Abstract
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.
Highlights
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular disorder [1]
What is the natural distribution of fatty infiltration? How is this related to clinical severity, to muscle weakness and to energy metabolism? Is there prevalence for specific muscles to be affected and does fatty infiltration vary within muscles? What is the natural progression over time and what are predictive signs of progression?
In 41 FSHD patients we investigated 446 leg muscles, of which 4.3% showed edema, which was mostly present in the quadriceps muscles
Summary
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common hereditary muscular disorder [1]. The disease is characterized by progressive asymmetric weakness and fatty infiltration of skeletal muscles. In recent years it was demonstrated that FSHD is associated with a contraction of D4Z4 repeats on chromosome 4q35 [2], leading to lost repression of DUX4, a protein that exerts toxic effects on muscle cells [3]. Progress is hampered because the trigger for DUX4 expression and the further unfolding of disease processes leading to fatty infiltration and muscle weakness are not known. Clarification of the underlying mechanisms is expected to offer clues for a more targeted approach in the search for treatment [5]. Understanding these mechanisms first requires that some key questions concerning the process of fatty infiltration are addressed. What is the natural distribution of fatty infiltration? How is this related to clinical severity, to muscle weakness and to energy metabolism? Is there prevalence for specific muscles to be affected and does fatty infiltration vary within muscles? What is the natural progression over time and what are predictive signs of progression?
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