Enzyme replacement therapy for the treatment of Hunter disease: A systematic review with narrative synthesis and meta-analysis.

BACKGROUND: In the last 10 years enzyme replacement therapy (ERT) has become an alternative for the treatment of patients with Hunter disease (HD). Nevertheless, the information regarding efficacy and safety is scarce and mainly based on the pivotal trials. This scarcity is especially evident for adults and severe forms of HD. METHODS: A systematic review of publications in the electronic databases PUBMED, EMBASE and Cochrane Central was undertaken. Clinical trials and observational studies were included. The data about efficacy and security were retrieved and analysed with Review Manager version 5.3. RESULTS: 677 records were found, 559 remaining after the removal of duplicates. By title and abstract review, 427 were excluded. Full reading of the rest was made (122 publications) and 42 were finally included. It was not possible to perform meta-analysis of all the endpoints due to high heterogeneity in the reporting and measuring of variables in each publication. Eight clinical trials were included, 6 with high risk of bias. The quality of the other studies was low in 12%, average in 68% and good in 21%. Main findings were: a reduction in the elimination of glycosaminoglycans (GAG) in urine in all the studies (26/26), decrease in liver and spleen size (18/18), increase of 52.59 m (95% CI, 36, 42-68.76, p < .001) in the 6-min walk test (TM6M), increase in forced vital capacity (FVC) of 9.59% (95% CI 4.77-14.51, p < .001), reduction of the left ventricular mass index of 3.57% (95% CI 1.2-5.93) and reduction in mortality (OR) of 0.44 (0.27-0.71). DISCUSSION: The data suggests a clear and consistent effect of ERT in HD reducing the accumulation of GAGs in the body, demonstrated by the reduction of its urinary excretion, as well as by the reduction of its deposits (spleen, liver and heart). Likewise, there is an improvement in physical and respiratory function. In addition, a reduction in mortality has been observed. Lack of studies, small size of the samples, and methodological deficiencies are the main limitations to establish definite conclusions. CONCLUSIONS: The data suggests that ERT is effective and safe in the treatment of HD. There is a need to evaluate patient-centred outcomes and the impact on quality of life.

Ten years of enzyme replacement therapy in paediatric onset mucopolysaccharidosis II in England.

The outcome of 110 patients with paediatric onset mucopolysaccharidosis II (MPS II) since the commercial introduction of enzyme replacement therapy (ERT) in England in 2007 is reported. Median length of follow up was 10 years 3 months (range = 1 y 2 m to 18 years 6 month). 78 patients were treated with ERT, 18 had no ERT or disease modifying treatment 7 had haematopoietic stem cell transplant, 4 experimental intrathecal therapy and 3 were lost to follow up. There is clear evidence of improved survival (median age of death of ERT treated (n = 16) = 15.13 years (range = 9.53 to 20.58 y), and untreated (n = 17) = 11.43 y (0.5 to 19.13 y) p = .0005). Early introduction of ERT improved respiratory outcome at 16 years, the median FVC (% predicted) of those in whom ERT initiated <8 years = 69% (range = 34-86%) and 48% (25-108) (p = .045) in those started >8 years. However, ERT appears to have minimal impact on hearing, carpal tunnel syndrome or progression of cardiac valvular disease. Cardiac valvular disease occurred in 18/46 (40%), with progression occurring most frequently in the aortic valve 13/46 (28%). The lack of requirement for neurosurgical intervention in the first 8 years of life suggests that targeted imaging based on clinical symptomology would be safe in this age group after baseline assessments. There is also emerging evidence that the neurological phenotype is more nuanced than the previously recognized dichotomy of severe and attenuated phenotypes in patients presenting in early childhood.

Survival in idursulfase-treated and untreated patients with mucopolysaccharidosis type II: data from the Hunter Outcome Survey (HOS).

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a life-limiting, multisystemic disease with varying presentation and severity. Enzyme replacement therapy with intravenous idursulfase (EC 3.1.6.13) has been available since 2006. Data from the Hunter Outcome Survey (July 2016) were used to compare survival in idursulfase-treated (n = 800) and untreated (n = 95) male patients followed prospectively in this multinational, observational registry. Median age at symptom onset was similar for the treated and untreated groups (1.6 and 1.5 years, respectively), as was median age at diagnosis (3.3 and 3.2 years) and the proportion of patients with cognitive impairment (58.0%; 57.9%). The proportion of idursulfase-treated patients differed according to geographical region. Overall, 124/800 (15.5%) treated and 28/95 (29.5%) untreated patients had died. Respiratory failure was the most common cause of death (treated, 43/124 [34.7%]; untreated, 10/28 [35.7%]). Median survival (95% confidence interval [CI]) was 33.0 (30.4, 38.4) years in treated patients and 21.2 (16.1, 31.5) years in untreated patients; median follow-up time from birth to death or last visit was 13.0 and 15.1 years, respectively. A Cox model adjusted for treatment status, cognitive impairment, region and age at diagnosis indicated a 54% lower risk of death in treated compared with untreated patients: hazard ratio (HR), 0.46 (95% CI: 0.29, 0.72). Patients with cognitive impairment had nearly a fivefold higher risk of death than those without (HR, 4.84 [3.13, 7.47]). This analysis in a large population of patients with MPS II indicates for the first time that idursulfase treatment is associated with increased survival.

Causes of death and clinical characteristics of 34 patients with Mucopolysaccharidosis II in Taiwan from 1995-2012.

BACKGROUND: Mucopolysaccharidosis type II (MPS II) is an X-linked recessive, multisystemic lysosomal storage disorder caused by a deficiency of iduronate-2-sulfatase. MPS II has a variable age of onset and variable rate of progression. In Asian countries, there is a relatively higher incidence of MPS II compared to other types of MPS. METHODS: A retrospective analysis was carried out of 34 Taiwanese MPS II patients who died between 1995 and 2012. The clinical characteristics, medical records, age at death, and cause of death were evaluated to better understand the natural progression of this disease. RESULTS: The mean age at death of 31 of the patients with a severe form of the disease with significant cognitive impairment was 13.2 ± 3.2 years, compared with 22.6 ± 4.3 years in the three patients with a mild form of the disease without cognitive involvement (n = 2) or the intermediate form (n = 1) (p < 0.001). The mean ages at onset of symptoms and confirmed diagnosis were 2.5 ± 2.1 and 4.8 ± 3.1 years, respectively (n = 32). Respiratory failure was the leading cause of death (56 %), followed by cardiac failure (18 %), post-traumatic organ failure (3 %), and infection (sepsis) (3 %) (n = 27). Age at onset of symptoms was positively correlated with life expectancy (p < 0.01). Longevity gradually increased over time from 1995 to 2012 (p < 0.05). CONCLUSIONS: Respiratory failure and cardiac failure were the two major causes of death in these patients. The life expectancy of Taiwanese MPS II patients has improved in recent decade.

Modulation of expression of genes involved in glycosaminoglycan metabolism and lysosome biogenesis by flavonoids.

Flavonoids were found previously to modulate efficiency of synthesis of glycosaminoglycans (GAGs), compounds which are accumulated in cells of patients suffering from mucopolysaccharidoses (MPSs). The aim of this work was to determine effects of different flavonoids (genistein, kaempferol, daidzein) used alone or in combinations, on expression of genes coding for proteins involved in GAG metabolism. Analyses with DNA microarray, followed by real-time qRT-PCR revealed that genistein, kaempferol and combination of these two compounds induced dose- and time-dependent remarkable alterations in transcript profiles of GAG metabolism genes in cultures of wild-type human dermal fibroblasts (HDFa). Interestingly, effects of the mixture of genistein and kaempferol were stronger than those revealed by any of these compounds used alone. Similarly, the most effective reduction in levels of GAG production, in both HDFa and MPS II cells, was observed in the presence of genistein, keampferol and combination of these compounds. Forty five genes were chosen for further verification not only in HDFa, but also in MPS II fibroblasts by using real-time qRT-PCR. Despite effects on GAG metabolism-related genes, we found that genistein, kaempferol and mixture of these compounds significantly stimulated expression of TFEB. Additionally, a decrease in MTOR transcript level was observed at these conditions.

Effect of rapid cessation of enzyme replacement therapy: a report of 5 cases and a review of the literature.

UNLABELLED: Enzyme replacement therapy (ERT) is a treatment modality available for several of the lysosomal storage diseases including mucopolysaccharidosis type II (MPS II). We report a series of patients with MPS II (n = 5, age range at the start of ERT 11-21 years, median 15 years) and the effects of ERT cessation (range 2-8 months, median 3 months) on their clinical status. Additionally, we review previously published cases. In our series, a worsening of the patients' clinical status was observed. Symptoms after ERT discontinuation included recurrent respiratory infections (severe pneumonia) with respiratory insufficiency (80%), difficulty with walking/standing (60%), increased joint stiffness (40%), but also decreased hematological parameters (40%), renal insufficiency (40%) and death (20%). The literature review confirms that the beneficial clinical effects of ERT are soon lost if treatment is discontinued in MPS I and Pompe patients. CONCLUSIONS: 1. Rapid cessation of ERT results not only in the loss of the beneficial effects, but in a significant worsening of the patient's clinical status. 2. Decisions about the introduction of ERT, especially in patients severely affected, should be made carefully. 3. Once started, it is essential to keep an adequate administration schedule of ERT to maintain the clinical benefits of enzyme therapy.

Natural progression of neurological disease in mucopolysaccharidosis type II.

OBJECTIVE: Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder characterized by insufficiency of the iduronate-2-sulfatase enzyme, which results in excess heparan and dermatan sulfates within the lysosomes of various tissues and organs, including the central nervous system. The purpose of this study was to investigate the natural progression of neurologic disease in a large cohort of patients evaluated with standardized testing at a single institution. METHODS: During the period of December 2002 to October 2010, patients with MPS II were referred to the Program for Neurodevelopmental Function in Rare Disorders. A retrospective review of patient data was performed, which included the use of detailed questionnaires that addressed medical history, notes from previous health care providers, and the results of a multidisciplinary evaluation that lasted 4 to 6 hours and was performed by a team of neurodevelopmental pediatricians, speech pathologists, psychologists, audiologists, psychometricians, and occupational and physical therapists. Patients were evaluated annually for management of disease progression. RESULTS: A total of 50 male patients with MPS II were evaluated over 152 encounters. Two distinct subgroups of children were identified. One subset of patients had normal cognitive, speech and language, and adaptive functions whereas the other showed a dramatic decline in these areas. All patients developed fine and gross motor deficits. CONCLUSION: The natural progression of MPS II manifests as 2 divergent and distinct neurologic phenotypes with similar somatic disease. Patients may have primary neural parenchymal disease with cognitive involvement or may maintain normal cognitive abilities.

Incidence and timing of infusion-related reactions in patients with mucopolysaccharidosis type II (Hunter syndrome) on idursulfase therapy in the real-world setting: a perspective from the Hunter Outcome Survey (HOS).

OBJECTIVE: To evaluate the occurrence of infusion-related reactions (IRRs) in patients with mucopolysaccharidosis type II (MPS II) receiving idursulfase enrolled in the observational database HOS - the Hunter Outcome Survey. STUDY DESIGN: Information in HOS regarding the frequency, timing and severity of reported IRRs during the first year of treatment with idursulfase was analyzed, and formation of antibodies to idursulfase was characterized. The analysis was restricted to patients who started treatment with idursulfase at or after enrolment in HOS and for whom at least 1 year of follow-up data was available (n=104; data collected on or before 16 October 2009). RESULTS: A total of 65 IRRs were reported in 33 (31.7%) patients in the first year of enzyme replacement therapy (ERT). Six of these patients experienced more than three events. Nearly all of the initial IRRs occurred during the first 3months of ERT; five patients (4.8% of the total patient population) experienced their first IRR after 3months of treatment. Only two patients (1.9% of the total patient population) experienced their first IRR after more than 6 months of ERT. Most of the IRRs were of mild-to-moderate severity. After initially stopping the infusion, IRRs were generally readily managed by slowing the infusion and/or use of antihistamines or antipyretics. No patient in this analysis discontinued ERT because of an IRR event. IgG antibodies to idursulfase were detected in 32/63 patients (50.8%) for whom samples were taken; no patient developed IgE to idursulfase. Serum antibody levels were measured within 24h of an IRR for 10 IRRs in 7 patients; 7/9 samples contained IgG to idursulfase, 2 of which had neutralizing activity. CONCLUSIONS: IRRs in patients receiving idursulfase can typically be readily managed without interruption of treatment. Initial IRRs usually occur in the first 3 months of treatment, but in rare instances may occur after more than 6 months of therapy. Physicians using ERT to treat patients with MPS II, either in the clinic or at home, should therefore be familiar with the timing, nature and recommended management of IRRs.

Mortality and cause of death in mucopolysaccharidosis type II-a historical review based on data from the Hunter Outcome Survey (HOS).

Mucopolysaccharidosis type II (MPS II or Hunter syndrome) is a progressive, multisystemic disease caused by a deficiency of iduronate-2-sulfatase. Patients with the severe form of the disease have cognitive impairment and typically die in the second decade of life. Patients with the less severe form do not experience significant cognitive involvement and may survive until the fifth or sixth decade of life. We studied the relationship of both severity of MPS II and the time period in which patients died with age at death in 129 patients for whom data were entered retrospectively into HOS (Hunter Outcome Survey), the only large-scale, multinational observational study of patients with MPS II. Median age at death was significantly lower in patients with cognitive involvement compared with those without cognitive involvement (11.7 versus 14.1 years; p = 0.024). These data indicate that cognitive involvement is indicative of more severe disease and lower life expectancy in patients with MPS II. Median age at death was significantly lower in patients who died in or before 1985 compared with those who died after 1985 (11.3 versus 14.1 years; p alpha 0.001). The difference in age at death between patients dying in or before, relative to after, the selected cut-off date of 1985 may reflect improvements in patient identification, care and management over the past two decades. Data from patients who died after 1985 could serve as a control in analyses of the effects of enzyme replacement therapy with idursulfase on mortality in patients with MPS II.

Incidence of the mucopolysaccharidoses in Northern Ireland.

An epidemiological study of the mucopolysaccharidoses (MPS) in Northern Ireland using multiple ascertainment sources was carried out and the incidence rate for the period 1958-1985 was estimated. An incidence of approximately 1 in 76,000 live births was obtained for MPS 1H (Hurler phenotype); 1 in 280,000 for MPS 1 H/S (Hurler/Scheie phenotype); 1 in 140,000 live births (1 in 72,000 male live births) for MPS II (Hunter syndrome); 1 in 280,000 for MPS III (Sanfilippo syndrome) and 1 in 76,000 for MPS IV A (Morquio syndrome type A). No cases of MPS IS (Scheie phenotype), MPS IV B (Morquio syndrome type B) or MPS VI (Maroteaux-Lamy syndrome) were ascertained during the study period. Three cases of non-immune hydrops fetalis born to consanguineous parents were thought to be due to beta-glucuronidase deficiency (MPS VII) on the basis of placental histology and enzyme studies on both parents but no living cases of MPS VII were ascertained. The overall incidence for all types of mucopolysaccharidosis was approximately 1 in 25,000 live births. A comparison is made with incidence estimates obtained from other published studies.