The Respiratory Phenotype of Pompe Disease Mouse Models

Abstract

Pompe disease is a glycogen storage disease caused by a deficiency in acid α-glucosidase (GAA), a hydrolase necessary for the degradation of lysosomal glycogen. This deficiency in GAA results in muscle and neuronal glycogen accumulation, which causes respiratory insufficiency. Pompe disease mouse models provide a means of assessing respiratory pathology and are important for pre-clinical studies of novel therapies that aim to treat respiratory dysfunction and improve quality of life. This review aims to compile and summarize existing manuscripts that characterize the respiratory phenotype of Pompe mouse models. Manuscripts included in this review were selected utilizing specific search terms and exclusion criteria. Analysis of these findings demonstrate that Pompe disease mouse models have respiratory physiological defects as well as pathologies in the diaphragm, tongue, higher-order respiratory control centers, phrenic and hypoglossal motor nuclei, phrenic and hypoglossal nerves, neuromuscular junctions, and airway smooth muscle. Overall, the culmination of these pathologies contributes to severe respiratory dysfunction, underscoring the importance of characterizing the respiratory phenotype while developing effective therapies for patients.

Airway abnormalities and pulmonary complications in long‐term treated late‐onset Pompe disease: Diagnostic and interventional by flexible bronchoscopy

“…Animal studies presented that GAA deficiency results in pathology in hypoglossal motor neurons, glycogen accumulation, and a disruption of the architecture of the airway smooth muscles of Gaa −/− mice 29 . Pompe patients have similar pathology in the genioglossus muscle and hypoglossal motor neurons as Pompe mice 19 . The airway anatomic collapsibility, including narrowed nasal tract, compromised oral cavity, oropharynx, compromised tracheal, and bronchial lumens are noted in all of our LOPD patients (Figure 3).…”

“…29 Pompe patients have similar pathology in the genioglossus muscle and hypoglossal motor neurons as Pompe mice. 19 The airway anatomic collapsibility, including nasal tract, compromised oral cavity, oropharynx, compromised tracheal, and bronchial lumens are noted in all of our LOPD patients (Figure 3). These also contributed to the increasing apnea-hypopnea index (AHI) in the PSG exam.…”

“…[23][24][25][26] To evaluate dynamic anatomic airway disorders in patients with LOPD Glycogen accumulates in tracheal and bronchial smooth muscles with reduced calcium signaling, which leads to poor contractility. 6,19,28 Glycogen is also accumulated in the diaphragm, intercostal muscles, tongue, and respiratory motor neurons. 12,19 Animal studies presented that GAA deficiency results in pathology in hypoglossal motor neurons, glycogen accumulation, and a disruption of the architecture of the airway smooth muscles of Gaa −/− mice.…”

“…6,19,28 Glycogen is also accumulated in the diaphragm, intercostal muscles, tongue, and respiratory motor neurons. 12,19 Animal studies presented that GAA deficiency results in pathology in hypoglossal motor neurons, glycogen accumulation, and a disruption of the architecture of the airway smooth muscles of Gaa −/− mice. 29 Pompe patients have similar pathology in the genioglossus muscle and hypoglossal motor neurons as Pompe mice.…”

Respiratory dysfunction in a mouse model of spinocerebellar ataxia type 7

“…Near end stage of disease, SCA7 mice can still maintain a minute ventilation comparable to wild-type littermates during eupneic breathing. This minute ventilation is achieved via a compensatory elevation in baseline breath frequency that suppresses respiratory insufficiency and is observed in mouse models of amyotrophic lateral sclerosis and other SCAs ( Fusco et al, 2020 ; Orengo et al, 2018 ). However, when respiratory demand increases, SCA7 mice can no longer compensate to sustain adequate ventilation and their respiratory dysfunction becomes apparent.…”