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Respiratory Function and Fatigue in Pompe Disease

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Respiratory Function and Fatigue in Pompe Disease
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Barquin, Jennifer Nicole
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Pompe Disease is an inherited disorder caused by a mutation in the specific gene that is responsible for encoding the enzyme acid α-glucosidase, which is responsible for the breakdown of glycogen. The leading cause of death for patients with Pompe disease is respiratory failure. While current treatments have temporarily aided some of the symptoms attributed to the disease, progressive respiratory muscle weakness persists. The objective of this study was to determine the effect of fatiguing inspiratory resistive loading on breathing parameters. A Threshold Inspiratory Muscle Trainer was used to conduct this prospective cohort study on 7 subjects diagnosed with Pompe disease as well as 7 healthy comparison subjects all with ages ranging from 20 to 63. With p-values <0.05, a significant difference was found within the variables of end-tidal carbon dioxide and peak inspiratory flow as well as the time to fatigue when comparing the two groups. The significant elevation of ETCO2 in subjects with Pompe disease is due to their progressive respiratory muscle weakness, which makes it difficult to expel carbon dioxide. Next steps may include determining if respiratory muscle training could improve the maximal inspiratory pressure and endurance time for patients with Pompe disease. ( en )
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Awarded Bachelor of Health Science, summa cum laude, on May 8, 2018. Major: Health Science. Emphasis/Concentration: General Health Sciences
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College or School: College of Public Health & Health Professions
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Advisor: Barbara K. Smith. Advisor Department or School: Department of Physical Therapy

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University of Florida
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Copyright Jennifer Nicole Barquin. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.

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Running head: RESPIRATORY FUNCTION AND FATIGUE IN POMPE 1 Respiratory Function and Fatigue in Pompe Disease Jennifer N. Barquin University of Florida

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 2 Abstract Pompe Disease is an inherited disorder caused by a mutation in the specific gene that is responsible for encoding the enzyme acid glucosidase, which is responsible for the breakdown of glycogen The leading cause of death for patients with Pompe disease is respiratory failure. While current treatments have temporarily aided some of the symptoms attributed to the disease, progressive respiratory m uscle weakness persist s The objective of this study was to determine the effect of fatiguing inspiratory resistive loading on breathing parameters. A Threshold Inspiratory Muscle Trainer was used to conduct this prospective cohort study on 7 subjects diagnosed with Pompe disease as well as 7 healthy comparison subjects all with ages ranging from 20 to 63. With p values <0.05, a significant difference was found within the variables of end tidal carbon dioxide and peak inspiratory fl ow as well as the time to fatigue when comparing the two groups. The significant elevation of ETCO2 in subjects with Pompe disease is due to their progressive respiratory muscle weakness, which makes it difficult to expel carbon dioxide. Next steps may inc lude determining if respiratory muscle training could improve maximal inspiratory pressure and endurance time for patients with Pompe disease

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 3 Introduction Pompe disease is a chronic autosomal recessive disorder caused by a mutation in the gene that en codes acid glucosidase (GAA) a lysosomal enzyme involved in the breakdown of glycogen (Pellegrini et al., 2005) When the GAA levels drop below 30% of normal values glycogen begins to accumulate in certain tissues, specifically the skeletal, cardiac, and smooth muscles, impairing their ability to function properly ( Kishnani et al., 2006). Although it has been argued that the current incidence rates may not be a true representation of the population due to under diagnosis eth n ic distributions, and geographic divisions the reported prevalence of Pompe disease is about 1 in 40,000 (Cavalcanti et al., 2017). Typically, Pompe disease is categorized into infantile onset and late onset, but there is a clear range in disease severity (Chien & Hwu, 2007). While other hereditary neuromuscular diseases, such as Duchen n e muscular dystrophy, typically present with loss of ambulation prior to respiratory difficulties, respiratory complications are often one of the first clinical ma nifestations of Pompe disease (Meilles & Lofaso, 2009). In adult onset Pompe Disease, respiratory muscle weakness begins subtly with weakness of the diaphragm. This first occurs as nocturnal hypoventilat ion leading to sleep disruption, which results in ex cessive sleepiness during the day. F atigue also contribute s significantly to the muscular weakness and decreased motor function in patients with Pompe disease (Boentert et al., 2014). Respiratory muscle impairment is currently the most common cause of earl y death in Pompe disease (Meilles & Lofaso, 2009). In comparison to the infantile onset form adult onset Pompe disease is typically slower and ambulation can be maintained for years (Meilles & Lofaso, 2009). However, symptoms and outcomes tend to vary across individuals. The most prominently affected respiratory muscle is the diaphragm with less extensive involvement of the intercostal muscles (Fuller et al., 2013) While skeletal muscle weakness contributes significantly to respiratory dysfunction, neural defects can also affect respiratory control. As the glycogen accumulates in the respiratory motor units and neural networks, the

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 4 respiratory decline appears to prog ress (Fuller et al., 2014). Physiologically, the restrictive dysfunction is exhibited by a reduction in vital capacity (VC), maximal expiratory pressure (MEP), and maximal inspiratory pressure (MIP). As the dysfunction progresses, patients begin to develop alveolar hypoventilation and respiratory failur e, which eventually lead to depend ence on a mechanical ventilator (Berger et al 2016). Although the rate of progression may vary 75% of patients with Pompe disease eventually rely on a mechanical ventilator ( Fuller et al., 2014). While there is currently no cure for Pompe disease, the most common route of treatment is enzyme replacement therapy (ERT) to infuse the missing GAA enzyme (Lim, Li, & Raben, 2014). Studies have demonstrated that ERT temporarily improve s mobility and muscl e strength in adults with Pompe disease but after two years of treatment these symptoms begin to worsen once again ( Anderson et al., 2014). Similarly, E RT initially improve s pulmonary function during the first year and stabilize s function for months, but then lung function begin s to diminish (Schneider et al., 2012) While ERT helps to stabilize symptoms and delay the use of mechanical ventilation progressive respiratory muscle weakness continues to be a critical concern for patients wi th Pompe d isease. With declining respiratory muscle function, the mechanical load required to take a breath increases leading to fatigue and ultimate ly respiratory failure (Matecki et al., 2000). The ability to test for susceptibility of respir atory muscle fatigue in Pompe might be important for identifying who could be at risk for respiratory failure. A standardized method for evaluating respiratory muscle endurance could be beneficial when analyzing the effects of a treatment and also for tra ining of respiratory muscles ( Matecki et al., 2000). Aims and Hypotheses The objective s of this study are (1) to analyze the effect of fatiguing inspiratory threshold loading on breathing parameters and (2) to compare the responses of subjects with Pompe disease to healthy control groups. The goal is to examine the responses so it can be predicted when subjects are about to reach maximum fatigue. This would explain which breathing

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 5 parameters are primarily affected prior to the fatigue. W e expect variables, such as end tidal carbon dioxide, to be elevated in patients with Pompe disease but variables, such as maximal inspiratory pressure, to be reduced W e also hypothesize that patients will fatigue significantly faster than the healthy comparison group. Method s This study design was a prospective cohort trial of respiratory strength and endurance in adults with Pompe disease as well as age and gender matched controls. Subjects were recruited by word of mouth through clinicaltrials.gov, or locally using HealthStreet, a University of Florida research matching program. The University of Florida Institutional Review Board approved th e study design and procedures and i nformed consent wa s obtained from each subject prior to participation. Eligibility requirements included a confi rmed diagnosis of Pompe disease, unless they were healthy controls, no use of mechanical ventilation when awak e and upright, and an age between 18 and 70 years ol d Exclusions included a diagnosis of asthma or obstructive lung disease, pregnancy, inability to travel to the designated study site, or a forced vital capacity of less than 30% of the predicted values. R espiratory muscle endurance can be measured through a variety of different methods. In this project a Threshold Inspiratory Muscle Trainer (IMT) v alve was used to apply a consistent pressure load to breathing ( Matecki et al, 2000). For the endurance test, patients breath e d through a mout hpiece with a nose clip connected to the Threshold IMT device A pneumotachograph and pressure transducer attached to the mouthpiece was used to measure breathing parameters. A data acquisition system ( Powerlab S35/16 ) and computer were used to record the breathing parameters. While there was no resistance placed on exhalati on, the IMT device applied a load of 40% of maximal inspiratory pressure (MIP) with each inspiratory effort Prior to the endurance test, each subject s individual resting breathing pat tern was measured. The subject's natural unloaded respiratory rate was the rate for the endurance test. A metronome was used in order to cue inhalation and exhalation, using a 50% duty cycle

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 6 (Ti/Ttot = 0.5) (Matecki, et al., 2000). The following breathing p arameters were recorded during the endurance test: end tidal carbon dioxide (ETCO2), blood oxygen saturation (SpO2), peak inspiratory flow (PIF), peak expiratory flow (PEF), inspiratory work of breathing (WOBi), inspiratory power of breathing (POBi), tid al volume (VT), inspiratory time (Ti), expiratory time (Te), Ti/Ttot and occlusion pressure (P 0.1 ), which is a non invasive estimate of respiratory drive In addition, occlusion pressure (P 0.1 ) was calculated, to determine the inspiratory pressure generat ed in the first 0.1 second of a breath. P 0.1 is a reliable, indirect measure of the activity of the respiratory centers; therefore, the P 0.1 was used as an estimate of the subject's respiratory drive during the unloaded and loaded conditions (Conti, Antonelli, Arzano, & Gasparetto, 1997). The study d ata w ere exported from the PowerLab i nto an excel spreadsheet and then into Prism statistical software (Graph Pad, Inc) I ndependent sample t t est s were used to compare patient and control P 0.1 values and endurance time in minutes. To determine how the breathing parameters changed as subjects fatigue d each subject's endurance test time was normalized to a 100% scale and clustered into 5 periods, accounting for 0 20%, 20 40%, 40 60%, 60 80%, and 80 100% of the time to fatigue Then, each breathing parameter was evaluated with a 2 way ANOVA Factors were subject group (patient vs control) and time (20% increments of the normalized endurance time). A level of p<0.05 was considered significant. Results In total, fourteen subjects participated in the study. Seven of whom had been diagnosed with Pompe disease and the other seven, who were used as the healthy comparison group. The average age for subjects with Pompe disease (n=7) w as 43.6 (12.79) y ears. The average age for the healthy comparison group (n=7) was 42.6 (15.66). Specific demographic info rmation is highlighted in Tables 1 and 2 During the endurance test, the time to fatigue for subjects with Pompe disease was significantly shorter (p <0.01) shown in Figure 1 Subjects with Pompe disease fatigued in an average 2.9 3 ( 2.83 ) minutes in comparison to control subjects who fatigued after an average

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 7 of 7.7 ( 3.15 ) minutes. In contrast, the P 0.1 did not differ significantly between the two groups. For resting breaths, P 0.1 was 0.52 ( 0.30 ) in Pompe disease and 0.39 (0.29) in controls (p= 0.43 ), while during the loaded breaths, P 0.1 was 2.086 ( 0.90 ) in Pompe disease and 1.97 ( 1.95 ) in controls (p= 0.89 ). Of the breathing parameters only ETCO2 and PIF variables differed significant ly during the endurance test V ariation between groups with p value s of <0.0001 and 0.047 respectively T hroughout the duration of the endurance test, t he mean ETCO2 for subjects with Pompe disease was 47.83 (1.52) and the control group had a mean of 41.75 (0.50). Values for subjects with Pompe disease remained relatively constant and higher than the control grou p, which can be seen in Figure 2 There w as no significant interaction effect (p=0.86) as well as no significant time effect (p= 0.83). While mean PIF for subjects with Pompe disease was 55.8 (4.99) the mean PIF for the control group was 42.63 (13.05) As depicted in Figure 3 PIF values for th e control subjects showed much greater variability than subjects with Pompe disease, who remained fairly stable and consistent. Similar to ETCO2 results, there was no significant interaction (p=0.85) or time (p=0.21) effect with PIF. Discussion In terms of time of fatigue during the endurance test, there was a significant difference found showing that healthy controls lasted longer when performing these tests. There were two healthy individuals who did not reach the 10 minute mark due to high systolic and diastolic blood pressure as well as sustained inspiratory loading despite having no reported history of hypertension and having a normal resting blood pressure. These values lowered the mean for the healthy control group, but there was still a difference found between the two groups indicating that subjects with Pompe disease fatigue significantly faster than their healthy comparisons. One explanation for the fatigue in subjects with Pompe disease is their low MIP. The average MIP for subjects with Pompe d isease was 58.6 (19.76) in contrast to the average

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 8 MIP for the control group, which was 95.3 (31.71). Low MIP scores indicate respiratory muscle weakness and, therefore, lead to less endurance. As predicted, ETCO2 levels were significantly higher in subjects with Pompe disease in comparison to the control group. This is primarily due to the fact that the progressive weakness in their respiratory muscles makes it difficult for patients with Pompe disease to expel carbon dioxide. Increases in ETCO2 can be seen as a function of reduced minute ventilation or weakness. ETCO2 levels remained fairly stable in control subjects, but significantly lower than subjects with Pompe disease. While PEF levels wer e not found to be significant, PIF levels were found to show significance. This indicates that there was little variation in expiration between subjects, but there was variation in inspiration which is where the 40% load was applied. Control subjects showed greater variability in PIF, which may be because that they have more muscular ability to overcome the resistance load in various ways Subjects with Pompe disease showed very little variability and remained at a r elatively stable. Since patients with Pompe disease do not have mu ch respiratory muscle strength these subjects showed little variability in defeating the inspiratory load versus the control subjects that showed a variety of methods. PIF measurements can be used as an indication of strength with low PIF scores depicting an inadequate amount of respiratory muscle strength. Not only is respiratory muscle weakness a symptom of Pompe disease, but neural problems can also result. Without proper GAA activity, gl ycogen accumulates not only in muscles, but also within neurons, where glycogen is typically not present (DeRuisseau et al., 2009). Increased glycogen accumulation within the spinal cord can cause respiratory deficits. In order to test for neural involveme nt, P 0.1 can be used as a measurement of the medullary respiratory drive. According to the p values, there was no significant difference found for P 0.1 values between subjects with Pompe disease and healthy controls. This may be due to the fact that the subjects with Pompe disease's respiratory centers are signaling properly indicating that

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 9 there is not an extensive amount of glycogen accumulated in the neurons so P 0.1 measurements are similar to healthy subjects While most of the subjects in the contro l group lasted 10 minutes or close to 10 minutes, one subject fatigued at 2.5 minutes and another at 4.1 minutes. Variations within this group may have been due to the amount of exercise regularly done by each individual subject. When recruited participant s, subject's activity was permitted to be "recreationally active" or "sedentary". Younger subject's interpretation of recreationally active may have been more vigorous allowing for increased endurance and extreme values for some breathing parameters Futur e research may include determining if respiratory muscle training, using the Threshold IMT device, could improve MIP and endurance time for patients with Pompe disease.

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 10 Tables and Figures Table 1. Demographic Information on subjects with Pompe Disease BMI, Body Mass Index; FVC, Forced Vital Capacity; FEV1, Forced Expiratory Volume; MIP, Maximum Inspiratory Pressure; P 0.1 Occlusion Pressure ; RR, 1/heart rate; VT, Tidal Volume; ERT, Enzyme Replacement Therapy. Table 2 Demographic Information on Control subjects. BMI, Body Mass Index; FVC, Forced Vital Capacity; FEV1, Forced Expiratory Volume; MIP, Maximum Inspiratory Pressure; P 0.1 Occlusion Pressure ; RR, 1/heart rate; VT, Tidal Volume

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 11 Figure 1 Relationship betwee n the length of the endurance t ime test for subjects with Pompe disease and c ontrol subjects Figure 2 Relationship between ETCO2 and percent of e n durance t ime t est c ompleted Figure 3 Relationship between PIF and the percent of endurance time test c ompleted LOPD Control 0 5 10 15 Endurance Time (minutes) 0-20% 20-40% 40-60% 60-80% 80-100% 30 35 40 45 50 55 60 Percent of Endurance Time End-tidal CO 2 (mm Hg) Pompe Control 0-20% 20-40% 40-60% 60-80% 80-100% 0 50 100 150 Percent of Endurance Time Peak Inspiratory Flow (L/min) Pompe Control

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 12 References Anderson, L. J., Henley, W., Wyatt, K. M., Nikolaou, V., Waldek, S., Hughes, D. A., . Logan, S. (2014). Effectiveness of enzyme replacement therapy in adults with late onset Pompe disease: results from the NCS LSD cohort study. Journal of Inherited Metabolic Disease,37 (6), 945 952. doi:10.1007/s10545 014 9728 1 Berger, K. I., Chan, Y., Rom, W. N., Oppenheimer, B. W., & Goldring, R. M. (2016). Progression from respiratory dysfunction to failure in late onset Pompe disease. Neuromuscular Disorders, 26 (8), 481 489. doi:10.1016/j.nmd.2016.05.018 Boentert, M., Karabul, N., Wenninger, S., Stubbe DrŠger, B., Mengel, E., Schoser, B., & Young, P. (2014). Sleep related symptoms and sleep disordered breathing in adult Pompe disease. E uropean Journal of Neurology, 22 (2). doi:10.1111/ene.12582 Chien, Y. H., & Hwu, W. L. (2007). A review of treatment of Pompe disease in infants. Biologics!: Targets & Therapy 1 (3), 195 201. Conti, G., Antonelli, M., Arzano, S., & Gasparetto, A. (1997). Equipment review: Measurement of occlusion pressures in critically ill patients. Critical Care, 1 (3), 89. doi:10.1186/cc110 Deruisseau, L. R., Mah, C., Fuller, D. D., & Byrne, B. J. (2006). 892. Neural Deficits Contribute to Respiratory Insufficiency in P ompe Disease: A Therapeutic Approach with AAV1. Molecular Therapy, 13 doi:10.1016/j.ymthe.2006.08.981 Fuller, D. D., Elmallah, M. K., Smith, B. K., Corti, M., Lawson, L. A., Falk, D. J., & Byrne, B. J. (2013). The respiratory neuromuscular system in Pompe disease. Respiratory Physiology & Neurobiology,189 (2), 241 249. doi:10.1016/j.resp.2013.06.007 Kishnani, P. S., Steiner, R. D., Bali, D., Berger, K., Byrne, B. J., Case, L. E., . Watson, M. S. (2006). Pompe disease diagnosis and management guideline. Genetics in Medicine,8 (5), 267 288. doi:10.1097/01.gim.0000218152.87434.f3 Larson, J. L., Kim, M. J., Sharp, J. T., & Larson, D. A. (1988). Inspiratory Muscle Training with a Pressure Threshold Breathing Device in Patients with Chronic Obstructive Pulmonary

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RESPIRATORY FUNCTION AND FATIGUE IN POMPE 13 Disease. American Review of Respiratory Disease,138 (3), 689 696. doi:10.1164/ajrccm/138.3.689 Lim, J. A., Li, L., & Raben, N. (2014). Pomp e disease: from pathophysiology to therapy and back again. Frontiers in Aging Neuroscience 6 177. http://doi.org/10.3389/fnagi.2014.00177 Matecki, S., Topin, N., Hayot, M., Rivier, F., Echenne, B., Prefaut, C., & Ramonatxo, M. (2001). A standardized method for the evaluation of respiratory muscle endurance in patients with Duchenne muscular dystrophy. Neuromuscular Disorders, 11 (2), 171 177. doi:10.1016/s0960 8966(00)00179 6 Mellies, U., & Lofaso, F. (2009). Pompe disease: A neuromuscular disease with respiratory muscle involvement. Respiratory Medicine, 103 (4), 477 484. doi:10.1016/j.rmed.2008.12.009 Pellegrini, N., Laforet, P., Orlikowski, D., Pellegrini, M., Caillaud, C., Eymard, B., . Lofaso, F. (2005). Respiratory insufficiency and limb muscle weakness in adults with Pompes disease. European Respiratory Journal, 26 (6), 1024 1031. doi:10.1183/09031936.05.00020005 Schneider, I., Hanisch, F., MŸller, T., Schmidt, B., & Zierz, S. (2012). Respiratory function in late onset Pompe disease patients receiving long term enzyme replacement therapy for more than 48 months. Wiener Medizinische Wochenschrift, 163 (1 2), 40 44. doi:10.1007/s10354 012 0153 5