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Clinical practice considerations in facioscapulohumeral muscular dystrophy Sydney, Australia, 21 September 2015

Published:April 25, 2016DOI:https://doi.org/10.1016/j.nmd.2016.03.007

      Highlights

      • Best practice molecular diagnostic reference standards require international collaboration.
      • Information on lifestyle management, physical therapy and bone health were provided.
      • Respiratory and extramuscular complications and options for palliative therapy were discussed.
      • Potential investigative disease-modifying agents for FSHD were identified.
      • The role and requirements for FSHD registries were explored.

      1. Introduction

      The Facioscapulohumeral Muscular Dystrophy Global Research Foundation recently convened a workshop of international experts to discuss practical aspects of the clinical management of patients with facioscapulohumeral muscular dystrophy (FSHD). Participating in the meeting were 11 physicians from academic centers representing Australia, Canada, France, the Netherlands, and the USA, who met on 21 September 2015. The aim of the meeting was to expand on the recently published American Academy of Neurology (AAN) evidence-based guidelines [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ], considering practice points covering areas of the care of patients with FSHD for which there is limited evidence, such as evolving genetic diagnostic techniques, lifestyle management, physical therapy, bone health, respiratory and extramuscular complications, and surgical options for palliative therapy. Investigational disease-modifying agents and patient registries were also discussed.

      2. Overview of FSHD

      (Rabi Tawil)
      FSHD is one of the most common forms of muscular dystrophy. It is typically an autosomal dominant disorder that can begin at any age from infancy to late adulthood, although the majority of patients become symptomatic in the second and third decades of life. The regional distribution of initial muscle involvement is distinctive, affecting the face and shoulder girdle muscles in the absence, as a rule, of masticatory, lingual, extraocular, or deltoid muscle involvement. There is generally a rostral–caudal progression of muscle weakness. Extramuscular manifestations can occur in severe disease, including respiratory compromise, retinal vascular disease leading to exudative retinopathy, and hearing loss [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ].
      Individuals with FSHD show chromatin relaxation at the D4Z4 macrosatellite repeat array on the 4qA background of chromosome 4. This enables expression of the DUX4 retrogene in skeletal muscle. In approximately 95% of patients with FSHD there is a contraction of this repeat array; patients with type 1 FSHD (FSHD1) carry only 1–10 D4Z4 repeat units compared with a general population range of 11–100 D4Z4 units. About 5% of individuals with type 2 FSHD (FSHD2) show chromatin relaxation at D4Z4 without a D4Z4 contraction as a result, in most cases, of mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene on chromosome 18, which modifies chromatin [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ,
      • Daxinger L.
      • Tapscott S.J.
      • van der Maarel S.M.
      Genetic and epigenetic contributors to FSHD.
      ].
      There is a wide spectrum of clinical severity in FSHD, with typically slows linear progression in weakness over time. The size of the D4Z4 contraction and early age at onset are factors linked to increased likelihood of severe disease in patients with FSHD. Patients with fewer D4Z4 repeat units tend to have more severe disease; early-onset disease is associated with fewer D4Z4 repeat units, earlier loss of ambulation, and increased likelihood of extramuscular features [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ].

      3. FSHD: disease mechanism

      (Stephen J. Tapscott)
      The misexpression of the DUX4 transcription factor in skeletal muscle causes FSHD [
      • Tawil R.
      • van der Maarel S.M.
      • Tapscott S.J.
      Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.
      ]. The DUX4 retrogene is normally expressed in the testes, likely in the spermatogonia and primary spermatocytes, but is epigenetically repressed in most somatic tissues, including skeletal muscle. DUX4 is present in the D4Z4 macrosatellite, a repeat array present in the subtelomeric regions of chromosomes 4q and 10q. However, the polymorphism that creates a polyadenylation signal for the somatic expression of DUX4 mRNA only occurs with the 4qA haplotype [
      • Tawil R.
      • van der Maarel S.M.
      • Tapscott S.J.
      Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.
      ]. Normally chromatin repression silences DUX4 in somatic tissues; however, a decrease in the number of D4Z4 repeats (FSHD1) or a mutation in the SMCHD1 gene (FSHD2) enables chromatin relaxation that results in periodic expression of DUX4 in skeletal muscle and the activation of genes regulated by DUX4, many of them representing stem cell– or germ line–associated genes that are normally expressed in the testes [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ,
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ].
      There are a number of possible mechanisms of tissue damage resulting from DUX4 expression in skeletal muscle, including (but not limited to) apoptosis, RNA toxicity and induction of an immune response [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ,
      • Daxinger L.
      • Tapscott S.J.
      • van der Maarel S.M.
      Genetic and epigenetic contributors to FSHD.
      ]. DUX4 induces apoptosis when expressed in muscle cells; the accumulated loss of muscle nuclei and accompanying damage to myofibrils may contribute to the progressive loss of muscle. Furthermore, there is a dramatic alteration in RNA splicing and an accumulation of aberrant RNA transcripts, suggesting that RNA toxicity might also cause muscle damage. In addition, some of the proteins expressed in muscle as a consequence of DUX4 might be immunogenic, and an immune response to these antigens might also contribute to muscle damage [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ,
      • Daxinger L.
      • Tapscott S.J.
      • van der Maarel S.M.
      Genetic and epigenetic contributors to FSHD.
      ]. Future work is needed to determine whether the muscle damage seen in FSHD can be attributed to a single dominant mechanism, or to multiple mechanisms induced by DUX4 expression.

      4. Clinical and genetic diagnosis of FSHD

      (Sabrina Sacconi)
      The clinical diagnosis of FSHD can be complicated by the clinical variability of the disease, which can range from a severe rapidly progressive and generalized disease in early-onset children, to a mild and slowly progressive disease in late-onset adults. In the very severe form, additional features, such as extramuscular involvement and respiratory muscle weakness, may confuse the picture, while in very mild disease the typical features may be missed. If the clinical presentation of FSHD is typical and the diagnosis is genetically confirmed in a first-degree relative, molecular testing is not necessary for each affected individual. However when the presentation is atypical or sporadic, genetic confirmation is important for genetic counseling [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Although the genetic diagnosis is relatively simple for 90% of patients, in more complex cases, there is no agreement about the best molecular test in terms of sensitivity, specificity and cost effectiveness.
      All current molecular diagnostic techniques for FSHD1 involve determining the length of the D4Z4 repeat array on chromosome 4 using genomic DNA isolated from peripheral blood lymphocytes [
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ,
      • Lemmers R.J.
      • O'Shea S.
      • Padberg G.W.
      • et al.
      Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: workshop. 9th June 2010, LUMC, Leiden, The Netherlands.
      ]. The most commonly used method involves Southern blot analysis. The DNA is digested with restriction enzymes (e.g. EcoRI, or EcoRI/HindIII and EcoRI/BlnI) releasing complete D4Z4 repeat arrays that are separated by size with linear gel electrophoresis (LGE) and then visualized using the DNA probe p13E-11, which hybridizes proximally to the D4Z4 region [
      • Lemmers R.J.
      • O'Shea S.
      • Padberg G.W.
      • et al.
      Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: workshop. 9th June 2010, LUMC, Leiden, The Netherlands.
      ]. This technique enables correct molecular diagnosis in most patients that display the classic clinical picture of FSHD. Nevertheless, in a few patients it yields false negatives (due to a proximal extending D4Z4 deletion which also deletes the p13E-11 probe region, somatic mosaicism, or complex rearrangements of chromosomes 4 and 10). A false-positive test can also result from the detection of contractions on the 4qB allele [
      • Lemmers R.J.
      • O'Shea S.
      • Padberg G.W.
      • et al.
      Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: workshop. 9th June 2010, LUMC, Leiden, The Netherlands.
      ]. If a false-positive test is suspected, most diagnostic laboratories, upon request, will be able to determine whether the contraction is occurring on the 4qA allele.
      For the more complicated cases, use of extensive D4Z4 genotyping that involves additional restriction enzymes with the fragments run in a pulsed-field gel electrophoresis (PFGE) should be considered. Other techniques that have been proposed include long-range polymerase chain reaction and molecular combing, but neither are considered standard methods [
      • Lemmers R.J.
      • O'Shea S.
      • Padberg G.W.
      • et al.
      Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: workshop. 9th June 2010, LUMC, Leiden, The Netherlands.
      ], and both are expensive (10 times the cost of the standard Southern blot analysis using LGE), tend only to be performed in research laboratories, and currently only have value as research tools.
      FSHD2 genetic diagnosis is even more complicated because it requires identification of a permissive allele together with a pathogenic mutation in the SMCHD1 gene. The standard genetic test to identify mutations in SMCHD1 is based on next generation sequencing (NGS). However, NGS may not cover the entire gene and can miss some deep intronic mutations. Moreover, the pathogenic role of variants found in SMCHD1 has to be confirmed because of the frequency of polymorphisms. Furthermore, the clinical effect of SMCHD1 mutations may depend on the number of D4Z4 repeats; the impact of D4Z4 repeat length in FSHD2 penetrance and expression of clinical phenotype needs clarification.
      DNA methylation testing can help in confirming the pathogenicity of a mutation, or with screening patients before undergoing FSHD2 genetic diagnostic testing. The average methylation of D4Z4 in control individuals is 45%, while in individuals with FSHD2 the methylation levels drop below 25%. Methylation tests have high sensitivity (all FSHD2 patients are hypomethylated in the D4Z4 region on chromosome 4) but less specificity (not all the hypomethylated patients carry the SMCHD1 mutation). There are several methods for measuring DNA methylation, including Southern blot analysis using methylation-sensitive restriction enzymes [
      • Lemmers R.J.
      • Goeman J.J.
      • van der Vliet P.J.
      • et al.
      Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2.
      ] and, more recently, by bisulfite sequencing of DR1 region [
      • Jones T.I.
      • Yan C.
      • Sapp P.C.
      • et al.
      Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing.
      ]. There is currently no agreement on the best methylation test (sensitivity, specificity and cost effectiveness) or the cut-off threshold.
      To summarize, all molecular diagnostic methods for FSHD have limitations due to technical issues and are associated with some false-positive or false-negative results. To overcome this issue, a constant interplay between expert clinicians and geneticists needs to be established. Also, laboratories testing for FSHD across the world need to be identified and made available to clinicians and patients, including the type of facility (research or hospital) and the methods used in each laboratory. Currently the majority of hospital laboratories offer Southern blot A analysis using LGE alone. Comparison of the results between laboratories will facilitate the establishment and harmonization of best practice molecular diagnostic reference standards for FSHD.

      5. Establishing clinical standards of care for patients with FSHD

      (Alistair Corbett)
      Patients with FSHD are typically managed in a general neuromuscular disease (NMD) or a neurogenetic clinic. The exact constitution and organization of a FSHD neuromuscular service will depend on the funding and the model of care used. The clinic should deliver continuity of expert care and ready access to the services required for FSHD patients, specifically providing expert clinical assessments, diagnosis, genetic counseling, rehabilitation assessment, screening and management for complications, accurate up-to-date information, and social support. In addition, the clinic should provide medical training, as well as liaising with patient support organizations and participating in research.
      Ideally, the core staff in the service ought to include a neurologist or pediatric neurologist with training and experience in managing NMDs, a geneticist with experience in NMDs and a genetic counselor, a NMD nurse, a rehabilitation specialist/team with experience in managing NMDs, dedicated secretarial staff/clinic coordinator, and a data manager. Additional services that should be readily accessible to the clinic include a physiotherapist with experience in NMDs, social worker, orthotist, respiratory/sleep physician with experience in NMDs, seating service/occupational therapist with NMD expertise, psychological counseling, chronic pain service, ophthalmologist with expertise in retinal disorders, endocrinologist with expertise in bone disorders, dietitian, orthopedic surgeon with expertise in shoulder surgery and an understanding of scapular fixation for FSHD, audiologist to monitor hearing for early-onset FSHD, and for children, a speech pathologist, specialists in pediatric respiratory disorders and a transition coordinator/manager for patients moving from pediatric to adult care. Clinics should liaise with and refer to support organizations, which may be able to provide financial, counseling, social, employment and other forms of assistance. Adequate clinic space with good access to waiting and clinic rooms, and to disabled toilets and parking facilities are also important physical requirements for an ideal clinic.
      Patients with FSHD should be reviewed annually in the clinic, with more frequent review when there are active issues associated with diagnosis and/or management. Members of the treating team should meet after each clinic to review management plans and make certain that appropriate management, investigations, referrals, and clinical review are organized.
      Transition is an essential function for both pediatric and adult NMD clinics, and requires planning and appropriate organization. Planning for transition and education about the transition process for patients and families should begin several years before the transition occurs. Transition should occur in the last year of schooling or the following year, but may vary when appropriate. Where possible, clinicians from adult clinics and clinic coordinators/genetic counselors should meet patients in the pediatric clinic prior to transition, to enable a seamless transfer of clinical and social information and familiarization with the patient. Communication is essential to ensuring that all relevant information and data accompany the patient in a timely fashion. The psychological impact on patients and families of moving from pediatric to adult services must be recognized and managed. As a general rule, transition to the adult clinic means greater autonomy for the patients and acceptance of a more supportive role for families. It will often occur at the same time as other major life changes. Ongoing education and training, transition to employment, availability of community and respite services, sexuality and appropriate social activities all become significant issues to the late-teenage patient. Transition to adult care will generally involve sourcing more support and rehabilitation services locally rather than centrally, a process that can be facilitated by case management. Transition is a good time for the patient and family to access patient support organizations for assistance outside the medical model (i.e. demedicalizing support), and patient organizations should be encouraged to become involved and support this process.
      Clinics should remain alert to opportunities to participate in research, clinical trials and registries/databases, which document the clinical course, and can help identify patients appropriate for clinical trials. Clinics also have an education and training role, and should take available opportunities to provide clinicians and trainees with exposure to patients with NMDs and their management. Clinicians planning an NMD service need to develop a model for the FSHD clinical services with guidelines promoting optimal standards of care which should be achievable with optimal staffing, funding and administrative support. These guidelines can be used to justify requests for appropriate resources and funding. An inability to reach all criteria laid out in the model, however, should not stand in the way of starting a FSHD service. Clinics may fall short of the guidelines, but should aspire to at least these standards of care.

      6. Lifestyle management in FSHD

      (Baziel van Engelen)
      Few studies have investigated the effect of lifestyle factors (diet and physical activity) in FSHD. Regarding diet, there is currently little evidence to suggest that the dietary requirements for patients with FSHD differ from those without FSHD, with the possible exception of vitamin D, which may contribute to musculoskeletal pain in some patients with suboptimal levels [
      • Le Goaziou M.F.
      • Kellou N.
      • Flori M.
      • et al.
      Vitamin D supplementation for diffuse musculoskeletal pain: results of a before-and-after study.
      ]. A recent study investigated antioxidant supplementation based on the premise that oxidative stress may contribute to FSHD pathology, and that antioxidants might modulate or delay oxidative insults and help maintain muscle bulk in FSHD. In this study, dietary supplementation with vitamin E, vitamin C, zinc, and selenium did not have a significant effect on the study's primary outcome, as defined by the 2-minute walk test, but did improve the maximal voluntary contraction and endurance of the quadriceps [
      • Passerieux E.
      • Hayot M.
      • Jaussent A.
      • et al.
      Effects of vitamin C, vitamin E, zinc gluconate, and selenomethionine supplementation on muscle function and oxidative stress biomarkers in patients with facioscapulohumeral dystrophy: a double-blind randomized controlled clinical trial.
      ]. This was a preliminary study involving a small number of patients; thus, more rigorous data will be needed to confirm these findings. Folic acid and methionine supplementation, which can boost DNA methylation, has no effect on D4Z4 methylation [
      • van der Kooi E.L.
      • de Greef J.C.
      • Wohlgemuth M.
      • et al.
      No effect of folic acid and methionine supplementation on D4Z4 methylation in patients with facioscapulohumeral muscular dystrophy.
      ].
      Cochrane reviews have suggested that moderate-intensity strength training in patients with FSHD appears to do no harm, but there is insufficient evidence to conclude any benefit [
      • Voet N.B.
      • van der Kooi E.L.
      • Riphagen I.I.
      • et al.
      Strength training and aerobic exercise training for muscle disease.
      ]. However, aerobic exercise may reduce fatigue and improve fitness in patients with FSHD. A broader systematic review that included data from all sources found that aerobic exercises and the combination of muscle strengthening and aerobic exercises were effective in a heterogeneous group of muscle disorders, including FSHD [
      • Cup E.H.
      • Pieterse A.J.
      • ten Broek-Pastoor J.M.
      • et al.
      Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review.
      ]. Both aerobic exercise (15–30 minutes on a stationary bicycle three times/week for 16 weeks) and cognitive behavior therapy (CBT, five sessions to increase overall physical activity) were shown to increase activity and reduce fatigue in patients with FSHD in a recently published randomized trial involving 57 patients [
      • Voet N.
      • Bleijenberg G.
      • Hendriks J.
      • et al.
      Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT.
      ]. The patients who received exercise therapy had an increase in registered physical activity only, whereas the patients who received CBT had an increase in registered and experienced physical activity, sleep quality, and social participation [
      • Voet N.
      • Bleijenberg G.
      • Hendriks J.
      • et al.
      Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT.
      ]. After a 12-week follow-up without supervision, more than 70% of the exercise and CBT participants continued their adjusted level of activity. Overall, CBT was more efficient than aerobic exercise (numbers needed to treat [NNT] were 1.3 and 2.1 for CBT and exercise, respectively) [
      • Voet N.
      • Bleijenberg G.
      • Hendriks J.
      • et al.
      Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT.
      ]. Another recent study found that aerobic exercise improved fitness (NNT = 2.1), but post-exercise protein supplements provided no additional benefit [
      • Andersen G.
      • Prahm K.P.
      • Dahlqvist J.R.
      • Citirak G.
      • Vissing J.
      Aerobic training and postexercise protein in facioscapulohumeral muscular dystrophy: RCT study.
      ]. For both muscle strengthening and aerobic exercise programs, the training should last at least 10 weeks with regular supervision to optimize the effect, and improve safety and compliance [
      • Cup E.H.
      • Pieterse A.J.
      • ten Broek-Pastoor J.M.
      • et al.
      Exercise therapy and other types of physical therapy for patients with neuromuscular diseases: a systematic review.
      ].

      7. Rehabilitation management for patients with FSHD

      (Veena Raykar)
      It is important that all patients with FSHD who have functional limitations should receive an initial rehabilitation consultation [
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ]. An effective rehabilitation program can help people with FSHD maintain their quality of life (QoL) and independence, minimize secondary medical comorbidities, and prevent or limit physical deformity. The initial assessment should cover muscle function; functional level in activities of daily living at home and in the community; pain history; home access issues; previous trial of exercise programs, orthoses and adaptive devices; and the patient's goals and expectations. Exercise, together with bracing, may prolong ambulation and prescription of appropriate mobility aids, and assistive devices can maximize function and participation.
      An exercise prescription in FSHD can be challenging because of asymmetrical muscle weakness, variable progression, age of onset and functional levels, as well as different compensatory mechanisms. Potential benefits of exercise include maintenance and improvement in muscle strength, improved exercise tolerance/endurance/function, and prevention of decline in gait parameters. Exercise can also assist in preventing obesity, deconditioning and in the management of pain and fatigue. Exercise programs should be started early in the course the disease and be individualized, targeted, practical and largely goal oriented (e.g. maintaining independence and/or preventing falls). The prescription should include the type of exercise, frequency, duration, intensity, and the format of exercise session customized to the disease history of the individual. Home-based training programs in particular can offer multifactorial benefits. Regular review and modification are essential. Elements of the program can include balance training, core strengthening, flexibility and endurance training, practical sessions on floor transfers and sit-to-stand transfers, as well as education on energy conservation. Vigorous exercise training to the level of fatigue and longer-lasting muscle soreness should be avoided, and education regarding signs of overwork and weakness should be provided. Regular stretching exercises and proper positioning can be useful in preventing contractures, and education regarding proper posture can help manage pain and improve exercise tolerance. Hydrotherapy is useful for general cardiopulmonary fitness, managing pain, and stretching and strengthening muscles. Individualized sessions of Pilates and yoga may also assist with focus-strength, balance, flexibility, and posture.
      Use of walking aids (e.g. single point canes, quad sticks, wheeled walkers) should be considered to maintain mobility. The optimal use of mobility aids is best directed by rehabilitation physician or physical therapy experts. Walking aids can assist with balance, compensate for weak muscles, reduce fatigue or pain, facilitate a safe walking pattern, and reduce the risk of falls. However, walking aids can increase weight bearing on upper limbs and increase existing shoulder pain and muscle fatigue. There is insufficient information to recommend routine use of lumbar supports (braces and corsets) and there are concerns that these may decondition back muscles; however, these may be useful in the short term for improving sitting posture, patient awareness, and acute back pain.
      Foot dorsiflexion weakness leading to foot drop is common in FSHD and can lead to falls due to poor toe clearance in swing phase. The problem may be accommodated with the use of customized ankle–foot orthoses (AFO). A customized prescription of an AFO needs comprehensive assessment of orthotic goals and patient's expectations, muscle strength, joint range, knee control, presence of joint pain, and upper limb function. The aims are to provide adequate toe clearance in swing phase and hence prevent falls, decrease excessive hip and knee flexion and ankle plantar flexion during the swing phase, decrease excessive knee extension/flexion in the stance phase, restore heel strike, and to improve energy efficiency, confidence, safety and endurance. Knee–ankle–foot orthoses are less commonly used because of their poor cosmetic appeal and difficulty in donning and doffing, but these provide better stance control, improve gait safety, decrease fatigue, and are helpful in managing knee pain. Orthotic and mobility aid prescriptions should be followed by gait retraining and education.
      About 20% of patients with FSHD become wheelchair-dependent after 50 years of age [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Patients may transition to a wheelchair because of fatigue from walking, or an increased falls risk due to poor mobility. The transition can be gradual, starting initially with a backup wheelchair when needed. A customized prescription of an appropriate wheelchair (manual or power-assisted) is important in order to maintain postural alignment in sitting, provide a stable base of support, minimize/compensate for skeletal deformity, maximize upper limb function, minimize fatigue, and prevent secondary complications of an inappropriate prescription. Specialized seating clinic assessment will optimize accessories, such as tilt in space mechanisms, back supports, front, mid, rear wheel combinations, cushions, and head rests. Power-assisted wheelchairs can be more energy efficient, biomechanically advantageous, and more time-saving for patients with FSHD [
      • Love J.A.
      • Benson J.
      Community use of a pushrim activated power-assisted wheelchair by an individual with facioscapulohumeral muscular dystrophy.
      ]. Collaboration between the wheelchair user, carers, other relevant people, clinicians, suppliers and funding bodies is key to a successful wheelchair prescription.

      8. Respiratory evaluation and management in FSHD

      (Stephen McNamara)
      Respiratory insufficiency due to respiratory muscle weakness occurs in a relatively small proportion of FSHD patients (about 10%), but is more likely in moderate-to-severe disease with kyphoscoliosis, and when there is co-existent lung disease [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]; nevertheless, it needs to be considered in all patients. Regular monitoring of respiratory function is recommended because patients can have compensated respiratory insufficiency without presenting signs over a long period and may only experience symptoms of respiratory insufficiency during sleep, or when it is exposed by a stressor such as infection. The evaluation should include spirometry measuring forced vital capacity (FVC), upright/seated and supine maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) [
      • Shahrizaila N.
      • Kinnear W.J.
      • Wills A.J.
      Respiratory involvement in inherited primary muscle conditions.
      ,
      • Wohlgemuth M.
      • van der Kooi E.L.
      • van Kesteren R.G.
      • van der Maarel S.M.
      • Padberg G.W.
      Ventilatory support in facioscapulohumeral muscular dystrophy.
      ]. Serial measurements of vital capacity are helpful for monitoring respiratory muscle function, and supine vital capacity measurements can be used to detect diaphragmatic weakness, although this is unlikely to occur in FSHD [
      • Shahrizaila N.
      • Kinnear W.J.
      • Wills A.J.
      Respiratory involvement in inherited primary muscle conditions.
      ]. Spirometry can be difficult in patients with FSHD due to the facial weakness causing a poor mouth seal [
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ,
      • Shahrizaila N.
      • Kinnear W.J.
      • Wills A.J.
      Respiratory involvement in inherited primary muscle conditions.
      ]. Unless this is addressed, spirometry values can be less accurate, and mouth pressures unreliable. Arterial blood gas analysis, paying particular attention to arterial carbon dioxide (PCO2), becomes important once an issue with respiratory muscle strength is apparent. The AAN guidelines recommend that patients should be tested at baseline as a reference point and prior to any anesthetic sedation [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Annual respiratory evaluation is suggested if the baseline measure is abnormal or when warranted by the clinical picture [
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ], but otherwise may not be necessary because of the typical slow progression of FSHD. As most respiratory crises are precipitated by a respiratory tract infection, pneumococcal and influenza vaccinations should be recommended. If a respiratory tract infection develops, prompt review and intervention is advised [
      • Shahrizaila N.
      • Kinnear W.J.
      • Wills A.J.
      Respiratory involvement in inherited primary muscle conditions.
      ].
      Sleep-disordered breathing due to upper airway obstruction or nocturnal hypoventilation with hypercapnia during REM sleep occurs infrequently in patients with FSHD, but it is advisable to be particularly suspicious in patients with very poor respiratory function and/or kyphoscoliosis. It is important to ask about symptoms of sleep-disordered breathing, including disturbed sleep (insomnia), nocturnal choking, morning headaches, cognitive difficulties, daytime fatigue, and somnolence [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. This type of information often comes from partners because patients may become tolerant of these symptoms. If symptoms are present, consider evaluation with an overnight sleep study, including measurement of arterial oxygen saturation (PO2) and transcutaneous measurement of carbon dioxide (TcCO2) during sleep [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. The need for night-time ventilator support is most likely in patients with FVC less than 50% predicted, MIP greater than −30 cm H2O, MEP less than 40 cm H2O, and vital capacity less than 20 mL/kg or 1.0 L [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ,
      • Mehta S.
      Neuromuscular disease causing acute respiratory failure.
      ]. Intervention with bilevel positive pressure support (noninvasive ventilation, NIV) is a labor-intensive process, particularly in patients with NMD, and needs to be carried out in a specialized unit. The mask fit is critical and difficult to achieve in the presence of orofacial muscle weakness. Periodic reassessment is essential for optimal care. In milder forms of obstructive apnea in FSHD patients, position therapy may be helpful. If muscle weakness progresses and gas exchange worsens, breathing may need to be supported with NIV during wakefulness, requiring a second NIV device.

      9. Hearing loss and retinal vasculopathy

      (Jean K. Mah)
      The AAN guidelines report that an estimated 15.5% (95% confidence interval, CI, 12.1%–19.4%) of patients with FSHD have audiometric abnormalities, especially high-frequency hearing loss, although the true prevalence is unknown [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Symptomatic hearing loss typically affects people with childhood-onset FSHD who have large D4Z4 deletions and may be progressive. An estimated 25% (95% CI 20.9%–30.8%) of people with FSHD1 have peripheral retinal vascular abnormalities seen on fluorescein angiography, and in approximately 0.6% (95% CI 0.2%–1.5%) of patients, severe retinal vasculopathy results in visual impairment [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. The severe form of retinovascular disease is associated with large D4Z4 deletions; most FSHD patients with retinal vascular abnormalities do not experience visual problems.
      The AAN guidelines recommend that young children with FSHD should be screened for hearing loss at diagnosis and yearly thereafter until school entry. Older children and adults should be assessed if symptomatic [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Patients with FSHD and large deletions (10–20 kb) should be referred to an experienced ophthalmologist for dilated indirect ophthalmoscopy. Subsequent monitoring will depend on the degree of retinal vasculopathy at initial screening [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Those with early-onset FSHD and large deletions will likely to need ongoing monitoring for retinal complications. Areas where more data are required include the prevalence of hearing loss in patients with FSHD2 and whether there is a relationship between the degree of tortuosity and gender in FSHD patients with retinal vasculopathy.
      Referring to the severe form of retinal vasculopathy in FSHD patients as Coats' disease can be misleading. Coats' disease is a congenital disorder of retinal vascular development, characterized by unilateral peripheral retinal telangiectasia as well as progressive subretinal and intraretinal exudation that can lead to retinal detachment and blindness. It predominately affects males during the first two decades of life [
      • Grosso A.
      • Pellegrini M.
      • Cereda M.G.
      • et al.
      Pearls and pitfalls in diagnosis and management of coats disease.
      ]. Retinal telangiectasia presenting in FSHD can be bilateral, occurs at any age, and affects males and females equally, although the more severe form seems to occur more frequently in females [
      • Statland J.M.
      • Sacconi S.
      • Farmakidis C.
      • et al.
      Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size.
      ]. A more appropriate description of the retinal syndrome presenting in patients with FSHD is retinal vessel tortuosity progressing to bilateral exudative retinitis [
      • Fitzsimons R.B.
      Retinal vascular disease and the pathogenesis of facioscapulohumeral muscular dystrophy. A signalling message from wnt?.
      ]. Severe FSHD retinopathy would be a more appropriate term than Coats' disease or Coats' syndrome.

      10. FSHD and bone health

      (Scott Baker)
      There is a close correlation between reductions in skeletal muscle mass and bone loss, although the factors important in this relationship are yet to be fully elucidated [
      • Blain H.
      • Jaussent A.
      • Thomas E.
      • et al.
      Appendicular skeletal muscle mass is the strongest independent factor associated with femoral neck bone mineral density in adult and older men.
      ]. Therefore, the diagnosis of FSHD might be expected to be associated with an increased risk of osteoporotic fractures due to mechanical factors, such as impaired mobility and an increased risk of falls, and pathological factors increasing the prevalence of osteopenia and osteoporosis. However, there are limited data in adults with hereditary myopathies and the risk to bone health posed by FSHD is unknown, although a study to address this is under way (ClinicalTrials.gov identifier NCT02413190). Due to the significant clinical heterogeneity among patients with FSHD, a significant range of bone densities and fracture risk is likely to be present.
      There are no specific guidelines for screening for osteoporosis in patients with FSHD; however, based on general recommendations, screening using dual-energy x-ray absorptiometry (DXA) would be recommended in any patient with a history of a minimal trauma fracture and should be considered in any wheelchair-bound patient; any ambulatory patient with significant mobility impairment and/or a history of recurrent falls; patients of low body weight (e.g. body mass index < 20 kg/m2); patients with a known risk factor for osteoporosis, such as hypogonadism, patients with a first-degree relative with osteoporosis or a history of minimal trauma fracture; and patients aged >45 years (women) or >50 years (men) [
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      ]. Screening could be considered in other patients according to clinical suspicion, although the cost-effectiveness is unclear.
      Patients with osteopenia or osteoporosis according to DXA bone mineral density criteria (T-score between −1.0 standard deviation (SD) and −2.5 SD, and T-score −2.5 SD or below, respectively) should be screened for known risk factors and secondary causes of osteoporosis on clinical history (such as smoking, excess alcohol intake, low dietary calcium, glucocorticoid exposure) and laboratory investigations (including 25-OH vitamin D deficiency) [
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      ]. Radiography of the thoracolumbar spine can identify patients with symptomatic or occult vertebral compression fractures.
      The natural history of osteoporosis in FSHD is unknown; however, it may be reasonable to consider a further DXA scan 2 years or more following a normal study. In the normal population, the T-score decline is usually approximately 0.1 SD per year (1 SD per decade). Screening is suggested at a frequency closer to 2 years in patients close to treatment thresholds (e.g. a T-score of −2.5 SD) and less frequently in others. Repeat screening with DXA should also be considered according to the clinical picture, including the onset of a new minimal trauma fracture, age >70 years, or commencement of therapies that may alter bone density, such as menopausal hormone therapy or corticosteroids [
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      ].
      In the absence of specific evidence in patients with FSHD, management of osteoporosis should be based on recommendations for the general population. Prevention of osteoporotic fractures is based on lifestyle modification (e.g. smoking cessation) and treatment of any secondary cause. Weight-bearing exercise early in life may increase peak bone mass, while later in life may reduce fatigue and possibly improve gait stability, but evidence for a reduction in falls or fractures in FSHD is absent. Vitamin D (cholecalciferol) supplementation is recommended for vitamin D-deficient patients and for those at risk of deficiency, with at least 800 IU/day, aiming for end-of-winter serum vitamin D concentrations of at least 50 nmol/L, although optimal levels are probably above 75 nmol/L [
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      ]. Supplementation may reduce the risk of falls, although evidence in FSHD specifically is lacking. Antiresorptive therapy in addition to calcium and vitamin D supplementation is recommended in patients with a history of minimal trauma fracture, or those at high risk. Bisphosphonates and denosumab (a monoclonal antibody to RANK ligand) are antiresorptive agents proven to reduce the risk of vertebral, nonvertebral, and hip fractures in patients at risk of osteoporotic fractures [
      • Cosman F.
      • de Beur S.J.
      • LeBoff M.S.
      • et al.
      Clinician's guide to prevention and treatment of osteoporosis.
      ]. There is no clinical trial evidence to guide the choice between agents in FSHD; hence, the choice of therapy is best tailored with a discussion between patient and physician. In conclusion, physicians should be aware of a potentially increased risk for osteoporosis and fracture, especially in patients with advanced FSHD.

      11. Scapular fixation in FSHD

      (Kathryn R. Wagner)
      The shoulder joint has the greatest range of motion of all joints in the body. Normal shoulder motion results from the combined motion of the ball and socket joint and the shoulder blade moving relative to the rib cage. FSHD primarily involves the muscles responsible for control of the scapula (i.e. rhomboids, serratus anterior, trapezius), with the deltoid and rotator cuff muscles typically preserved [
      • Cooney A.D.
      • Gill I.
      • Stuart P.R.
      The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy.
      ]. This imbalance of the shoulder girdle muscles can lead to winging of the scapula. Also, the inability to fix the scapula to the thorax creates an unstable deltoid origin, resulting in weakness of shoulder flexion and abduction. Stabilizing the scapula by fusing it to the underlying ribs creates a stable platform for the intact ball and socket muscles to function, making it easier to achieve overhead positions, making winging impossible, and reducing fatigue and pain [
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ,
      • Cooney A.D.
      • Gill I.
      • Stuart P.R.
      The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy.
      ].
      In this procedure the scapula is wired to the adjacent ribs with or without bone grafts at the contact points [
      • Cooney A.D.
      • Gill I.
      • Stuart P.R.
      The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy.
      ,
      • Giannini S.
      • Faldini C.
      • Pagkrati S.
      • et al.
      Fixation of winged scapula in facioscapulohumeral muscular dystrophy.
      ]. The rehabilitation protocol typically begins 7–12 weeks after surgery, starting with full active motion and increasing day-to-day function but limiting the weight lifted. A solid fusion is anticipated after 20 weeks with improvement in shoulder function expected by 6 months, although this can continue to improve up to 1 year after surgery. Complications are infrequent but include hemothorax or pneumothorax, rib or scapula facture, pain, infection, nonunion, reduced lung capacity, and stiff shoulder [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ,
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ,
      • Cooney A.D.
      • Gill I.
      • Stuart P.R.
      The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy.
      ,
      • Giannini S.
      • Faldini C.
      • Pagkrati S.
      • et al.
      Fixation of winged scapula in facioscapulohumeral muscular dystrophy.
      ,
      • Demirhan M.
      • Uysal O.
      • Atalar A.C.
      • Kilicoglu O.
      • Serdaroglu P.
      Scapulothoracic arthrodesis in facioscapulohumeral dystrophy with multifilament cable.
      ]. Scapular fixation surgery may be considered in patients with FSHD who have normal deltoid strength at 45° abduction, a positive response to a compression test (gain of function when the scapulae are manually fixed), normal pulmonary function, and who have decreased QoL due to weakness in the muscles of scapular fixation or from pain. The procedure should be performed by a surgeon who can provide data on the number of procedures and complications, and recommended by a neuromuscular neurologist or physiatrist and by a patient with FSHD. There is a need for comparative studies of the various surgical techniques available in order to determine preferred options.

      12. Management of pain and other palliative therapy

      (Rabi Tawil)
      The majority (up to 79%) of patients with FSHD experience pain that is typically musculoskeletal in origin. The most common areas affected by pain, in descending order, include the lower back, legs, shoulders, and neck [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. The AAN guidelines recommend that clinicians routinely inquire about pain because patients may not volunteer their experience of pain [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Options for managing pain include referral for physical therapy and consideration of episodic shoulder bracing during exacerbations of the pain (Table 1). Shoulder bracing may help realign the shoulders, reducing the stretch on the musculoskeletal structures of the neck and upper back resulting in pain reduction [
      • Tawil R.
      • Kissel J.T.
      • Heatwole C.
      • et al.
      Evidence-based guideline summary: evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy.
      ]. Anecdotal reports suggest that appropriately applied kinesiology tape may also be helpful. Lower back pain is frequently associated with a protuberant abdomen; in this situation, abdominal binders, particularly those that are custom-made, may be of assistance in less extreme cases. For persisting pain, consider nonsteroidal anti-inflammatory medications and possibly antidepressants and antiepileptics, which are effective in pain with a neuropathic or myofascial component.
      Table 1Options for managing pain in patients with FSHD.
      • Referral for physical therapy
      • Bracing to change shoulder position
      • Kinesiology tape
      • Abdominal binders
      • Nonsteroidal anti-inflammatory drugs
      • Antidepressant and/or antiepileptic agents for neuropathic or myofascial pain
      Many patients with FSHD also experience chronic fatigue, but this is rarely addressed as an issue in the literature. Energy conservation strategies can help some patients in managing fatigue, as can moderated aerobic training and CBT in particular [
      • Tawil R.
      • van der Maarel S.
      • Padberg G.W.
      • van Engelen B.G.
      171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy.
      ,
      • Voet N.B.
      • van der Kooi E.L.
      • Riphagen I.I.
      • et al.
      Strength training and aerobic exercise training for muscle disease.
      ]. Pharmacological options used for fatigue in other conditions that may be considered include modafinil, a nonamphetamine stimulant approved for improving wakefulness. Successfully managing pain and mood disorders can also assist with fatigue.
      There are a range of palliative surgical interventions used in other conditions that may be of assistance in FSHD, such as upper eyelid gold-weight implants and reconstructive lower lid surgery [
      • Sansone V.
      • Boynton J.
      • Palenski C.
      Use of gold weights to correct lagophthalmos in neuromuscular disease.
      ], which is used in the correction of lagophthalmos; this allows patients to fully close their eyelids reducing the risk of exposure keratitis caused by orbicularis oculi weakness in FSHD, as well as markedly improving facial appearance. Another approach is to build up the lower lid with injectable dermal fillers (e.g. hyaluronic acids) or implants. Various surgical techniques and dermal fillers have also been used for both functional and cosmetic improvement in patients with severe orbicularis oris weakness causing poor speech, drooling, and spillage of food when eating. The published experience with these approaches, however, is almost exclusively in patients with traumatic facial injuries or with neurogenic facial palsy.
      Tendon transplant for treatment of foot drop is another potential palliative intervention for patients with FSHD. Here again experience in this surgical technique is almost exclusively in neurogenic causes of foot drop. Long-term benefit is possible by carefully selecting patients with slowly progressive disease and with intact posterior leg muscles that are viable candidates for such a procedure. There are also reports of polypropylene mesh being used to reinforce abdominal wall defects in cases of abdominal muscle laxity in FSHD [
      • Rappoport Stramwasser J.
      • Figueroa M.
      • Albán M.
      • Silva J.
      • Carrasco J.
      Plastia de la pared abdominal. Nueva alternativa en el manejo de la distrofia muscular facioescapulohumeral.
      ]. This can be done laparoscopically. While this may provide a short-term cosmetic benefit, it is unlikely to provide functional improvement and there is no information on long-term outcomes with this procedure and it is not without complications. Caution is recommended with spinal fusion procedures in FSHD patients with severe lumbar lordosis due to increasing paraspinal and hip extensor muscle weakness. Because of hip extensor weakness, this intervention can be counterproductive; the patient may not be able to sit up or walk after the procedure.
      Currently there are no standard palliative surgeries for addressing the complications of FSHD and little published data for procedures other than scapular fixation (Table 2). It is critical that surgeons considering interventions in patients with FSHD consult with neuromuscular specialists to fully understand the underlying disease mechanism and prognosis. This information is crucial in a surgeon's decision to proceed with a particular surgical intervention and for selection of the most appropriate approach.
      Table 2Potentially useful palliative surgical interventions for patients with FSHD.
      Orbicularis oculi weakness

      • Upper eyelid gold-weight implants and reconstructive lower lid surgery
      • Injectable dermal fillers (e.g. hyaluronic acids) or implants


      Orbicularis oris weakness

      • Surgical or minimally invasive techniques to improve lower lip function and appearance
      • Injectable dermal fillers (e.g. hyaluronic acids)


      Others

      • Tendon transplant for foot drop
      • Polypropylene mesh to reinforce abdominal wall defects

      13. Investigational agents for FSHD

      (Kathryn R. Wagner)
      With the etiology of FSHD becoming clearer, a range of disease-specific and nonspecific targets for treating the disease are beginning to be investigated (Table 3). One disease-specific approach is to use RNA interference to suppress DUX4 mRNA expression in the muscle to slow disease progression. There is evidence that DUX4 gene silencing, triggered by engineered artificial microRNAs, is myoprotective in vivo [
      • Wallace L.M.
      • Liu J.
      • Domire J.S.
      • et al.
      RNA interference inhibits DUX4-induced muscle toxicity in vivo: implications for a targeted FSHD therapy.
      ]. Another possible approach is to increase methylation of the D4Z4 repeat region in FSHD1 patients by increasing SMCHD1 activity in order to repress DUX4 expression and slow progression.
      Table 3Investigational agents for treating FSHD.
      Disease-specific approaches

      • DUX4 gene silencing
        • DUX4 ASO
        • AAV-siRNA-DUX4
        • AAV-siRNA DUX4 promoter
      • Increasing methylation of the D4Z4 repeat region
        • AAV-SMCHD1


      Nonspecific approaches

      • Immunomodulatory agents
        • Physiocrines (e.g. histidyl-tRNA synthetase)
      • Anabolic agents
        • Myostatin inhibitors (e.g. PF-06252616, BYM338)
      Nonspecific approaches include immunomodulation with, for example, physiocrines and the use of anabolic agents, such as myostatin inhibitors. Physiocrines are tRNA synthetases, which have both an intracellular protein synthesis and extracellular physiologic role in the regenerative, vascular, and immune systems. Resolaris (histidyl-tRNA synthetase, aTyr Pharma, Inc., San Diego, CA, USA) has been shown to reverse immune cell invasion of muscle tissue in an animal model of myopathy [
      • McKew J.
      • Ashlock M.
      • Ogilvie K.
      • et al.
      Resolaris, a potential therapeutic for rare myopathies with an immune component.
      ]. Furthermore, autoantibodies to cytoplasmic histidyl-tRNA synthetase have been associated with inflammatory myositis [
      • Zhou J.J.
      • Wang F.
      • Xu Z.
      • et al.
      Secreted histidyl-tRNA synthetase splice variants elaborate major epitopes for autoantibodies in inflammatory myositis.
      ]. A multinational Phase Ib/II clinical trial of this agent in adult patients with FSHD is under way in Europe.
      The aim of myostatin inhibition in FSHD is to increase muscle growth and decrease fibrosis/fatty infiltration. Myostatin is a negative regulator of skeletal muscle mass that is upregulated in many conditions of muscle wasting. At the molecular level, myostatin binds to and activates the activin receptor IIB (ActRIIB)/Alk 4/5 complex. The majority of approaches used to inhibit the myostatin signaling pathway involve neutralizing monoclonal antibodies engaging with the ActRIIB/Alk4/5 receptor complex, either by binding directly to myostatin itself, or by binding to components of this receptor complex [
      • Smith R.C.
      • Lin B.K.
      Myostatin inhibitors as therapies for muscle wasting associated with cancer and other disorders.
      ]. There is evidence in an animal model that myostatin inhibitors can improve muscle function (muscle mass and strength) and attenuate muscle fibrosis by inducing fibroblast apoptosis [
      • Wagner K.R.
      • McPherron A.C.
      • Winik N.
      • Lee S.J.
      Loss of myostatin attenuates severity of muscular dystrophy in mdx mice.
      ,
      • Li Z.B.
      • Kollias H.D.
      • Wagner K.R.
      Myostatin directly regulates skeletal muscle fibrosis.
      ]. There is also some evidence from Phase I/II clinical trials that myostatin inhibitors may be useful in individuals with muscular dystrophy, but the safety of these agents is likely to be a significant issue [
      • Wagner K.R.
      • Fleckenstein J.L.
      • Amato A.A.
      • et al.
      A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy.
      ,
      • Campbell C.
      • Escolar D.
      • Mah J.
      • et al.
      A Phase 2, randomized, placebo-controlled, multiple ascending-dose study of ACE-031, a soluble activin receptor type IIB, in boys with Duchenne muscular dystrophy (DMD).
      ]. There are some ongoing studies of myostatin inhibitors in muscle-wasting states, but none currently in FSHD.

      14. Considerations for establishing FSHD registries

      (Monique M. Ryan)
      Despite published studies relevant to the natural history of FSHD, precise information about the overall incidence of the various disease-related complications, and the rate and degree of their progression, remains relatively limited. There is also a lack of consensus on the most appropriate endpoint measures to assess long-term progression in this condition, particularly with respect to which biomarkers are informative, cost-effective, and correlate best with specific disease manifestations and patient-reported outcomes of well-being and burdens of disease. Identifying patients with rare diseases, gathering and collating their genetic test results and clinical status parameters is time-consuming and expensive. Most rare disease registries are operated by patient organizations, academic researchers, or the private sector. Historically, most have originated in one specific country, but the number of international registries is on the rise. The National Institutes of Health in the USA has now built a Global Rare Diseases Patient Registry Data Repository (GRDR®), which allows any rare disease population, regardless of size, to collect patient data that can identify clinical trial candidates and fuel research. Registry establishment, to facilitate accruing of subjects for natural history studies and clinical trials, has been identified as an important research priority in FSHD [
      • Tawil R.
      • van der Maarel S.M.
      • Tapscott S.J.
      Facioscapulohumeral dystrophy: the path to consensus on pathophysiology.
      ].
      There are a number of national registries across the world that collect data on patients with FSHD, including in Canada, France, Italy, the Netherlands, the UK and the USA (University of Rochester), and one is being developed in Australia. The aim of this latter registry is to identify the number and location of affected individuals in Australia, and to collate basic clinical and genetic data together with information on progression and disease-specific complications. Other FSHD registries have additional stated aims, such as increasing the understanding of FSHD, disseminating disease-specific information, and improving quality care and outcomes. Benefits to patients who join registries should include receiving notification of research studies and connecting with NMD experts. Ultimately, the Australian FSHD registry will interface with other research efforts in a similar way to the European RD-Connect network; this would enable cross-linking of the registries and any stored biomaterials, as well as genomic and trial data.
      To enable standardized aggregation of patient information, registries need standardized ontologies and common data elements for collection. The framework for the Australian FSHD registry, therefore, needs to be consistent with the existing protocols and best practice recommendations produced by the leading database and registry initiatives internationally. These include RD-Connect in Europe and the existing FSHD databases. The dataset collected in a registry needs to be sufficient to enable the registry's aims to be met, but not so detailed that data entry and curation becomes excessively burdensome. A core dataset for FSHD was established in 2011 to set out the information that all registries should collect in order for their data to be comparable (http://www.treat-nmd.eu/downloads/file/registries_toolkit/FSH_core_dataset_May2011.pdf). In most registries information is entered by patients and clinicians with a data curator. One of the current problems with some existing FSHD databases is the lack of molecular confirmation of the FSHD diagnosis for a significant proportion of the subjects. This is important for identifying potential clinical trial participants. In some countries this issue has been addressed by patient support organizations paying for genetic testing.

      15. Participants

      • Scott Baker, Melbourne, Victoria, Australia
      • Alistair Corbett, Sydney, NSW, Australia
      • Baziel van Engelen, Nijmegen, The Netherlands
      • Stephen McNamara, Sydney, NSW, Australia
      • Jean K Mah, Calgary, Alberta, Canada
      • Monique M Ryan, Melbourne, Victoria, Australia
      • John Rasko, Sydney, NSW, Australia
      • Veena Raykar, Sydney, NSW, Australia
      • Sabrina Sacconi, Nice, France
      • Stephen J Tapscott, Seattle, Washington, USA
      • Rabi Tawil, Rochester, New York, USA
      • Kathryn R Wagner, Baltimore, Maryland, USA
      • Alan Watts, Sydney, NSW, Australia

      Acknowledgments

      This workshop was made possible by the financial support of the FSHD Global Research Foundation .

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