Longitudinal Assessment of Muscle Involvement in Late-Onset Pompe Disease Using Quantitative MRI: A Prospective Cohort Study.

BACKGROUND

Late-onset Pompe disease (LOPD) is a progressive metabolic myopathy characterised by lysosomal glycogen accumulation and leading to secondary disruptions in autophagy and cellular energy metabolism. While enzyme replacement therapy (ERT) has improved outcomes, early detection remains critical, because irreversible muscle damage often precedes overt clinical symptoms.

This study investigates whether quantitative MRI (qMRI) can detect subclinical disease progression and correlate with clinical decline.

METHODS

Over a 2-year period, 25 participants (10 LOPD (disease duration 131 ± 127 months; ERT 76 ± 72 months; two dropouts) and 15 age/sex-matched controls) underwent longitudinal clinical and MRI assessments at intervals of ~4 months (± 4 weeks; T1-T7). Clinical tests included strength measurements (Medical Research Council, MRC), the Quick Motor Function Measure (QMFM), patient-reported outcomes (ACTIVLIM; Neuromuscular Symptom Score-NSS) and gait analysis.

The 3.0T lower extremity MRI included multi-echo, gradient-echo, a Dixon-based sequence for fat quantification (fat fraction [FF]), a multi-echo, spin-echo sequence for T2 mapping (wT2) and a spin-echo EPI diffusion-weighted sequence. Baseline differences in quantitative MRI (qMRI) metrics between patients and controls were assessed using multivariate analysis of variance.

Longitudinal changes and associations with clinical outcomes were evaluated using linear mixed-effects models (LMMs).

RESULTS

Group differences were found for ACTIVLIM (p ≤ 0.027), NSS (p ≤ 0.001) and MRC (p = 0,027) from T6/T7. Baseline differences of qMRI metrics between groups were found for FF (mean difference = 0.071, p < 0.001), wT2 (mean difference = 1.925, p < 0.001) and fractional anisotropy (mean difference = 0.010, p = 0.029).

In muscles with FF < 10%, diffusion metrics did not differ (p ≥ 0.332), whereas wT2 remained elevated in LOPD (p < 0.001). LMMs revealed a significant increase in FF in LOPD patients from T4 onward (p ≤ 0.029), particularly in thigh muscles, while wT2 and diffusion metrics remained stable over time.

LMMs demonstrated significant associations between thigh muscle qMRI metrics and clinical outcomes, for example between FF and QMFM (estimate: -5.16; R 2 = 0.76; p < 0.001) or wT2 and QMFM (estimate: -0.64; R 2 = 0.83; p = 0.009). Interestingly, wT2 showed a modest positive association over time for ACTIVLIM (estimate: 0.005; R 2 = 0.517; p = 0.010).

CONCLUSION

Although muscle function is measurable clinically, qMRI captured alterations beyond clinical detection; its correlation with clinical scores supports qMRI as a more sensitive surrogate marker.

Our findings indicate that FF changes preceded alterations in clinical outcome, highlighting sensitivity to early disease progression. The lack of a consistent temporal pattern in wT2 and diffusion metrics warrants further studies to fully understand underlying mechanisms in LOPD.

Larger, long-term studies are needed to validate qMRI for monitoring disease progression and therapeutic response in LOPD.