Distinct Disease Phases in Muscles of Facioscapulohumeral Dystrophy Patients Identified by MR Detected Fat Infiltration

University of Ulm, Germany
PLoS ONE (Impact Factor: 3.23). 01/2014; 9(1):e85416. DOI: 10.1371/journal.pone.0085416
Source: PubMed


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 (31)P 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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Available from: Hermien E Kan, Jan 29, 2014
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    • "In addition, the abnormalities in the kinematic responses of the body to balance perturbations appeared to be dependent mainly on trunk muscle involvement and lumbarlordosis angle. As FI and muscle weakness are generally strongly correlated (Iosa et al., 2007; Janssen et al., 2014; Rijken et al., 2014), our results suggest that trunk muscle weakness is the main factor leading to loss of postural stability in patients with FSHD. This finding seems to be in contrast with previous studies that pointed at an important contribution of lower leg muscle weakness to impaired sagittal-plane balance control in these patients (Horlings et al., 2009b; Winter, 1995). "
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    ABSTRACT: Background Although it is known that muscle weakness is a major cause of postural instability and leads to an increased incidence of falls in patients with neuromuscular disease, the relative contribution of lower extremity and trunk muscle weakness to postural instability has not been studied well. Methods We determined the relationship between muscle fatty infiltration and sagittal-plane balance in ten patients with facioscapulohumeral muscular dystrophy. Sagittal-plane platform translations were imposed in forward and backward direction on patients with facioscapulohumeral muscular dystrophy and healthy controls. Stepping thresholds were determined and kinematic responses and centre-of-mass displacements were assessed using 3 dimensional motion analysis. In the patients, magnetic resonance imaging was used to determine the amount of fatty infiltration of trunk and lower extremity muscles. Findings Stepping thresholds in both directions were decreased in patients compared to controls. In patients, significant correlations were found for fatty infiltration of ventral muscles with backward stepping threshold and for fatty infiltration of dorsal muscles with forward stepping threshold. Fatty infiltration of the rectus abdominis and the back extensors explained the largest part of the variance in backward and forward stepping threshold, respectively. Centre-of-mass displacements were dependent on intensity and direction of perturbation. Kinematic analysis revealed predominant ankle strategies, except in patients with lumbar hyperlordosis. Interpretation These findings indicate that trunk muscle involvement is most critical for loss of sagittal-plane postural balance in patients with facioscapulohumeral muscular dystrophy. This insight may help to develop rehabilitation strategies to prevent these patients from falling.
    Clinical Biomechanics 09/2014; 29(8). DOI:10.1016/j.clinbiomech.2014.07.008 · 1.97 Impact Factor
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    • "A partial limitation of our study is the absence of quantitative measurements of both fat content and muscle edema with dedicated techniques such as fat infiltration fraction, T2-mapping, DWI and DTI, and MR spectroscopy [35], [36]. Acquisition of scans with such techniques could be particularly useful in a less clinically-oriented, diagnostic context but for instance in longitudinal natural history studies, where more objective and sensitive measurements are of key importance. "
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    ABSTRACT: Background In Facioscapulohumeral muscular dystrophy (FSHD), the upper girdle is early involved and often difficult to assess only relying on physical examination. Our aim was to evaluate the pattern and degree of involvement of upper girdle muscles in FSHD compared with other muscle diseases with scapular girdle impairment. Methods We propose an MRI protocol evaluating neck and upper girdle muscles. One hundred-eight consecutive symptomatic FSHD patients and 45 patients affected by muscular dystrophies and myopathies with prominent upper girdle involvement underwent this protocol. Acquired scans were retrospectively analyzed. Results The trapezius (100% of the patients) and serratus anterior (85% of the patients) were the most and earliest affected muscles in FSHD, followed by the latissimus dorsi and pectoralis major, whilst spinati and subscapularis (involved in less than 4% of the patients) were consistently spared even in late disease stages. Asymmetry and hyperintensities on short-tau inversion recovery (STIR) sequences were common features, and STIR hyperintensities could also be found in muscles not showing signs of fatty replacement. The overall involvement appears to be disease-specific in FSHD as it significantly differed from that encountered in the other myopathies. Conclusions The detailed knowledge of single muscle involvement provides useful information for correctly evaluating patients' motor function and to set a baseline for natural history studies. Upper girdle imaging can also be used as an additional tool helpful in supporting the diagnosis of FSHD in unclear situations, and may contribute with hints on the currently largely unknown molecular pathogenesis of this disease.
    PLoS ONE 06/2014; 9(6):e100292. DOI:10.1371/journal.pone.0100292 · 3.23 Impact Factor
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    ABSTRACT: Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.
    Skeletal Muscle 06/2014; 4(1):12. DOI:10.1186/2044-5040-4-12
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