Muscle MRI may detect early changes in late-onset Pompe disease

Quantitative MRI (qMRI) may detect muscle changes in people with late-onset Pompe disease (LOPD) before clear declines are seen on standard clinical tests, a study found.

The study also revealed that MRI changes tracked with measures of muscle strength, physical function, and patient-reported symptoms over two years of follow-up.

“Looking forward, integrating qMRI metrics into routine Pompe disease monitoring could bridge the current gap between molecular [disease mechanisms] and clinical function,” the researchers wrote.

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The study, “Longitudinal Assessment of Muscle Involvement in Late-Onset Pompe Disease Using Quantitative MRI: A Prospective Cohort Study,” was published in the Journal of Cachexia, Sarcopenia and Muscle.

Pompe is caused by mutations in the GAA gene, which provides instructions for producing acid alpha-glucosidase (GAA), an enzyme that helps break down glycogen — the body’s stored form of sugar. When GAA is missing or defective, glycogen accumulates to toxic levels in cells, particularly muscle cells, damaging tissues and leading to Pompe symptoms.

LOPD onset typically occurs during adolescence or adulthood, presenting with slowly progressive muscle weakness that affects muscles closest to the center of the body. While enzyme replacement therapies (ERT) have notably improved outcomes and experimental treatments have led to promising results, the benefits are generally greater if treatment is started early. As such, detecting disease-related alterations before they are seen on standard clinical assessments is key.

Here, researchers investigated whether qMRI could detect subclinical disease progression that remains undetected in routine examination.

The final analysis included eight patients with LOPD and eight age- and sex-matched controls. Patients had a mean age of 42 years, a mean disease duration of almost 11 years, and were receiving ERT for about six years. ERT provides a functional version of the GAA enzyme.

Participants underwent clinical assessments and MRI scans approximately every four months for two years. Clinical tests assessed muscle strength, gait, and motor function, whereas patient-reported measures focused on symptom severity and daily activity limitations.

Overall, there were no significant differences in walking capacity and some motor function measures during the study. However, patient-reported daily activity limitations showed significant worsening by about 20 months. Muscle strength and patient-reported symptom severity showed significant worsening by the final 24-month assessment.

MRI measures tracked with clinical outcomes

The researchers used MRI scans to examine 12 muscles in the thighs and 11 muscles in the lower legs. At the start of the study, patients already had more fat replacement – when healthy muscle tissue is lost and replaced by fat – and a higher water T₂ relaxation time, a marker of muscle tissue changes, than healthy controls.

According to the researchers, these “findings indicate that [fat content] changes preceded alterations in clinical outcome, highlighting sensitivity to early disease progression.”

Notably, the elevated water-related signal was present even in muscles with low fat replacement, defined as less than 10% fat content, suggesting MRI can detect muscle involvement before substantial fat replacement has occurred. By contrast, most diffusion-based MRI measurements, which assess muscle fiber structure, showed no significant differences between patients and controls.

Over time, patients experienced a gradual increase in muscle fat content, starting after eight months of study, mainly in the thigh muscles. However, there was no consistent significant progression in the water T₂ relaxation time metric or in measures of muscle fiber structure. Results were similar in the subgroup analysis of muscles with less than 10% fat content.

Further analysis demonstrated that MRI measures in the thigh were closely linked with clinical outcomes in people with LOPD. Higher levels of muscle fat replacement in the thigh and a higher water T₂ relaxation time were associated with poorer motor function. Other associations were found between MRI metrics and both muscle strength and patient-reported daily activity limitations.

Several MRI markers of muscle structure also changed alongside clinical measures over time, particularly patient-reported symptom severity.

Among the study’s limitations, the investigators mentioned its small number of participants. “Our findings should therefore be interpreted with appropriate caution and confirmed in larger, independent cohorts,” the team noted.