MRI review
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Genetic disorders often result in a mosaic of pathologies that work together to lead to a disease phenotype. Physicians should see most genetic illnesses through a multidisciplinary lens; any one aspect of the disease can trigger a runaway cascade of pathways that result in a reduced quality of life in their patients and increased mortality.

Pompe disease is one such disease that clearly illustrates this dynamic. It is a glycogen storage disorder inherited in an autosomal recessive manner. Pathological glycogen accumulation occurs, which affects multiple organs, especially the heart and the lungs. In this article, we will examine its impact on respiratory function. 

Read more about Pompe disease etiology 

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Harlaar and colleagues conducted a study that investigated the role of chest MRI to diagnose early diaphragmatic weakness in Pompe disease. How does Pompe disease affect diaphragmatic function, and how early? The researchers attempted to answer these questions through a cross-sectional study. 

Diaphragmatic Weakness

The research team characterized respiratory insufficiency as a typical observation in patients with advanced Pompe disease. In recent years, enzyme replacement therapy (ERT) has resulted in improved muscle strength and the stabilization of respiratory function. “However, the effect of ERT is much smaller on respiratory function than on skeletal muscle function,” wrote the authors of the study. 

International guidelines recommend starting ERT when skeletal or respiratory muscle weakness is observed. International guidelines define respiratory muscle weakness as the patient having a forced vital capacity (FVC) below 80% predicted. “However, it is possible that damage to the diaphragm had already become irreversible before ERT was started,” Harlaar et al warned. 

The research team thus decided to investigate if chest MRI could be used to accurately identify signs of diaphragmatic weakness so that physicians can make the necessary interventions. “We used advanced image-analysis techniques to evaluate the motion and shape of the diaphragm in detail,” they wrote. 

The researchers conducted spirometer-controlled MRI scans in Pompe disease patients (over 8 years of age), as well as healthy controls matched for sex and age. This study was conducted in the Center for Lysosomal and Metabolic Diseases at Erasmus University Medical Center in the Netherlands, a prominent referral center for Pompe disease. The inclusion criteria were a diagnosis of non-classic Pompe disease and the ability of participants to lie in a supine condition for 30 minutes without aid. Recruited participants had pulmonary function tests, as well as detailed MRI scans, performed. 

The findings of this study led the researchers to conclude that “even in early-stage Pompe disease, when spirometry results are still within normal range, the motion of the diaphragm is already reduced and the shape is more curved during inspiration.” This means that diaphragmatic weakness can occur even before it becomes immediately obvious. The researchers also found chest MRI to be a valuable tool for detecting early signs of diaphragmatic weakness. 

A Clearer Picture 

To better understand how respiratory defects develop in patients with Pompe disease, scientists have turned to the use of mice models. Scientists have disrupted exons 6 and 13 of mice models to create conditions similar to Pompe disease. Fusco et al, in their literature review on the respiratory phenotype of Pompe disease mice models, commented that mice models in which exon 13 has been disrupted had “a near-complete absence of GAA in all tissues and displays progressive accumulation of lysosomal glycogen in cardiomyocytes, hepatocytes, and skeletal muscle fibers.” 

Fusco and colleagues uncovered a few notable effects on respiratory pathology in Pompe disease mice models. They wrote, “Although respiratory dysfunction was traditionally attributed to muscle pathology and weakness, recent evidence in mice and humans indicate pathology in both respiratory muscles and the neurons that control those muscles.” In other words, neuronal involvement is indispensably linked to respiratory weakness. 

Glycogen accumulation also severely disrupts normal respiratory function. Fusco et al commented, “Glycogen accumulation in the phrenic motor neurons results in neurodegeneration and denervation of the diaphragm.” In addition, glycogen accumulation occurs in the tongue, leading to macroglossia, which can obstruct the airway. Glycogen accumulation in the bronchial and tracheal smooth muscle tissue of Pompe disease mice models has been observed to reduce airway patency.

Read more about Pompe disease diagnosis 

In other words, scientists have observed specific pathologies due to the abnormal accumulation of glycogen in Pompe disease that lead to respiratory difficulties. Fusco et al summed up their findings by stating that “Pompe disease causes pathology throughout the respiratory system, which without treatment can result in devastating respiratory dysfunction and eventual respiratory failure.” 

Since respiratory weaknesses feature so prominently in Pompe disease, what can clinicians do to dent the course of the disease? While treatments that completely halt respiratory decline do not yet exist, clinicians can invest in a proper early surveillance system to detect respiratory weaknesses at their earliest manifestation.

Harlaar and colleagues concluded, “MRI provides insight into the process of increasing diaphragmatic weakness, and when FVC starts to decline, possible irreversible functional changes of the diaphragm may have already taken place,” which should prompt clinicians to initiate further measures to preserve breathing function for as long as possible. 


Harlaar L, Ciet P, van Tulder G, et al. Chest MRI to diagnose early diaphragmatic weakness in Pompe disease. Orphanet J Rare Dis. Published online January 7, 2021. doi:10.1186/s13023-020-01627-x

Fusco AF, McCall AL, Dhindsa JS, et al. The respiratory phenotype of Pompe disease mouse modelsInt J Mol Sci. Published online March 24, 2020. doi:10.3390/ijms21062256