Effects Of Enzyme Replacement Therapy Research Articles

Quantification of muscle pathology in infantile Pompe disease

The effects of enzyme replacement therapy (ERT) in infantile Pompe disease are variable, necessitating the identification of biomarkers to assess the severity of disease and response to ERT. The aims of this study were to investigate whether quantification of muscle pathology in infantile Pompe disease prior to and during ERT is feasible at the light microscope, and to develop a score that summarizes the degree of muscle pathology in a comprehensive manner from PAS-stained resin sections alone. We, therefore, determined glycogen load, extent of muscle fibre disruption, and amount of autophagic vacuoles in resin-embedded muscle biopsy specimens from 11 infantile Pompe patients and 2 with early childhood phenotype by quantitative methods, correlated the findings with ultrastructural analyses, compared PAS-stained resin sections with conventional PAS-stained cryosections, and related the quantified degree of muscle damage from infantile patients to the effects of ERT. Comparison of electron and light microscopic findings demonstrated that important alterations of skeletal muscle morphology can also be depicted by examining PAS stained resin sections. Infantile patients with good response to ERT had lower muscle pathology score values prior to and during ERT than those with moderate and poor response, but the number of tissue samples available for evaluation was limited. These findings suggest that quantification of muscle pathology by analysing PAS stained resin sections is in principle feasible and useful to monitor disease progression and therapy response. These results have to be validated by investigating a larger group of patients.

P.67 - Effect of enzyme replacement therapy with alglucosidase alfa (Myozyme®) in 12 patients with advanced late-onset Pompe disease

Glycogen storage disease type II (Pompe disease) is a lysosomal disorder caused by deficiency in acid α-glucosidase. Enzyme replacement therapy (ERT) with recombinant human alglucosidase alfa (Myozyme®, Genzyme) is available since 2006. So far, treatment benefit in adults has been mostly evaluated in patients who maintained ability to walk, and without permanent ventilator assistance. The aim of this study is to evaluate ERT efficacy in twelve patients with advanced Pompe disease, identified from the French Pompe registry. Inclusion criteria were wheelchair dependency and ventilation support (>12 h/24) upon ERT initiation. Home mechanical ventilation hours, forced vital capacity (FVC), maximal inspiratory pressure (MIP), maximal expiratory pressure (MEP), ability to walk a few steps and motor function measure (MFM) scale prior and after ERT were studied, where available. Age at ERT initiation ranged from 20 to 73 years (mean = 49.3) and disease duration from 13 to 40 years (mean = 23.9). Years on ventilation varied from 4 to 40 (mean = 15.4) and of wheelchair use from 1 to 20 (mean = 9). ERT duration ranged from 9 to 111 months (mean 54.4). During follow-up, one patient reduced his daily time of ventilatory support, 9 remained fully dependant (24 h/24) and two became fully dependant of assisted ventilation. Values of FVC, MIP and MEP did not change significantly. At ERT initiation, 3 patients could walk a few meters with aid. Two of them increased their walking distance, while a decrease was observed in the third one. There were no significant changes of MFM values between start of ERT and last follow-up. Moreover, 5 patients died, after a treatment period ranging from 9 to 64 months (mean = 33.4). In our series of 12 patients who started ERT in an advanced stage of Pompe disease, we observed a clinically meaningful improvement of respiratory or muscle functions in two patients. Five patients died and five remained wheelchair bound and fully dependant of ventilatory support.

Cochleovestibular Manifestations in Fabry Disease

Fabry disease is a rare, X-linked lysosomal storage disorder resulting from deficient α-galactosidase A activity and globotriaosylceramide accumulation throughout the body. This accumulation leads to various clinical disorders, including inner ear lesions, with sensorineural hearing loss and dizziness. Although hearing loss is recognized in these patients, its incidence and natural history have not been characterized. Hearing disorders develop mainly in adulthood, and tinnitus may be an earlier symptom in Fabry disease. A significant incidence of mid- and high-frequency sensorineural hearing loss in affected males is commonly reported, whereas in female carriers, it is much less frequent. In addition, a high incidence of vestibular disorders with dizziness and chronic instability is also observed in these patients. The few studies about the effects of enzyme replacement therapy (ERT) on cochleovestibular symptoms show controversial results. Based on the model of densely stained material accumulation in th...

Long time enzyme replacement therapy stabilizes obstructive lung disease and alters peripheral immune cell subsets in Fabry patients.

Fabry disease is an X-linked lysosomal storage disorder, causing accumulation of globotriaosylceramid in different organs. Glycolipids are activators of different immune cell subsets the resulting inflammation is responsible for organ damage. Pulmonary involvement leads to airway inflammation; however, data on severity, as well as the effect of enzyme replacement therapy on lung function parameters and changes in peripheral immune cell subsets on lung involvement are sparse. Seven Fabry patients and four carriers underwent detailed clinical examinations screening for pulmonary manifestations. Repetitive measurements were performed on five patients on ERT (average follow-up 5 years). Patients with Fabry disease and control volunteers were included into peripheral blood cell measurements. Lung involvement was present in all patients. Symptoms suggestive for lung disease were mild, however, obstructive ventilatory disorder, dominantly affecting small airways accompanied by hyperinflation was demonstrated in all affected patients. ERT resulted in small improvement of FEV1 in most treated patients. Decreased ratio of myeloid DC, Th17 cells while increase in T helper (Th)1 cells, and no change in Th2 and regulatory T (Treg) cells were detected in Fabry patients. Fabry disease results mainly in mild symptoms related to lung involvement, characterized by moderate non-reversible obstructive ventilatory disorder. Stabilization of airway obstruction during follow-up was observed using ERT in most patients, emphasizing the importance of this treatment in respect of pulmonary manifestations. Changes of immune cell subsets in the peripheral blood might play a role in inflammatory process, including small airways in Fabry patient's lung.

Cardiac structure and function and effects of enzyme replacement therapy in patients with mucopolysaccharidoses I, II, IVA and VI.

While enzyme replacement therapy (ERT) has been shown to improve endurance and joint mobility for patients with mucopolysaccharidoses (MPS) I, II, IVA and VI, the impact of ERT on cardiac abnormalities remains uncertain. Medical records and echocardiograms of 28 Taiwanese MPS patients (9 with MPS I, 7 with MPS II, 7 with MPS IVA, and 5 with MPS VI) treated with ERT for 1-10.8years were retrospectively reviewed. At start of ERT, z scores>2 were identified in 46% and 75% for left ventricular mass index (LVMI) and interventricular septum thickness in diastole (IVSd) in these patients, respectively. Twenty-four patients (86%) had valvular heart disease. After ERT, the mean IVSd z score of all patients decreased significantly from 3.87 to 2.57 (p=0.016). For 11 patients starting ERT before 12years of age, z scores for both LVMI and IVSd decreased significantly (p<0.01) after ERT. However, the condition of valve regurgitation or stenosis did not show improvement despite ERT. ERT was shown to be an effective therapy for reducing cardiac hypertrophy, with best results seen when ERT was started at an early age. ERT, however, had little impact on valvular heart disease.

Effect of Enzyme Replacement Therapy on Disease Burden Biomarkers in Gaucher's Disease

Effect of Enzyme Replacement Therapy on Disease Burden Biomarkers in Gaucher's Disease

Functional capacity in a late-onset Pompe disease patient: Effect of enzyme replacement therapy and exercise training

Functional capacity in a late-onset Pompe disease patient: Effect of enzyme replacement therapy and exercise training

Effect of enzyme replacement therapy (ERT) added to Home Mechanical Ventilation (HMV) in Adult Pompe disease

Adult Pompe disease/acid maltase deficiency is an autosomal recessive disorder resulting in accumulation of glycogen in skeletal muscles, leading to myopathy frequently involving respiratory muscles. This involvement can cause respiratory insufficiency that may present as acute hypercapnic respiratory failure. Enzyme replacement therapy (ERT) with alpha - glucosidase alfa, the only disease-specific treatment, has been available as treatment option since 2006. ERT has shown efficacy concerning muscle strength and pulmonary function in adult patients as well as positive association with survival. We present two cases where addition of ERT to Home Mechanical Ventilation (HMV) showed improvements in lung function and gas exchange that may not be entirely attributable to nocturnal HMV and therefore may further indicate the beneficial role of ERT in conjunction with HMV in Adult Pompe disease.

A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency

BackgroundLysosomal acid lipase is an essential lipid-metabolizing enzyme that breaks down endocytosed lipid particles and regulates lipid metabolism. We conducted a phase 3 trial of enzyme-replacement therapy in children and adults with lysosomal acid lipase deficiency, an underappreciated cause of cirrhosis and severe dyslipidemia.MethodsIn this multicenter, randomized, double-blind, placebo-controlled study involving 66 patients, we evaluated the safety and effectiveness of enzyme-replacement therapy with sebelipase alfa (administered intravenously at a dose of 1 mg per kilogram of body weight every other week); the placebo-controlled phase of the study was 20 weeks long and was followed by open-label treatment for all patients. The primary end point was normalization of the alanine aminotransferase level. Secondary end points included additional disease-related efficacy assessments, safety, and side-effect profile.ResultsSubstantial disease burden at baseline included a very high level of low-density lipoprotein cholesterol (≥190 mg per deciliter) in 38 of 66 patients (58%) and cirrhosis in 10 of 32 patients (31%) who underwent biopsy. A total of 65 of the 66 patients who underwent randomization completed the double-blind portion of the trial and continued with open-label treatment. At 20 weeks, the alanine aminotransferase level was normal in 11 of 36 patients (31%) in the sebelipase alfa group and in 2 of 30 (7%) in the placebo group (P=0.03), with mean changes from baseline of −58 U per liter versus −7 U per liter (P<0.001). With respect to prespecified key secondary efficacy end points, we observed improvements in lipid levels and reduction in hepatic fat content (P<0.001 for all comparisons, except P=0.04 for triglycerides). The number of patients with adverse events was similar in the two groups; most events were mild and were considered by the investigator to be unrelated to treatment.ConclusionsSebelipase alfa therapy resulted in a reduction in multiple disease-related hepatic and lipid abnormalities in children and adults with lysosomal acid lipase deficiency. (Funded by Synageva BioPharma and others; ARISE ClinicalTrials.gov number, NCT01757184.)

Quality of life in patients with Fabry disease: a systematic review of the literature.

Fabry disease (FD), caused by deficiency of the lysosomal enzyme α-galactosidase-A, is a progressive multisystem disease. The disease is X-linked with generally more severe manifestations in males, but can impact on quality of life (QoL) of both male and female patients. The purpose of this literature review is to analyse the currently available data concerning QoL measurement, specifically which questionnaires have been used to measure QoL, how patients with FD score compared to the general population, and the effects of enzyme replacement therapy (ERT) on QoL. Fifty-four articles were relevant for this literature review. Patients with FD had a lower QoL compared to the general population. No definite conclusions could be drawn from the studies on the effect of ERT on QoL; natural history data is scarce, changes observed were limited and the cohorts were of small size. We propose that a FD specific questionnaire be made to accurately assess QoL in patients with FD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-015-0296-8) contains supplementary material, which is available to authorized users.

P82 – 2690: Surgical history in the child neurology clinic and consideration of Hunter syndrome: Insights from the Hunter Outcome Survey (HOS)

Objective Hunter syndrome (mucopolysaccharidosis type II, MPS II, OMIM 309900) is a lysosomal storage disease with progressive multisystem manifestations caused by a deficiency in the enzyme iduronate-2-sulfatase. Prompt diagnosis and treatment may improve patient outcomes, but delays in diagnosis are common. This analysis used data from Hunter Outcome Survey (HOS) to assess the potential role of paediatric neurologists in achieving earlier diagnosis of Hunter syndrome. Methods HOS is a global, multicentre, longitudinal registry that collects comprehensive real-world data on the natural history of Hunter syndrome and the long-term safety and effectiveness of enzyme replacement therapy with idursulfase (Elaprase®). The registry contains data from patients followed prospectively, as well as from those who were deceased at HOS entry. We analysed data on neurological signs and symptoms and surgical procedures that preceded formal diagnosis in prospective patients in HOS. Results As of 15 September 2014, 864 patients were followed prospectively in HOS; median ages at symptom onset and diagnosis were 1.5 and 3.2 years, respectively. Of 587 patients with available information, 51 (8.7%) were first suspected of having Hunter syndrome by neurologists/neurosurgeons. Information on neurological manifestations was available for 797 patients; 184 (23.1%) had neurological symptoms before diagnosis, with cognitive impairment (13.3%), behavioural problems (both 13.0%), and gait abnormalities (5.6%) being most common. Of 666 patients who required surgery at any time, 52.0% had first undergone surgery before diagnosis, with hernia repair (46.3%), tympanostomy (36.3%) and adenoidectomy (38.8%) being most common. Conclusion Consulting neurologists may play an important role in identifying patients with Hunter syndrome and initiating appropriate follow-up. Multiple ear, nose and throat procedures or hernia surgeries are a diagnostic clue for consideration of Hunter syndrome, especially in patients with other characteristic disease symptoms, such as dysmorphic facial features, dysphagia, airway problems, seizures, joint stiffness, developmental delay or carpal tunnel syndrome.

Role of the cardio-pulmonary exercise test and six-minute walking test in the evaluation of exercise performance in patients with late-onset Pompe disease

In patients with late-onset Pompe disease, we explored the role of the Cardiopulmonary Exercise Test (CPET) and the Six-Minute Walking Test (6MWT) in the assessment of exercise capacity and in the evaluation of the effects of enzyme replacement therapy (ERT). Eight patients affected by late-onset Pompe disease, followed up at the Centre for Neuromuscular Diseases and treated with ERT, underwent a baseline evaluation with a spirometry, a CPET and a 6MWT. Four of them were restudied after 36 months of treatment. Three patients showed a reduction in exercise capacity as evaluated by peak oxygen uptake (VO2) measured at the CPET and Distance Walked (DW) measured at the 6MWT (median % predicted: 67.1 [range 54.3–99.6] and 67.3 [56.6–82.6], respectively). Cardiac and respiratory limitations revealed by the CPET were correlated to peak VO2, but not to the DW. Nevertheless, percent of predicted values of peak VO2 and DW were strongly correlated (rho = 0.85, p = 0.006), and close to identity. In the longitudinal evaluation forced vital capacity decreased, while peak VO2 and DW showed a trend to a parallel improvement. We concluded that although only the CPET revealed causes of exercise limitation, which partially differed among patients, CPET and 6MWT showed a similar overall degree of exercise impairment. That held true in the longitudinal assessment during ERT, where both tests demonstrated similar small improvements, occurring despite deterioration in forced vital capacity.

The neurocognitive impact of Fabry disease on pediatric patients.

Fabry disease (FD) is an X-linked lysosomal storage disorder that results in progressive multisystemic organ complications. Several studies have examined neurocognitive impairments in adults; however, there is a paucity of research examining neurocognitive functioning in children with FD. This is the first exploratory study to examine the neurocognitive functioning of pediatric patients with FD and to evaluate the effects of enzyme replacement therapy (ERT) on neurocognitive functioning within this population. Families attending a national conference with at least one child with FD and one parent affected by FD comprised the sample (n = 48; 24 pediatric patients, 24 parents). Pediatric participants (10 males, 14 females) between the ages of 6 and 18 years and their parent(s) were involved in the study. Data from a demographic questionnaire and two neurocognitive self-report and parent-report measures were analyzed. Parent reports of neurocognitive functioning were also compared to a sample of children with and without head injury and to a sample of children who had undergone liver transplant (LT). Children with FD had poorer cognitive and executive functioning than healthy peers, and were comparable to children with head injury and LT. In addition, children using ERT had higher scores on measures of overall cognitive functioning, as well as fewer problems with attention/working memory and executive functioning. Results of this study suggest that children with FD may exhibit poorer cognitive and executive functioning relative to healthy peers. The use of ERT may mitigate the negative impact of FD on neurocognitive functioning in pediatric patients.

Effects of enzyme replacement therapy started late in a murine model of mucopolysaccharidosis type I.

Mucopolysaccharidosis type I (MPS I) is a progressive disorder caused by deficiency of α-L-iduronidase (IDUA), which leads to storage of heparan and dermatan sulphate. It is suggested that early enzyme replacement therapy (ERT) leads to better outcomes, although many patients are diagnosed late and don’t receive immediate treatment. This study aims to evaluate the effects of late onset ERT in a MPS I murine model. MPS I mice received treatment from 6 to 8 months of age (ERT 6–8mo) with 1.2mg laronidase/kg every 2 weeks and were compared to 8 months-old wild-type (Normal) and untreated animals (MPS I). ERT was effective in reducing urinary and visceral GAG to normal levels. Heart GAG levels and left ventricular (LV) shortening fraction were normalized but cardiac function was not completely improved. While no significant improvements were found on aortic wall width, treatment was able to significantly reduce heart valves thickening. High variability was found in behavior tests, with treated animals presenting intermediate results between normal and affected mice, without correlation with cerebral cortex GAG levels. Cathepsin D activity in cerebral cortex also did not correlate with behavior heterogeneity. All treated animals developed anti-laronidase antibodies but no correlation was found with any parameters analyzed. However, intermediary results from locomotion parameters analyzed are in accordance with intermediary levels of heart function, cathepsin D, activated glia and reduction of TNF-α expression in the cerebral cortex. In conclusion, even if started late, ERT can have beneficial effects on many aspects of the disease and should be considered whenever possible.

Effect of enzyme replacement therapy on airway abnormalities in patients with Hunter syndrome

Effect of enzyme replacement therapy on airway abnormalities in patients with Hunter syndrome

Long-Term Follow-Up of Pompe Patients in Israel and Gaza: Insights into Therapeutic Effects of Enzyme Replacement Therapy

Long-Term Follow-Up of Pompe Patients in Israel and Gaza: Insights into Therapeutic Effects of Enzyme Replacement Therapy

Актуальні питання діагностики та корекції лактазної недостатності в дітей та дорослих

У статті обговорюються особливості клінічного перебігу та проблеми лікування лактазної недостатності в дітей та дорослих. Доведена терапевтична ефективність застосування замісної ферментотерапії при лікуванні первинної та вторинної лактазної недостатності в новонароджених та дітей раннього віку як на грудному, так і на штучному вигодовуванні та в дітей старшого віку й дорослих, що дозволяє зберегти споживання лактози та зменшити обсяг медикаментозної терапії.

Hearing loss in adult patients with Fabry disease treated with enzyme replacement therapy.

Data on prevalence, natural history, and effect of enzyme replacement therapy (ERT) on hearing loss (HL) in Fabry disease (FD) are scarce. This is a retrospective study with cross-sectional and longitudinal analyses. Low and high-frequency HL in the Dutch FD cohort was studied in four groups: classical and non-classical FD patients with or without ERT. To study effects of ERT, longitudinal data, corrected for age and gender according to ISO-1999 guidelines, were analyzed with mixed models. In the cross-sectional analysis, 107 FD patients (41 males), median age 47.6 years (18.8-80.6) were analyzed. At baseline, i.e., before start of ERT, HL was present in 18 patients (16.8 %), of whom four had bilateral sensorineural HL. HL was more often present in patients with the classical phenotype than non-classical patients (p < 0.01). Likewise, males had more often HL than females. Compared to the general population, FD patients show a median HL of 8.2 dB at low frequencies (p < 0.01) and 29.5 dB at ultra-high frequencies (p < 0.01). Longitudinal analyses (n = 91) revealed that ERT treated patients show a similar rate of decline, not significantly different from healthy controls. Adult FD patients, especially classical affected males, show impaired hearing. Longitudinal analyses during ERT in these patients demonstrates a decline of HL similar to healthy controls, but HL present before initiation of therapy cannot be reversed. Whether early therapy can prevent hearing loss is unknown.

Effect of enzyme replacement therapy in late onset Pompe disease: open pilot study of 48 weeks follow-up.

Late-onset Pompe disease (LOPD) is an autosomal recessive disorder caused by deficiency of the enzyme acid glucosidase alfa (GAA). Recently, enzyme replacement therapy (ERT) using recombinant human GAA (rhGAA) became clinically available, and is expected to modify the clinical course in LOPD of various stages. In this study, we evaluated the efficacy and adverse events of ERT for 48 weeks in Korean LOPD patients. Five Korean LOPD patients were included in the study. At baseline, clinical and laboratory features, including muscular and pulmonary function, were assessed, and rhGAA was infused every 2 weeks. Then, patients were examined at every 12-week interval for evaluation of changes in motor and pulmonary function for 48 weeks along with adverse reactions to ERT. The muscular and pulmonary function of the patients varied depending on the baseline condition of the patient after 48 weeks of ERT. However, the overall function of the patients showed stabilization of the disease rather than the improvement seen in infantile-onset Pompe disease. This is the first clinical study on ERT of Korean LOPD patients. Results of our study showed stabilization of muscular and pulmonary function in LOPD patients for 48 weeks with a favorable prognosis for patients who received early diagnosis and ambulatory patients. One of our patients developed a serious anaphylactic reaction, which necessitated the cessation of further ERT. Therefore, our study shows that early diagnosis and ERT are important in preventing further deterioration of the disease.

Biomarker responses correlate with antibody status in mucopolysaccharidosis type I patients on long-term enzyme replacement therapy

BackgroundAntibody formation can interfere with effects of enzyme replacement therapy (ERT) in lysosomal storage diseases. Biomarkers are used as surrogate marker for disease burden in MPS I, but large systematic studies evaluating the response of biomarkers to ERT are lacking. We, for the first time, investigated the response of a large panel of biomarkers to long term ERT in MPS I patients and correlate these responses with antibody formation and antibody mediated cellular uptake inhibition. MethodsA total of 428 blood and urine samples were collected during long-term ERT in 24 MPS I patients and an extensive set of biomarkers was analyzed, including heparan sulfate (HS) and dermatan sulfate (DS) derived disaccharides; total urinary GAGs (DMBu); urinary DS:CS ratio and serum heparin co-factor II thrombin levels (HCII-T). IgG antibody titers and the effect of antibodies on cellular uptake of the enzyme were determined for 23 patients. ResultsMedian follow-up was 2.3years. In blood, HS reached normal levels more frequently than DS (50% vs 12.5%, p=0.001), though normalization could take several years. DMBu normalized more rapidly than disaccharide levels in urine (p=0.02). Nineteen patients (83%) developed high antibody titers. Significant antibody-mediated inhibition of enzyme uptake was observed in 8 patients (35%), and this correlated strongly with a poorer biomarker response for HS and DS in blood and urine as well as for DMBu, DS:CS-ratio and HCII-T (all p<0.006). ConclusionsThis study shows that, despite a response of all studied biomarkers to initiation of ERT, some biomarkers were less responsive than others, suggesting residual disease activity. In addition, the correlation of cellular uptake inhibitory antibodies with a decreased biomarker response demonstrates a functional role of these antibodies which may have important clinical consequences.