance induction therapy at the time of initiation of enzyme replacement therapy (ERT) with idursulfase
There was a concern that she was at high risk of developing high and sustained anti-drug antibody titers upon initiation of idursulfase ERT, which would in turn limit the action or response to ERT
Summary
Mucopolysaccharidosis type II (MPS II; OMIM # 309900), known as Hunter syndrome, is a rare, X-linked lysosomal storage disease caused by a deficiency in the enzyme iduronate-2-sulfatase, encoded by the IDS gene [1,2,3]. We describe to our knowledge the first female patient with MPS II with zero IDS gene activity due to skewed X-inactivation to safely undergo concurrent immune tolerance induction therapy at the time of initiation of ERT with idursulfase. If the patient did go on to develop neutralizing antidrug antibodies, there are limited alternative therapeutic options including eligibility for clinical trials, which would likely be further limited due to the patient being female With these factors in mind, the decision was made to start weekly idursulfase (0.5 mg/kg) with concurrent immune tolerance induction during the first month of ERT therapy with the goal of reducing the likelihood that the patient would go on to develop high sustained neutralizing antibody titers. This is in stark contrast to the high antibody titers in patients with MPS II, which typically range from 1:1000 to 1:100,000
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