Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34–76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D ³¹P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p<0.05), FSHD severity score (p<0.0001), inversely with muscle strength (p<0.0001), and also occurred sub-clinically. Muscles were nearly dichotomously divided in those with high and with low fat fraction, with only 13% having an intermediate fat fraction. The intramuscular fat fraction along the muscle’s length, increased from proximal to distal. This fat gradient was the steepest for intermediate fat infiltrated muscles (0.07±0.01/cm, p<0.001). Leg muscles in this intermediate phase showed a decreased PCr/ATP (p<0.05) and the fastest increase in fatty infiltration over time (0.18±0.15/year, p<0.001), which correlated with initial edema (p<0.01), if present. Thus, in the MR assessment of fat infiltration as biomarker for diseased muscles, the intramuscular fat distribution needs to be taken into account. Our results indicate that healthy individual leg muscles become diseased by entering a progressive phase with distal fat infiltration and altered energy metabolite levels. Fat replacement then relatively rapidly spreads over the whole muscle.

Objective: To investigate the effect of aerobic exercise training (AET) and cognitive-behavioral therapy (CBT) on chronic fatigue in patients with facioscapulohumeral muscular dystrophy (FSHD). Methods: We performed a multicenter, assessor-blinded, randomized clinical trial (RCT). Fifty-seven patients with FSHD type 1 with severe chronic fatigue were randomly allocated to AET, CBT, or usual care (UC). Outcomes were assessed before treatment, following 16 weeks of intervention, and after a 12-week follow-up. A linear mixed model for repeated measurements was used to study the estimated group differences. Results: Following treatment, both the AET (28 participants) and CBT (25 participants) intervention groups had less fatigue relative to the UC group (24 participants), with a difference of −9.1 for AET (95% confidence interval [CI] −12.4 to −5.8) and −13.3 for CBT (95% CI −16.5 to −10.2). These beneficial effects lasted through follow-up, with a difference of −8.2 for AET (95% CI −12.4 to −5.8) and −10.2 for CBT (95% CI −14.0 to −6.3). The patients who received CBT had an increase in registered and experienced physical activity, sleep quality, and social participation. The patients who received AET had an increase in registered physical activity only. The increase in registered physical activity in both groups and the improvement in social participation following CBT were still present at follow-up. Conclusions: This RCT shows that AET and CBT can ameliorate chronic fatigue in patients with FSHD. Classification of evidence: This study provides Class III evidence that, in patients with FSHD type 1 and severe chronic fatigue, AET or CBT reduces the severity of chronic fatigue.

Objective: To investigate the effects of aerobic exercise training (AET) and cognitive-behavioral therapy (CBT), directed towards an increase in daily physical activity, on the progression of fatty infiltration and edema in skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD) type 1 by T2 MRI. Methods: Quantitative T2 MRI (qT2 MRI) and fat-suppressed T2 MRI of the thigh were performed at 3T on 31 patients, 13 of whom received usual care (UC), 9 AET, and 9 CBT. Muscle-specific fat fractions (%), derived from qT2 MRI, were recorded pretreatment and posttreatment. Intervention effects were analyzed by comparing fat fraction progression rates of the UC with the treated groups using Mann-Whitney tests, and intermuscle differences by a linear mixed model. Edematous hyperintense lesions were identified on the fat-suppressed T2 MRI. Results: The intraclass correlation coefficient for reproducibility of qT2 MRI fat assessment was 0.99. In the UC group, the fat fraction increased by 6.7/year (95% confidence interval [CI] 4.3 to 9.1). This rate decreased to 2.9/year (95% CI 0.7 to 5.2) in the AET (p = 0.03) and 1.7/year (95% CI −0.2 to 3.6) in the CBT group (p = 0.00015). The treatment effect differed among individual muscles. Fewer new edematous lesions occurred after therapy. Conclusions: Fat fraction derived from qT2 MRI is a reproducible and sensitive biomarker to monitor the effects of increased physical activity in individual muscles. This biomarker reports a favorable effect of AET and CBT on the rate of muscular deterioration in FSHD as reflected in decelerated fat replacement. Classification of evidence: This study provides Class II evidence that for patients with FSHD type 1, both AET and CBT decrease the rate of fatty infiltration in muscles.