Niamh Finnegan

Treatment of mucopolysaccharidosis type II (Hunter syndrome) with idursulfase: the relevance of clinical trial end points

The current treatment of mucopolysaccharidosis type II (MPS II, Hunter syndrome) is enzyme replacement therapy with recombinant idursulfase (Elaprase®). The efficacy of ERT was established based primarily on reduction in urine glycosaminoglycans:creatinine (GAG:Cr) ratio and improvement in a composite score of predicted forced vital capacity (FVC% predicted) and 6-min walk-test distance (6MWT). We retrospectively reviewed these parameters in 11 boys with MPS II treated with idursulfase between April 2007 (or the time of diagnosis) and February 2010. Some results were inconsistent with published trial data, and there was only a small number of analyzable results obtained for the FVC% predicted and 6MWT. A major drawback was the high prevalence of neurological involvement and young age of patients in the study cohort compared with the clinical trials. This study emphasizes the limitations of the current tools utilized to monitor ERT efficacy and MPS II disease burden in clinical practice.

Urine analysis of glucose tetrasaccharide by HPLC; a useful marker for the investigation of patients with Pompe and other glycogen storage diseases

A high performance liquid chromatography method, adapted from an established urinary sugars method, has been developed for the analysis of a tetraglucose oligomer (Glc4) in urine. Pompe disease results from defects in the activity of lysosomal acid α-glucosidase (GAA) with patients typically excreting increased amounts of Glc4. Rapid determination of GAA in dried blood spots is now possible. However, enzymatic analysis is unable to discriminate between patients with Pompe disease and those individuals harbouring pseudo deficiency mutations. This method was able to quantify Glc4 levels in all patients analysed with an established diagnosis of Pompe disease, and all controls analysed had Glc4 levels below the limit of detection for this method. Importantly the method was able to discriminate between an individual known to harbour a pseudo Pompe mutation and patients with Pompe disease, providing a useful supporting test to enzymatic analysis. Sequential measurement of urinary Glc4 has been proposed to monitor the effects of enzyme replacement therapy (ERT). We observed a clear decrease in Glc4 levels following commencement of treatment in three patients studied. Additionally, raised levels of Glc4 were observed in patients with glycogen storage disease (GSD) type Ia and type III suggesting that this method may have applications in other GSDs.

Successful Desensitisation in a Patient with CRIM-Positive Infantile-Onset Pompe Disease

Pompe disease (PD) is a severe life-threatening disease in which enzyme replacement therapy (ERT) with alglucosidase alfa is the only treatment available. Recently it has been shown that antibody formation may have a significant adverse effect on response to ERT. We report a cross-reactive immunologic material (CRIM)-positive PD infant who developed severe infusion-associated reactions (IARs) after 15 uneventful months of ERT. We successfully got the child to tolerate the ERT by a desensitisation protocol. We diluted the total amount of standard alglucosidase alfa infusion (20 mg/kg/dose) to 1/100 (0.2 mg/kg/dose). The original infusion rates were maintained. We doubled this dose every week. No premedication was given. In 8 weeks, we reached the standard dose without any IAR. No further reactions have been observed during 6 months of follow-up. Importantly, clinical deterioration that was observed during the period of reduced enzyme delivery has almost completely reversed. We conclude that this protocol was effective in our patient, while being safe and easy to follow, and may be suitable in selected cases.

Pulmonary hemorrhage in type 3 Gaucher disease: a case report

A 2-year-old boy with type 3 Gaucher disease (GD) on treatment with enzyme replacement therapy (ERT) was found dead in bed having been apparently well the night before. At the time of diagnosis, he had significant respiratory symptoms (severe and persistent bouts of coughing) that had been attributed to Gaucher lung infiltration and that were controlled by inhaled and orally administered steroids. These symptoms had begun to reappear just prior to death. Postmortem revealed extensive pulmonary hemorrhage and intra-alveolar collections of Gaucher cells. There was very little evidence of GD elsewhere. Death was ascribed to pulmonary hemorrhage secondary to GD. The pathogenesis was unclear. To the best of our knowledge, this is the first case of isolated pulmonary hemorrhage secondary to GD and may represent a hitherto unrecognized complication of this condition. Given the apparent temporal relationship, we propose that it represented a severe, terminal event in the course of Gaucher lung disease.