Muscle imaging data in late-onset Pompe disease reveal a correlation between the pre-existing degree of lipomatous muscle alterations and the efficacy of long-term enzyme replacement therapy

Abstract

BackgroundLate-onset Pompe disease (LOPD) is a metabolic myopathy caused by mutations in GAA and characterized by proximal muscle weakness and respiratory insufficiency. There is evidence from clinical studies that enzyme replacement therapy (ERT) with human recombinant alpha-glucosidase improves motor performance and respiratory function in LOPD.ObjectiveWe analyzed quantitative muscle MRI data of lower limbs to evaluate the effects of long-term ERT on muscle parameters.MethodsThree symptomatic LOPD patients who received ERT for five years and four untreated presymptomatic LOPD patients were included in the study. T1-weighted MRI images were used to determine volumes of thigh and lower leg muscles. In addition, mean gray values of eight individual thigh muscles were calculated to assess the degree of lipomatous muscle alterations.ResultsWe detected a decrease in thigh muscle volume of 6.7% (p < 0.001) and an increase in lower leg muscle volume of 8.2% (p = 0.049) after five years of ERT. Analysis of individual thigh muscles revealed a positive correlation between the degree of lipomatous muscle alterations at baseline and the increase of gray values after five years of ERT (R2 = 0.68, p < 0.001). Muscle imaging in presymptomatic patients showed in one case pronounced lipomatous alteration of the adductor magnus muscle and mild to moderate changes in further thigh muscles.ConclusionsThe results demonstrate that fatty muscle degeneration can occur before clinical manifestation of muscle weakness and suggest that mildly affected muscles may respond better to ERT treatment than severely involved muscles. If these findings can be validated by further studies, it should be discussed if muscle alterations detected by muscle MRI may be an objective sign of disease manifestation justifying an early start of ERT in clinically asymptomatic patients in order to improve the long-term outcome.

2-deoxy-2-[18]fluoro-D-glucose PET/CT (18FDG PET/CT) may not be a viable biomarker in Pompe disease

“…Our pilot study confirms the usefulness of MRI to delineate affected muscles in PD [ 9 , 12 , 14 – 16 ]. The pattern of involvement was similar in patients with and without ERT [ 14 ] and disease severity and duration were correlated to quantitative MRI findings.…”

Multi‐center evaluation of stability and reproducibility of quantitative MRI measures in healthy calf muscles

“…However, in these patients, fatty infiltration and muscle size and shape changes can hamper accurate segmentation, thereby possibly decreasing the reproducibility. Nevertheless, the main difficulty here is distinguishing between muscles, which currently has to be performed manually by an experienced examiner, which is time‐consuming, requires a lot of experience, and is currently the only limiting factor of a fully automated processing pipeline. However, provided muscles of patients are segmented correctly and similarly across centers, the reproducibility should still be similar for patients, as shown for fat fraction in DMD patients …”

Quantification of intramuscular fat in patients with late-onset Pompe disease by conventional magnetic resonance imaging for the long-term follow-up of enzyme replacement therapy

“…A literature review revealed inconsistency about whether T1- or T2-weighted images are preferred when assessing fatty muscle degeneration by conventional MR sequences. While the majority of authors prefer T1-weighted sequences [ 13 , 17 , 27 , 28 ], others have used T2-weighted images [ 19 , 25 ]. T2-weighted imaging risks overestimating fatty muscle degeneration because fat, edema, and high glycogen content appear hyperintense; thus, T1-weighted images would be preferable to monitor Pompe disease.…”

“…The assessment of fatty muscle degeneration by MRI using grayscale values based on signal intensity has been reported using T1-weighted images [ 17 ]. Another group recently introduced a quantification method based on signal intensity measurements of the paraspinal muscles in relation to a small encircled area of subcutaneous fat from the same level [ 18 ].…”