Facioscapulohumeral muscular dystrophy

Leiden University, Leyden, South Holland, Netherlands
Muscle & Nerve (Impact Factor: 2.28). 07/2006; 34(1):1 - 15. DOI: 10.1002/mus.20522


Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly inherited disorder with an initially restricted pattern of weakness. Early involvement of the facial and scapular stabilizer muscles results in a distinctive clinical presentation. Progression is descending, with subsequent involvement of either the distal anterior leg or hip-girdle muscles. There is wide variability in age at onset, disease severity, and side-to-side symmetry, which is evident even within affected members of the same family. Although FSHD is considered a relatively benign dystrophy by some, as many as 20% of patients eventually become wheelchair-bound. Associated nonskeletal muscle manifestations include high-frequency hearing loss as well as retinal telangiectasias, both of which are rarely symptomatic. The causal genetic lesion in FSHD was described over a decade ago, raising hope that knowledge about its molecular and cellular pathophysiology was soon to follow. In the vast majority of cases, FSHD results from a heterozygous partial deletion of a critical number of repetitive elements (D4Z4) on chromosome 4q35; yet, to date, no causal gene has been identified. The accumulating evidence points to a complex, perhaps unique, molecular genetic mechanism. The absence of detectable expressed sequences from D4Z4, the association of FSHD-causing 4q35 deletions with a specific distal genomic sequence (4qA allele), altered DNA methylation patterns on 4q35, as well as other direct and indirect evidence point to epigenetic mechanisms. As a consequence, partial deletion of D4Z4 results in a (local) chromatin change and ultimately results in the loss of appropriate control of gene expression. There is at present no effective treatment for FSHD. A better understanding of the underlying pathophysiology is needed to design targeted interventions. Despite these limitations, however, two randomized controlled clinical trials have been conducted on FSHD. These trials, along with a previous natural history study, have helped to better define outcome measures for future trials in FSHD as well as other dystrophies. Muscle Nerve, 2006

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    • "Since a loss of trunk stability cannot readily be resolved, an important clinical implication of our results seems to be that residual ankle plantarflexion power should be optimally preserved in patients with FSHD. Since many patients are prescribed anklefoot orthoses (AFOs) for the compensation of drop foot [32], maximal effort is warranted to support ankle dorsiflexion while maintaining the possibility to plantarflex the ankle joints during walking. This approach would imply the use of dynamic AFOs with a spring-like dorsiflexion support, allowing active plantarflexion during push-off. "
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    ABSTRACT: Facioscapulohumeral muscular dystrophy is a slowly progressive hereditary disorder resulting in fatty infiltration of eventually most skeletal muscles. Weakness of trunk and leg muscles causes problems with postural balance and gait, and is associated with an increased fall risk. Although drop foot and related tripping are common problems in FSHD, gait impairments are poorly documented. The effect of ankle plantarflexor involvement on gait propulsion has never been addressed. In addition to ankle plantarflexion, gait propulsion is generated through hip flexion and hip extension. Compensatory shifts between these propulsion sources occur when specific muscles are affected. Such a shift may be expected in patients with FSHD since the calves may show early fatty infiltration, whereas iliopsoas and gluteus maximus muscles are often spared for a longer time. In the current study, magnetic resonance imaging was used to assess the percentage of unaffected calf, iliopsoas and gluteus maximus muscles. Joint powers were analyzed in 10 patients with FSHD at comfortable and maximum walking speed to determine the contribution of ankle plantarflexor, hip flexor and hip extensor power to propulsion. Associations between muscle morphology, power generation and gait speed were assessed. Based on multivariate regression analysis, ankle plantarflexor power was the only factor that uniquely contributed to the explained variance of comfortable (R(2)=80%) and maximum (R(2)=86%) walking speed. Although the iliopsoas muscles were largely unaffected, they appeared to be sub-maximally recruited. This submaximal recruitment may be related to poor trunk stability, resulting in a disproportionate effect of calf muscle affliction on gait speed in patients with FSHD. Copyright © 2014 Elsevier B.V. All rights reserved.
    Gait & Posture 12/2014; 41(2). DOI:10.1016/j.gaitpost.2014.11.013 · 2.75 Impact Factor
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    • "For each patient, the number of muscles with an average FI score ≥ 2 was determined. A lumbar hyperlordosis is often seen in patients with FSHD (Lee et al., 2009; Tawil & Van Der Maarel, 2006a) and may affect the kinematic response of the body to a perturbation. Therefore, weightbearing total spine conventional radiographs were made in both the anterior–posterior and lateral direction to assess the spinal curvature. "
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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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    • "Shortening of the 4q35-linked D4Z4 tandem repeat [5] is associated with the prevalent form of facioscapulohumeral muscular dystrophy (FSHD, OMIM 158900), the third most common form of inherited myopathy in humans [6]. FSHD1 patients have 1–10 D4Z4 repeat units whereas non-affected individuals have 11–100 D4Z4 repeats [7], [8]. Pathogenic short D4Z4 alleles are hypomethylated and associated with a 4q polymorphic variant called 4qA [9], [10]. "
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    ABSTRACT: DUX4 (Double Homeobox Protein 4) is a nuclear transcription factor encoded at each D4Z4 unit of a tandem-repeat array at human chromosome 4q35. DUX4 constitutes a major candidate pathogenic protein for facioscapulohumeral muscular dystrophy (FSHD), the third most common form of inherited myopathy. A low-level expression of DUX4 compromises cell differentiation in myoblasts and its overexpression induces apoptosis in cultured cells and living organisms. In this work we explore potential molecular determinants of DUX4 mediating nuclear import and cell toxicity. Deletion of the hypothetical monopartite nuclear localization sequences RRRR(23), RRKR(98) and RRAR(148) (i.e. NLS1, NLS2 and NLS3, respectively) only partially delocalizes DUX4 from the cell nuclei. Nuclear entrance guided by NLS1, NLS2 and NLS3 does not follow the classical nuclear import pathway mediated by α/β importins. NLS and homeodomain mutants from DUX4 are dramatically less cell-toxic than the wild type molecule, independently of their subcellular localization. A triple ΔNLS1-2-3 deletion mutant is still partially localized in the nuclei, indicating that additional sequences in DUX4 contribute to nuclear import. Deletion of ≥111 amino acids from the C-terminal of DUX4, on a ΔNLS1-2-3 background, almost completely re-localizes DUX4 to the cytoplasm, indicating that the C-ter tail contributes to subcellular trafficking of DUX4. Also, C-terminal deletion mutants of DUX4 on a NLS wild type background are less toxic than wild type DUX4. Results reported here indicate that DUX4 possesses redundant mechanisms to assure nuclear entrance and that its various transcription-factor associated domains play an essential role in cell toxicity.
    PLoS ONE 10/2013; 8(10):e75614. DOI:10.1371/journal.pone.0075614 · 3.23 Impact Factor
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