Airway smooth muscle dysfunction in Pompe (<i>Gaa<sup>−/−</sup></i>) mice

Keeler, Allison M.; Liu, Donghai; Zieger, Marina; Xiong, Lang; Salemi, Jeffrey; Bellvé, Karl D.; Byrne, Barry J.; Fuller, David D.; ZhuGe, Ronghua; ElMallah, Mai K.

doi:10.1152/ajplung.00568.2016

Cited by 22 publications

(51 citation statements)

References 67 publications

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“…With such an effective system, we were able to initiate treatment with Myozyme in patients with IOPD at an average age of around 8 days, which is the earliest age reported globally. Comparison of prognostic parameters in our study (collected after 2010) to that of other studies of patients with IOPD suggests that patients receiving early Myozyme in our study had better outcomes (Confalonieri et al, ; Ebbink et al, ; Fuller et al, ; Jones et al, ; Keeler et al, ), including normal cognitive and motor function. All of our patients with IOPD survived without mechanical ventilation, walking devices or gastrostomy tube feeding (Lai et al, ; Yang et al, , ).…”

Section: Introductionsupporting

confidence: 61%

“…No patient reported significant dysphagia at the end of study and only two had symptoms of facial weakness (Figure ). In our series, early treated IOPD patients had normal cognitive and motor function, all our patients survived without mechanical ventilation, walking devices or gastrostomy tube feeding (Confalonieri et al, ; Ebbink et al, ; Fuller et al, ; Jones et al, ; Keeler et al, ; Lai et al, ; Yang et al, , ).…”

Section: Discussionmentioning

confidence: 62%

“…Airway problems are critical in patients with IOPD, even with regular ERT Yang et al, 2014). Previous studies suggest dysphonia, sleep-disordered breathing, daytime hypercapnia, and the eventual need for nocturnal ventilation in some of these patients (Bay et al, 2019;Ebbink et al, 2012;Keeler et al, 2017;Owens et al, 2018;Yang et al, 2014). Some other studies mention respiratory symptoms, including decreased cough and impaired airway clearance, increase in the risk of acute respiratory illness in these patients (Bay et al, 2019;Fuller et al, 2013;Jones et al, 2010;Owens et al, 2018;Yang et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

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Airway abnormalities in very early treated infantile‐onset Pompe disease: A large‐scale survey by flexible bronchoscopy

Yang

Niu

Tai

et al. 2020

American J of Med Genetics Pt A

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Early enzyme replacement therapy (ERT) improve long‐term outcomes in patients with infantile‐onset Pompe disease (IOPD). Our cohort of patients with IOPD at Taipei Veterans General Hospital (TVGH) joined Taiwan Pompe newborn screening program from 2008, testing more than one million newborns until 2018. By 2010, we had established rapid diagnostic strategies. Now, the average age of ERT initiation starts at an average age of <10 days‐old, the earliest group in the world. However, they still presented some airway problems. We present a retrospective study focused on airway abnormalities in these patients along 8 years of observation. Fifteen patients with IOPD, who received very early treatment at a mean age of 8.94 ± 3.75 days, underwent flexible bronchoscopy (FB) for dynamic assessment of the whole airway. Long‐term clinical outcomes and relevant symptoms of the upper airway were assessed. All patients in the study had varying degrees of severity of upper airway abnormalities and speech disorders. The three oldest children (Age 94, 93, and 88 months, respectively) had poor movement of the vocal cords with reduced abduction and adduction and had silent aspiration of saliva through the glottis during respiration. This is the largest cohort study presented to date about airway abnormalities in very early treated patients with IOPD patients by FB. Despite very early treatment, we observed upper airway abnormalities in these IOPD patients. In IOPD, upper airway abnormalities seem inevitable over time. We suggest early and continuous monitoring for all IOPD patients, even with early and regular treatment.

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Section: Introductionsupporting

confidence: 61%

Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

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Airway abnormalities in very early treated infantile‐onset Pompe disease: A large‐scale survey by flexible bronchoscopy

Yang

Niu

Tai

et al. 2020

American J of Med Genetics Pt A

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“…Despite the significant improvement in ventilator-free survival in CRIM-positive patients with Pompe disease, there continues to be evidence of respiratory insufficiency. The respiratory system is affected in Pompe disease with glycogen accumulation occurring in the diaphragm, 3 the tongue, 35 the tracheal smooth muscle, 36 and in the respiratory motor neurons. 35,37 In this current case series, there is a variable course with some patients showing an annual decline in FVC and others showing an improvement.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

ElMallah

Desai

Nading

et al. 2020

Pediatric Pulmonology

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Objectives To report the respiratory function of school‐aged children with infantile Pompe disease (IPD) who started enzyme replacement therapy (ERT) in infancy and early childhood. Study Design This is a retrospective chart review of pulmonary function tests of: (a) patients with IPD 5 to 18 years of age, (b) who were not ventilator dependent, and (c) were able to perform upright and supine spirometry. Subjects were divided into a younger (5‐9 years) and older cohort (10‐18 years) for the analysis. Upright and supine forced vital capacity (FVC), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were analyzed. Results Fourteen patients, all cross‐reactive immunologic material (CRIM)‐positive, met the inclusion criteria and were included in this study. Mean upright and supine FVC were 70.3% and 64.9% predicted, respectively, in the 5‐ to 9‐year‐old cohort; and 61.5% and 52.5% predicted, respectively, in the 10‐ to 18‐year‐old group. Individual patient trends showed stability in FVC overtime in six of the 14 patients. MIPs and MEPs were consistent with inspiratory and expiratory muscle weakness in the younger and older age group but did not decline with age. Conclusion Data from this cohort of CRIM‐positive patients with IPD showed that ERT is able to maintain respiratory function in a subgroup of patients whereas others had a steady decline. There was a statistically significant decline in FVC from the upright to a supine position in both the younger and older age groups of CRIM‐positive ERT‐treated patients. Before ERT, patients with IPD were unable to maintain independent ventilation beyond the first few years of life.

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“…Measures of airway resistance . Pulmonary mechanics were performed at the study end point using forced oscillometry (FlexiVent system, SCIREQ, Montreal, Canada) at baseline and in response to incremental doses of methacholine as previously described . See Supporting Information for details.…”

Section: Methodsmentioning

confidence: 99%

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

Zieger

Keeler

Flotte

et al. 2019

J of Inher Metab Disea

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Very‐long chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD) is an autosomal recessive disorder of fatty acid oxidation. Fatty acids are a major source of energy during catabolic stress, so the absence of VLCAD can result in a metabolic crises and respiratory insufficiency. The etiology of this respiratory insufficiency is unclear. Thus, our aims were: (1) to characterize respiratory pathophysiology in VLCADD mice (VLCAD−/−), and (2) to determine if AAV9‐mediated gene therapy improves respiratory function. For the first aim, VLCAD−/− and wild‐type (WT) mice underwent an exercise/fast “stress protocol” and awake spontaneous breathing was evaluated using whole‐body plethysmography (WBP) both at baseline and during a hypercapnic respiratory challenge (FiO2: 0.21; FiCO2: 0.07; nitrogen balance). During hypercapnia, VLCAD −/− mice had a significantly lower frequency, tidal volume, minute ventilation, and peak inspiratory and expiratory flow, all of which indicate respiratory insufficiency. Histologically, the cardiac and respiratory muscles of stressed VLCAD −/− animals had an accumulation of intramyocellular lipids. For the second aim, a single systemic injection of AAV9‐VLCAD gene therapy improved this respiratory pathology by normalizing breathing frequency and enhancing peak inspiratory flow. In addition, following gene therapy, there was a moderate reduction of lipid accumulation in the respiratory muscles. Furthermore, VLCAD protein expression was robust in cardiac and respiratory muscle. This was confirmed by immuno‐staining with anti‐human VLCAD antibody. In summary, stress with exercise and fasting induces respiratory insufficiency in VLCAD−/− mice and a single injection with AAV9‐VLCAD gene therapy ameliorates breathing.

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Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice

Cited by 22 publications

References 67 publications

Airway abnormalities in very early treated infantile‐onset Pompe disease: A large‐scale survey by flexible bronchoscopy

Airway abnormalities in very early treated infantile‐onset Pompe disease: A large‐scale survey by flexible bronchoscopy

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

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Airway smooth muscle dysfunction in Pompe (Gaa−/−) mice

Cited by 22 publications

References 67 publications

Airway abnormalities in very early treated infantile‐onset Pompe disease: A large‐scale survey by flexible bronchoscopy

Airway abnormalities in very early treated infantile‐onset Pompe disease: A large‐scale survey by flexible bronchoscopy

Pulmonary outcome measures in long‐term survivors of infantile Pompe disease on enzyme replacement therapy: A case series

AAV9 gene replacement therapy for respiratory insufficiency in very‐long chain acyl‐CoA dehydrogenase deficiency

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Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice