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.

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The muscular dystrophies are rare orphan diseases, characterized by progressive muscle weakness: the most common and well known is Duchenne muscular dystrophy which affects young boys and progresses quickly during childhood. However, over 70 distinct variants have been identified to date, with different rates of progression, implications for morbidity, mortality, and quality of life. There are presently no curative therapies for these diseases, but a range of potential therapies are presently reaching the stage of multi-centre, multi-national first-in-man clinical trials. There is a need for sensitive, objective end-points to assess the efficacy of the proposed therapies. Present clinical measurements are often too dependent on patient effort or motivation, and lack sensitivity to small changes, or are invasive. Quantitative MRI to measure the fat replacement of skeletal muscle by either chemical shift imaging methods (Dixon or IDEAL) or spectroscopy has been demonstrated to provide such a sensitive, objective end-point in a number of studies. This review considers the importance of the outcome measures, discusses the considerations required to make robust measurements and appropriate quality assurance measures, and draws together the existing literature for cross-sectional and longitudinal cohort studies using these methods in muscular dystrophy.

Both gray and white matter is affected in boys with DMD at a whole brain level. Differences between the DMD_Dp140(-) subgroup and controls indicate an important role for the Dp140 dystrophin isoform in cerebral development.

Duchenne muscular dystrophy (DMD) is a muscular dystrophy with high incidence of learning and behavioural problems and is associated with neurodevelopmental disorders. To gain more insights into the role of dystrophin in this cognitive phenotype, we performed a comprehensive analysis of the expression patterns of dystrophin isoforms across human brain development, using unique transcriptomic data from Allen Human Brain and BrainSpan atlases. Dystrophin isoforms show large changes in expression through life with pronounced differences between the foetal and adult human brain. The Dp140 isoform was expressed in the cerebral cortex only in foetal life stages, while in the cerebellum it was also expressed postnatally. The Purkinje isoform Dp427p was virtually absent. The expression of dystrophin isoforms was significantly associated with genes implicated in neurodevelopmental disorders, like autism spectrum disorders or attention-deficit hyper-activity disorders, which are known to be associated to DMD. We also identified relevant functional associations of the different isoforms, like an association with axon guidance or neuron differentiation during early development. Our results point to the crucial role of several dystrophin isoforms in the development and function of the human brain.

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Diffusion tensor imaging (DTI) is a popular method to assess differences in fiber organization in diseased and healthy muscle tissue. Previous work has shown that muscle DTI measurements depend on signal‐to‐noise ratio (SNR), %fat, and tissue T2. The goal of this study was to evaluate the potential biasing effects of these factors on skeletal muscle DTI data in patients with Duchenne Muscular Dystrophy (DMD). MR images were obtained of the right lower leg of 21 DMD patients and 12 healthy controls on a Philips 3T system. DTI measurements were combined with quantitative in‐vivo measures of mean water T2, %fat and SNR to evaluate their effect on DTI parameter estimation. All outcome measures were determined within ROIs drawn for six lower leg muscles. Between group analysis, using all ROIs, revealed a significantly elevated FA in the GCL, SOL and PER muscles (p<0.05) and an increased mean diffusivity (p<0.05) and λ3 (p<0.05) in the TA muscle of DMD patients. In‐vivo evaluation of the individual confounders showed behaviour in line with predictions from previous simulation work. To account for these confounders, subsequent analysis used only ROIs with SNR greater than 20. With this criterion we found significantly greater MD in the TA muscle of DMD patient (p<0.009) and λ3 in the TA and GCL muscles (p<0.001) of DMD patients, but no differences in FA. As both increased %fat and lower SNR are expected to reduce the apparent MD and λ3, these between‐group differences are likely due to pathophysiology. However, the increased FA, observed when using all ROIs, likely reflects the effect of low SNR and %fat on the DTI parameter estimation. These findings suggest that measuring mean water T2, %fat and SNR is essential to ascribe changes in DTI measures to intrinsic diffusion changes or to confounding influences. Copyright © 2015 John Wiley & Sons, Ltd.

There are minor differences between the various lipid spectral models in terms of quantifying fat fraction in a large number of skeletal muscles in the legs of Duchenne patients and healthy controls. Quantitative 3-point Dixon MRI is more precise and reliable than visual radiological methods for evaluation of fat fractions for potential longitudinal follow-up or therapy evaluation of Duchenne patients.