36 Months observational clinical study of 38 adult Pompe disease patients under alglucosidase alfa enzyme replacement therapy

Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians University Munich, Munich, Germany.
Journal of Inherited Metabolic Disease (Impact Factor: 3.37). 01/2012; 35(5):837-45. DOI: 10.1007/s10545-012-9451-8
Source: PubMed


Glycogen storage disease type 2(GSD2)/Pompe disease is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span.
We present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 38 adult-onset GSD2 patients (20 female, 18 male) with a mean age at disease onset of 36.2 ± 10.5 years. Mean delay between symptom onset and start of ERT was 14.5 ± 7.2 years. Assessments included serial Walton Gardner Medwin scale, arm function tests, timed 10-meter walk tests, 4- stair climb tests, modified Gowers' maneuvers, 6-minute walk test (6MWT), MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels, and SF-36 selfreporting questionnaires. All tests were performed at baseline and every 12 months for 36 months of ERT.
In the 6MWT we found 21 patients able to walk at baseline a mean distance of 312 ± 165.5 m, improving to 344 ± 165.8 m after 12 months (p=0.006), remaining at 356.4 ± 155.9 m at 24 months (p=0.033), and declining to 325.6 ± 174.8 m after 36 months of ERT (p=0.49, n.s.). The mean FVC in 28 patients was 80.27 ± 14.08% of predicted normal at baseline, after 12 months 79.19 ± 13.09%, at 24 months 78.62 ± 16.55%, and 77.19 ± 18.05%after 36 months. Only mean CK levels were significantly decreased by 8.8% (p=0.041). All other tests were statistically nonsignificant changed.
Our data denote a rather variable course of neuromuscular deficits in chronic adult-onset Pompe patients during 36 months of alglucosidase alfa ERT.

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    • "The clinical phenotype of LOPD is characterized by slowly progressive proximal muscle weakness involving axial and respiratory muscles that is associated with significant morbidity and reduced life expectancy [2] [3] [4] [5] [6] [7].S i n c e 2006, an enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase (rhGAA) is available for the treatment of Pompe disease (alglucosidase alfa, Myozyme®, Lumizyme®, Genzyme Corporation , a Sanofi company, Cambridge MA, USA). Clinical studies showed that motor performance, respiratory function and fatigue improved or stabilized in at least two-thirds of LOPD patients who received ERT over 6–36 months [8] [9] [10] [11] [12] [13] [14] [15]. The functional outcome seems to be best when ERT starts timely, i.e. at an early clinical stage of LOPD [12] [16]. "
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    ABSTRACT: Background Late-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD. Objective We analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters. Methods Three symptomatic LOPD patients who received ERT for five years and four untreated presymptomatic LOPD patients were included in the study. T1-weighted MRI images were used to determine volumes of thigh and lower leg muscles. In addition, mean gray values of eight individual thigh muscles were calculated to assess the degree of lipomatous muscle alterations. Results We detected a decrease in thigh muscle volume of 6.7% (p < 0.001) and an increase in lower leg muscle volume of 8.2% (p = 0.049) after five years of ERT. Analysis of individual thigh muscles revealed a positive correlation between the degree of lipomatous muscle alterations at baseline and the increase of gray values after five years of ERT (R2 = 0.68, p < 0.001). Muscle imaging in presymptomatic patients showed in one case pronounced lipomatous alteration of the adductor magnus muscle and mild to moderate changes in further thigh muscles. Conclusions The results demonstrate that fatty muscle degeneration can occur before clinical manifestation of muscle weakness and suggest that mildly affected muscles may respond better to ERT treatment than severely involved muscles. If these findings can be validated by further studies, it should be discussed if muscle alterations detected by muscle MRI may be an objective sign of disease manifestation justifying an early start of ERT in clinically asymptomatic patients in order to improve the long-term outcome.
    Full-text · Article · Jun 2015 · Molecular Genetics and Metabolism Reports
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    • "aspx; Bembi et al. 2008). In adult patients, observations regarding the nutritional status only included changes of body mass index under ERT (van der Beek et al. 2009; Ravaglia et al. 2010a; Ravaglia et al. 2010b; Kobayashi et al. 2010; Papdimas et al. 2010; Bernstein et al. 2010; Regnery et al. 2012; Sch€ uller et al. 2012). Recent reports on small cohorts addressed the issue of gastrointestinal symptoms in adults with Pompe disease as well as symptoms such as chronic diarrhoea, bowel urge incontinence, meteorism, gastrointestinal reflux, and obstipation (Bernstein et al. 2010; Sacconi et al. 2010; Remiche et al. 2012). "
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    ABSTRACT: Objective: To determine the frequency and impact of gastrointestinal symptoms, and bowel and urinary incontinence, as this is currently unknown in adults with Pompe disease. Methods: Adult German Pompe patients and age- and gender-matched controls were asked about symptoms in the upper and lower intestinal tract as well as urinary incontinence using the Gastrointestinal Symptoms Questionnaire and the International Consultation on Incontinence Questionnaires for Bowel Symptoms and Urinary Incontinence. Results: The overall response rate was 78%; 57 patients and 57 controls participated. The mean age of the patients was 48.3 years ±14.7 (28 female, 29 male). 84% of patients were receiving enzyme replacement therapy. Stool urgency, diarrhoea, and urinary urge incontinence were reported significantly more frequently in patients compared to the age- and gender-matched controls (55%, 56%, 33% vs. 20%, 18%, 7%). 20% of Pompe patients used loperamide daily against diarrhoea. No other gastrointestinal tract-related symptoms were reported to occur more frequently in Pompe patients than in controls. Conclusions: Compared to age- and gender-matched controls, both urinary and bowel incontinence occur in a higher frequency in adults with Pompe disease and have a major impact on daily life.
    Full-text · Article · Aug 2014
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    • "Nine clinical studies of late-onset Pompe patients were identified that used % predicted FVC as an outcome measure [12,13,18,31,34,42-45]. When the MCID ranges established for FVC in IPF were applied to these studies, both the absolute and relative change in FVC were above the MCID range in 2 studies [44,45], within the MCID in 3 studies [12,13,43], and below the MCID in 4 studies (Table  2) [18,31,34,42]. In the majority of studies of alglucosidase alfa treatment, patients who had a change in FVC within or above the MCID range established for IPF also reported a noticeable improvement. "
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    ABSTRACT: Pompe disease/glycogen storage disease type II, is a rare, lysosomal storage disorder associated with progressive proximal myopathy, causing a gradual loss of muscular function and respiratory insufficiency. Studies of patients with late-onset Pompe disease have used endpoints such as the 6-minute walking test (6MWT) and forced vital capacity (FVC) to assess muscular and respiratory function during disease progression or treatment. However, the relevance of these markers to late-onset Pompe disease and the minimal clinically important difference (MCID) for these endpoints in late-onset Pompe disease have not yet been established. A literature search was carried out to identify studies reporting the MCID (absolute and relative) for the 6MWT and FVC in other diseases. The MCIDs determined in studies of chronic respiratory diseases were used to analyze the results of clinical studies of enzyme replacement therapy in late-onset Pompe disease. In 9 of the 10 late-onset Pompe disease studies reviewed, changes from baseline in the 6MWT were above or within the MCID established in respiratory diseases. Clinical improvement was perceived by patients in 6 of the 10 studies. In 6 of the 9 late-onset Pompe disease studies, the changes from baseline in percentage change in predicted FVC were above or within the MCID established for respiratory diseases and the difference was perceived as either an improvement or stabilization by patients." with "In 6 of the 9 late-onset Pompe disease studies that reported FVC, the changes from baseline in percentage predicted FVC were above or within the MCID established in respiratory diseases and the difference was perceived as either an improvement or stabilization by patients. However, applying the 6MWT and FVC MCIDs from studies of chronic respiratory diseases to late-onset Pompe disease has several important limitations. Outcome measures in muscular dystrophies include composite measures of muscle function and gait, as well as Rasch-designed and validated tools to assess disease-related quality of life and activities of daily living. Given that the relevance to patients with late-onset Pompe disease of the 6MWT or FVC MCIDs established for chronic respiratory diseases is unclear, these measures should be evaluated specifically in late-onset Pompe disease and alternative outcome measures more specific to neuromuscular disease considered.
    Full-text · Article · Oct 2013 · Orphanet Journal of Rare Diseases
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