Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): A protocol for a sham-controlled clinical trial.

INTRODUCTION: Morbidity and mortality in adults with late-onset Pompe disease (LOPD) results primarily from persistent progressive respiratory muscle weakness despite treatment with enzyme replacement therapy (ERT). To address this need, we have developed a 12-week respiratory muscle training (RMT) program that provides calibrated, individualized, and progressive pressure-threshold resistance against inspiration and expiration. Our previous results suggest that our RMT regimen is safe, well-tolerated, and results in large increases in respiratory muscle strength. We now conduct an exploratory double-blind, randomized control trial (RCT) to determine: 1) utility and feasibility of sham-RMT as a control condition, 2) the clinically meaningful outcome measures for inclusion in a future efficacy trial. This manuscript provides comprehensive information regarding the design and methods used in our trial and will aid in the reporting and interpretation of our future findings. METHODS: Twenty-eight adults with LOPD will be randomized (1:1) in blocks of 4 to RMT (treatment) or sham-RMT (control). Assessments will be conducted at pretest, posttest, 3-months detraining, and 6-months detraining. The primary outcome is maximum inspiratory pressure (MIP). Secondary outcomes include maximum expiratory pressure (MEP), 6-min walk test (6MWT), Gait, Stairs, Gowers, and Chair test (GSGC), peak cough flow (PCF), and patient-reported life activity/social participation (Rasch-built Pompe-specific Activity scale [R-Pact]). Exploratory outcomes include quantitative measures from polysomnography; patient reported measures of fatigue, daytime sleepiness, and sleep quality; and ultrasound measures of diaphragm thickness. This research will use a novel tool to provide automated data collection and user feedback, and improve control over dose. ETHICS AND DISSEMINATION: The results of this clinical trial will be promptly analyzed and submitted for publication. Results will also be made available on clinicaltrials.gov. ClinicalTrials.gov: NCT02801539, R21AR069880.

Exercise therapy for muscle and lower motor neuron diseases.

Muscle and lower motor neuron diseases share a common denominator of perturbed muscle function, most often related to wasting and weakness of muscles. This leads to a number of challenges, such as restricted mobility and respiratory difficulties. Currently there is no cure for these diseases. The purpose of this review is to present research that examines the effects of exercise in muscle and lower motor neuron diseases. Evidence indicates that moderate intensity aerobic- and strength exercise is advantageous for patients with muscle diseases, without causing harmful exercise-induced muscle damage. On the contrary, motor neuron diseases show a rather blunted response from exercise training. High-intensity training is a modality that seems safe and a promising exercise method, which may circumvent neural fatigue and provide effect to patients with motor neuron disease. Although we have come far in changing the view on exercise therapy in neuromuscular diseases to a positive one, much knowledge is still needed on what dose of time, intensity and duration should be implemented for different disease and how we should provide exercise therapy to very weak, non-ambulatory and wheelchair bound patients.

Safety and efficacy of short- and long-term inspiratory muscle training in late-onset Pompe disease (LOPD): a pilot study.

BACKGROUND: In patients with late-onset Pompe disease, progressive respiratory muscle weakness with predominantly diaphragmatic involvement is a frequent finding at later stages of the disease. Respiratory muscle training (RMT) is an established therapy option for patients with several neuromuscular disorders including Duchenne muscular dystrophy. Forced voluntary muscle contractions of inspiration and/or expiration muscles enhance ventilation by increasing respiratory coordination, endurance, and strength. Efficacy of RMT in LOPD is rarely examined, and the clinical studies performed are difficult to compare because of different training programs and protocols. This impedes a useful statement and recommendation about the safety and efficacy of respiratory muscle training. METHODS: We conducted a monocentric unblinded single-arm pilot study in patients with LOPD to evaluate the safety and efficacy of inspiratory muscle training (IMT). The primary objective was to determine the efficacy of a 6-week repetitive IMT with a gradual increase of inspiratory resistance, measured by MIP (maximum inspiratory pressure) in the upright position. For statistical analysis, we used an A-B-C single subject design. The 6-week training-period A was followed by a 6-week non-training period B and an optional training period of 40 weeks in period C. The total study duration for the periods A, B and C was 52 weeks. Throughout the study, spirometry assessments (FCV, FEV1) and measurements of respiratory strength (MIP, MEP) were performed at defined time points, as well as capillary oximetry and capnometry, motor function test and patient's questionnaires for quality of life and dyspnea, measured by St. George's Respiratory Questionnaire (SGRQ) and MMRC-Dyspnea scale. For the cross-sectional comparison, a paired two-sided t test, and for the longitudinal comparison, a two-sample, two-sided t test were used. When data were not normally distributed, a Wilcoxon-Mann-Whitney test was added. Finally, the annual decline in FVC and FEV1 before and after IMT was compared. FINDINGS: 11 subjects were included in this pilot study. Overall, IMT was well tolerated. In four subjects, a total of six adverse events related to the study procedures were noticed. Training compliance was excellent in the first weeks of training, but declined continuously in the extension period. There was a significant increase in our primary outcome measure MIP within the 6-week period of frequent IMT with a mean of 15.7% (p =0.024; d =0.402). A significant increase was also seen after week 52 by a mean of + 26.4% (mean + 13.4 cmH2O, p =0.001, d =0.636). In the 6-week non-training interim-period (period B), the values remained stable, and there was no clinically meaningful decline in secondary outcome measures. The increase in MIP did not have any effect on secondary outcome measures like spirometry tests (FVC, FEV1), capillary blood gas analysis, motor function tests, patient's perceived quality of life or any significant change in dyspnea score. CONCLUSIONS: Frequent IMT improves MIP and thereby stabilizes and decelerates the decline of the diaphragm strength. The gradual increase of inspiratory resistance is well tolerated without any increase of side effects, as long as IMT is supervised and resistance is individually adjusted to the patient's perceived grade of exhaustion. Although we could not detect a significant impact on secondary outcome measures, IMT should be offered to all LOPD patients, especially to those who demonstrate a progressive decline in respiratory muscle function or are unable to receive ERT.

Transfer of Therapeutic Genes into Fetal Rhesus Monkeys Using Recombinant Adeno-Associated Type I Viral Vectors.

Neuromuscular disorders such as Pompe disease (glycogen storage disease, type II), result in early and potentially irreversible cellular damage with a very limited opportunity for intervention in the newborn period. Pompe disease is due to deficiency in acid α-glucosidase (GAA) leading to lysosomal accumulation of glycogen in all cell types, abnormal myofibrillogenesis, respiratory insufficiency, neurological deficits, and reduced contractile function in striated muscle. Previous studies have shown that fetal delivery of recombinant adeno-associated virus (rAAV) encoding GAA to the peritoneal cavity of Gaa-/- mice resulted in high-level transduction of the diaphragm. While progression of other genetic disorders may occur later in life, the potential of fetal gene delivery to avoid the onset of irreversible damage suggests it is an attractive option for many inherited diseases. In this study, rhesus monkey fetuses were administered 4.5 × 1012 particles of rAAV type 1 expressing human GAA (rAAV1-CMV-hGAA), human α-1-antitrypsin (rAAV1-CBA-hAAT), or human mini-dystrophin (rAAV1-CMV-miniDMD) in the late first trimester using an established intraperitoneal ultrasound-guided approach. Fetuses were monitored sonographically and newborns delivered at term for postnatal studies. All animals remained healthy during the study period (growth, hematology, and clinical chemistry), with no evidence of adverse effects. Tissues were collected at a postnatal age of 3 months (∼7 months post-fetal gene transfer) for immunohistochemistry (IHC) and quantitative PCR. Both the diaphragm and peritoneum from vector-treated animals were strongly positive for expression of human GAA, AAT, or dystrophin by IHC, similar to findings when reporter genes were used. Protein expression in the diaphragm and peritoneum correlated with high vector copy numbers detected by real-time PCR. Other anatomical areas were negative, although the liver showed minimal evidence of human GAA, AAT, and DMD, vector genomes. In summary, delivery of rAAV vectors provided stable transduction of the muscular component of the diaphragm without any evidence of adverse effects.

Inspiratory Muscle Training in Late-Onset Pompe Disease: The Effects on Pulmonary Function Tests, Quality of Life, and Sleep Quality.

INTRODUCTION: Late-onset Pompe disease (LOPD) is characterized by progressive skeletal and respiratory muscle weakness. Little is known about the effect of inspiratory muscle training (IMT) on pulmonary function in subjects with LOPD. The aim of the present study was to investigate the effect of an 8-week IMT program on pulmonary function tests, quality of life, and sleep quality in eight patients with LOPD who were receiving enzyme replacement therapy (ERT). METHODS: Before and after the IMT program, spirometric measurements in sitting and supine positions, and measurements of maximum inspiratory and expiratory pressures, peak cough flow, quality of life (assessed using the Nottingham Health Profile), and sleep quality (assessed using the Pittsburgh sleep quality index) were performed. RESULTS: A significant increase in maximum inspiratory pressure (cmH2O and % predicted) (median [interquartile range]: 30.0 cmH2O [21.5-48] versus 39 cmH2O [31.2-56.5] and 38.3 % [28.1-48.4] versus 50.5 % [37.7-54.9]) was observed after training (p = 0.01). There were no significant changes in the other pulmonary function measurements. With the exception of the social isolation subscore (p = 0.02), quality of life subscores did not change after IMT (p > 0.05). Sleep quality subscores and total scores were similar before and after IMT. CONCLUSION: These results suggest that IMT has a positive effect on maximum inspiratory pressure in subjects with LOPD who are under ERT.

Respiratory muscle training (RMT) in late-onset Pompe disease (LOPD): Effects of training and detraining.

BACKGROUND: Determine the effects of a 12-week respiratory muscle training (RMT) program in late-onset Pompe disease (LOPD). METHODS: We investigated the effects of 12-weeks of RMT followed by 3-months detraining using a single-subject A-B-A experimental design replicated across 8 adults with LOPD. To assess maximal volitional respiratory strength, our primary outcomes were maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP). Effect sizes for changes in MIP and MEP were determined using Cohen's d statistic. Exploratory outcomes targeted motor function, and peak cough flow (PCF) was measured in the last 5 subjects. RESULTS: From pretest to posttest, all 8 subjects exhibited increases in MIP, and 7 of 8 showed increases in MEP. Effect size data reveal the magnitude of increases in MIP to be large in 4 (d≥1.0) and very large in 4 (d≥2.0), and effect sizes for increases in MEP were large in 1 (d≥1.0) and very large in 6 (d≥2.0). Across participants, pretest to posttest MIP and MEP increased by a mean of 19.6% (sd=9.9) and 16.1% (sd=17.3), respectively. Respiratory strength increases, particularly for the inspiratory muscles, were generally durable to 3-months detraining. CONCLUSIONS: These data suggest our 12-week RMT program results in large to very large increases in inspiratory and expiratory muscle strength in adults with LOPD. Additionally, increases in respiratory strength appeared to be relatively durable following 3-months detraining. Although additional research is needed, RMT appears to offer promise as an adjunctive treatment for respiratory weakness in LOPD.

Altered activation of the diaphragm in late-onset Pompe disease.

Pompe disease is an inherited neuromuscular disorder that affects respiratory function and leads to dependence on external ventilatory support. We studied the activation of the diaphragm using bilateral phrenic magnetic stimulation and hypothesized that diaphragm compound muscle action potential (CMAP) amplitude and evoked transdiaphragmatic pressure (Twitch PDI) would correlate to disease severity. Eight patients with late onset Pompe disease (LOPD, aged 14-48 years) and four healthy control subjects completed the tests. Maximal Twitch PDI responses were progressively reduced in patients with LOPD compared to control subjects (1.4-17.1cm H2O, p<0.001) and correlated to voluntary functional tests (p<0.05). Additionally, CMAP amplitude (mA) was lower in the patients who used nighttime or fulltime ventilatory support, when compared to controls and patients who used no ventilatory support (p<0.005). However, the normalized (%peak) Twitch PDI and CMAP responses were similar between patients and controls. This suggests a loss of functional phrenic motor units in patients, with normal recruitment of remaining motor units.

New therapeutic approaches for Pompe disease: enzyme replacement therapy and beyond.

Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). Prior to 2006, therapy was palliative. Severely affected infants with Pompe succumbed to cardiomyopathy or respiratory failure by one year of age. Enzyme replacement therapy (ERT) with alglucosidase alfa (Genzyme, Cambridge, MA, USA) is currently the only approved treatment for Pompe disease which has improved overall survival, ventilator-free survival, cardiomyopathy, and motor development in infants. In patients with late onset Pompe disease, ERT has resulted in disease course stabilization with motor and pulmonary improvements. Factors impacting outcome include age at start of ERT, muscle fiber type, underlying genotype and a multidisciplinary approach to care. This article highlights the lessons learned from infants and adults treated with ERT, limitations of ERT, and the development of adjunctive and alternative therapies, including immune modulation, upregulation of receptor expression, diet and exercise, second-generation recombinant ERT, chaperone therapy, substrate reduction therapy and gene therapy.

Desensitisation of the youngest patient with Pompe disease in response to alglucosidase alfa

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A large-scale nationwide newborn screening program for Pompe disease in Taiwan: towards effective diagnosis and treatment.

The aim of this study was to: (a) analyze the results of a large-scale newborn screening program for Pompe disease, and (b) establish an effective diagnostic protocol to obtain immediate, valid diagnosis of infantile-onset Pompe disease (IOPD) to promote earlier treatment and better outcomes. In this study, 402,281 newborns were screened for Pompe disease from January 1, 2008 to May 1, 2012. Infants with low acid α-glucosidase (GAA) activity were referred to Taipei Veterans General Hospital for diagnostic confirmation. Physical examination, biochemical parameter (creatine kinase [CK], alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase), and echocardiogram assessments were performed immediately to effectively differentiate IOPD from suspected late-onset Pompe disease (LOPD) or false-positive cases with pseudodeficiency mutation. Six infants with IOPD all presented with hypotonia, extremely low GAA enzyme activity (≤0.5 µmol/L/hr) in initial dried blood spot analysis, high CK (≥250 U/L), and high left ventricular mass index (LVMI, ≥80 g/m(2)). By analyzing these parameters, IOPD was distinguished effectively and immediately from suspected LOPD and false-positive cases. Except for the first referred case, five of the infants with IOPD received first-time enzyme replacement therapy (ERT) within 4 hr of admission and exhibited marked improvement. Our findings indicate that certain clinical manifestations (hypotonia, high CK, enlarged LVMI, and extremely low GAA enzyme activity in initial dried blood spot analysis) can help in the rapid and effective differentiation of patients with IOPD from other patient with low GAA activity. Such differentiation allows for the early application of first-time ERT and leads to better outcomes.

Improvement with ongoing Enzyme Replacement Therapy in advanced late-onset Pompe disease: a case study.

Benefits of enzyme replacement therapy with Myozyme (alglucosidase alfa), anecdotally reported in late-onset Pompe disease, range from motor and pulmonary improvement in less severely affected patients, to stabilization with minimal improvement in those with advanced disease. We report a case of a 63-year-old patient with significant morbidity who made notable motor and pulmonary function gains after two years on therapy. Thus, improvements in those with advanced disease may be possible after long-term treatment.

Biochemical and pharmacological characterization of different recombinant acid alpha-glucosidase preparations evaluated for the treatment of Pompe disease.

Pompe disease results in the accumulation of lysosomal glycogen in multiple tissues due to a deficiency of acid alpha-glucosidase (GAA). Enzyme replacement therapy for Pompe disease was recently approved in Europe, the U.S., Canada, and Japan using a recombinant human GAA (Myozyme, alglucosidase alfa) produced in CHO cells (CHO-GAA). During the development of alglucosidase alfa, we examined the in vitro and in vivo properties of CHO cell-derived rhGAA, an rhGAA purified from the milk of transgenic rabbits, as well as an experimental version of rhGAA containing additional mannose-6-phosphate intended to facilitate muscle targeting. Biochemical analyses identified differences in rhGAA N-termini, glycosylation types and binding properties to several carbohydrate receptors. In a mouse model of Pompe disease, glycogen was more efficiently removed from the heart than from skeletal muscle for all enzymes, and overall, the CHO cell-derived rhGAA reduced glycogen to a greater extent than that observed with the other enzymes. The results of these preclinical studies, combined with biochemical characterization data for the three molecules described within, led to the selection of the CHO-GAA for clinical development and registration as the first approved therapy for Pompe disease.

Modification of the natural history of adult-onset acid maltase deficiency by nutrition and exercise therapy.

Adult-onset acid maltase deficiency is an inherited lysosomal skeletal-muscle disease characterized by progressive myopathy and respiratory failure, for which there is no known therapy. In an uncontrolled, prospective study, we evaluated whether adherence to high-protein and low-carbohydrate nutrition and exercise therapy (NET) can slow the progressive deterioration of muscle function in this disease. Thirty-four patients have been treated with NET for periods of 2-10 years (mean 4.5 +/- 2.5). Pre-NET rate of muscle function deterioration, as measured by the Walton scale, was compared to post-NET rate. Twenty-six patients were deemed to be consistently compliant with NET. Difference between pre-NET slope of muscle function deterioration to that of post-NET slope in compliant patients was -0.29 (95% CI -0.19, 0.39) (P < 0.0001). We conclude that compliance with NET can slow deterioration of muscle function and improve the natural history of adult-onset acid maltase deficiency. Muscle Nerve, 2006.

L-alanine supplementation in late infantile glycogen storage disease type II.

We report a male with late infantile glycogen storage disease type II (Pompe's disease) who presented at 12 months of age with muscular hypotonia and developmental delay. Oral supplementation with L-alanine has been administered for 5 years. Progression of skeletal myopathy was slow, and cardiomyopathy resolved almost completely. L-alanine may be a valuable supplement for infants with glycogen storage disease type II.

Treatment of acid maltase deficiency with a diet high in branched-chain amino acids.

Acid maltase deficiency in adults is associated with progressive muscle weakness and may effect respiratory muscles resulting in respiratory failure. The biochemical and clinical manifestations of acid maltase deficiency arise from a marked deficiency of the lysosomal enzyme alpha-glucosidase (acid maltase), which normally degrades glycogen to free glucose. In the past few years, high-protein diets have provided an alternative energy source for these patients and resulted in improved muscle strength. Recently, we treated a ventilator-dependent acid maltase-deficient patient with a general diet supplemented with branched-chain amino acids. Branched-chain amino acids are the principal amino acids involved in muscle protein synthesis and utilization. While on this diet, the patient had improvement of respiratory function and muscle strength and was able to be weaned from the ventilator during the day. In addition to his nutritional status, levels of serum branched-chain amino acids, showed improvement within 2 months after the diet started. This diet shows potential advantages over a high-protein diet without supplemented branched-chain amino acids for the treatment of acid maltase deficiency. These include theoretical sparing of amino acids required for muscle protein synthesis by providing higher concentrations of postprandial branched-chain amino acids in the circulation. Also, the liquid formula would be better tolerated by a ventilator-dependent or debilitated patient rather than a high-protein general diet. Further experience with branched-chain amino acid formulas will be needed to substantiate their efficacy in the treatment of acid maltase deficiency.