Follow-up of late-onset Pompe disease patients with muscle magnetic resonance imaging reveals increase in fat replacement in skeletal muscles

Abstract

Background: Late-onset Pompe disease (LOPD) is a genetic disorder characterized by progressive degeneration of the skeletal muscles produced by a deficiency of the enzyme acid alpha-glucosidase. Enzymatic replacement therapy with recombinant human alpha-glucosidase seems to reduce the progression of the disease; although at the moment, it is not completely clear to what extent. Quantitative muscle magnetic resonance imaging (qMRI) is a good biomarker for the follow-up of fat replacement in neuromuscular disorders. The aim of this study was to describe the changes observed in fat replacement in skeletal muscles using qMRI in a cohort of LOPD patients followed prospectively.

Methods: A total of 36 LOPD patients were seen once every year for 4 years. qMRI, several muscle function tests, spirometry, activities of daily living scales, and quality-of-life scales were performed on each visit. Muscle MRI consisted of two-point Dixon studies of the trunk and thigh muscles. Computer analysis of the images provided the percentage of muscle degenerated and replaced by fat in every muscle (known as fat fraction). Longitudinal analysis of the measures was performed using linear mixed models applying the Greenhouse-Geisser test.

Results: We detected a statistically significant and continuous increase in mean thigh fat fraction both in treated (+5.8% in 3 years) and in pre-symptomatic patients (+2.6% in 3years) (Greenhouse-Geisser p < 0.05). As an average, fat fraction increased by 1.9% per year in treated patients, compared with 0.8% in pre-symptomatic patients. Fat fraction significantly increased in every muscle of the thighs. We observed a significant correlation between changes observed in fat fraction in qMRI and changes observed in the results of the muscle function tests performed. Moreover, we identified that muscle performance and mean thigh fat fraction at baseline visit were independent parameters influencing fat fraction progression over 4 years (analysis of covariance, p < 0.05).

Conclusions: Our study identifies that skeletal muscle fat fraction continues to increase in patients with LOPD despite the treatment with enzymatic replacement therapy. These results suggest that the process of muscle degeneration is not stopped by the treatment and could impact muscle function over the years. Hereby, we show that fat fraction along with muscle function tests can be considered a good outcome measures for clinical trials in LOPD patients.

Keywords: Enzymatic replacement therapy; Fatty replacement; Muscle MRI; Muscle degeneration; Muscle wasting; Pompe disease.

Figure 1

(A) Increase in mean thigh fat fraction at year 1, year 2 and year 3 related to the baseline value. Red bars show data from symptomatic patients treated while blue bars show data from presymptomatic patients. Mean increase and standard error is provided. (B) Increase in mean thigh fat fraction in every single patient of the cohort at visit 3 related to baseline. Red bars represent ERT treated patients. Blue bars represent presymptomatic non‐treated patients older than 25, and yellow bars represent patients younger than 25 years old. (C) Involvement of paraspinal and adductor major muscles in presymptomatic patients depending on the age. Fat replacement and atrophy of both muscles was observed in patients older than 25 years old.  *Paraspinal muscles **Adductor major muscles

Figure 2

Heatmaps showing changes in fat fraction of thigh muscles studied in symptomatic‐treated late‐onset Pompe disease patients. Patients and muscles are ordered according to hierarchical clustering with increasing replacement severity from bottom to top (patient‐rows) and from left to right (muscles‐columns). The increase in fat fraction over a 3 year period of time in the muscle of a patient is indicated by the colour of the square. Red colours mean increased fat fraction, while blue colours mean decreased fat fraction.

Figure 3

Images illustrate the change in fat replacement throughout the follow‐up. Fat fraction maps acquired from the thigh at Visits 0 and 3 (0–100% scale). Increase in fat replacement was visible in most of the muscles, with changes most obvious in the following muscles: (A and A') vastus lateralis (in this patient fat fraction increased from 15.5% to 35.7%), (B and B') long head of the biceps femoris (fat fraction increased from 57.6% to 79.4%), (C and C') semitendinosus (fat fraction rose from 20.3% to 51.4%), and (D and D') semimembranosus (fat fraction increased from 74.2% to 82.4%).

Figure 4

(A) Correlation between age at start of ERT and increase in mean thigh fat fraction. (B) Correlation between age at start of ventilation and increase in mean thigh fat fraction. (C) Correlation between results of the 6 min walking test (6MWT) at baseline and increase in mean thigh fat fraction. (D) Correlation between time to climb four steps at baseline and increase in mean thigh fat fraction. (E) Correlation between MRC for lower limbs at baseline and increase in mean thigh fat fraction. (F) Correlation between mean thigh fat fraction at baseline and increase in mean thigh fat fraction. ERT, enzymatic replacement therapy; MRC, magnetic resonance imaging.

Figure 5

Progression of fat fraction depending on the baseline mean thigh fat fraction. (A) Baseline image showing the localization of thigh muscles (VL: vastus lateralis, RF: rectus Femoris, VM: vastus medialis, VI: vastus intermedius, BFSH: biceps femoris short head, BFLH: biceps femoris long head, ST: semitendinosus, SM: semimembranosus, AM: adductor major, AL: adductor longus, Sa: sartorius, and Gra: gracilis). (B) Increase in fat fraction over a 4 year period in patients with baseline mean thigh fat fraction of 15% to 30%. (C) Increase in fat fraction over a 4 year period in patients with baseline mean thigh fat fraction of 30% to 45%. (D) Increase in fat fraction over a 4 year period in patients with baseline mean thigh fat fraction >45%. FF, fat fraction.