Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy

Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare X-linked recessive disease caused by deficiency of the lysosomal enzyme iduronate-2-sulphatase, leading to progressive accumulation of glycosaminoglycans in nearly all cell types, tissues and organs. Clinical manifestations include severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline. Death usually occurs in the second decade of life, although some patients with less severe disease have survived into their fifth or sixth decade. Until recently, there has been no effective therapy for MPS II, and care has been palliative. Enzyme replacement therapy (ERT) with recombinant human iduronate-2-sulphatase (idursulfase), however, has now been introduced. Weekly intravenous infusions of idursulfase have been shown to improve many of the signs and symptoms and overall wellbeing in patients with MPS II. This paper provides an overview of the clinical manifestations, diagnosis and symptomatic management of patients with MPS II and provides recommendations for the use of ERT. The issue of treating very young patients and those with CNS involvement is also discussed. ERT with idursulfase has the potential to benefit many patients with MPS II, especially if started early in the course of the disease

Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study

Background: Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat. Methods: The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if <3 scores were lower/unchanged between enrolment and last follow-up visit. Results: In total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early-infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (≥15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data. Conclusions: Disability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years