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Facioscapulohumeral muscular dystrophy
Handbook of Clinical Neurology, Vol. 148 (3rd series) Neurogenetics, Part II D.H. Geschwind, H.L. Paulson, and C. Klein, Editors https://doi.org/10.1016/B978-0-444-64076-5.00035-1 Copyright © 2018 Elsevier B.V. All rights reserved
Chapter 35
Facioscapulohumeral muscular dystrophy RABI TAWIL* Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development.
INTRODUCTION Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of its enigmatic genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. The recent description of a unifying mechanism for FSHD now allows for a targeted approach to therapeutic development.
PREVALENCE AND MODE OF INHERITANCE The prevalence of FSHD is estimated at between 1:15,000 and 1:20,000, making it the third most common form of muscular dystrophy after Duchenne dystrophy and myotonic dystrophy (Padberg et al., 1995b; Flanigan et al., 2001). A recent evaluation of the prevalence of FSHD in the Netherlands suggests a significantly higher prevalence of 2.4/20,000; confirmation of this new figure
would make the prevalence of FSHD nearly identical to that of myotonic dystrophy (Deenen et al., 2014). As life-threatening bulbar, respiratory, or cardiac involvement is rare in FSHD, life expectancy is generally unaffected (Lunt and Harper, 1991). The inheritance pattern in about 95% of patients with FSHD is autosomal dominant, with as many as a third the result of de novo mutations (Tawil, 2008). Inheritance in most of the 5% of patients who have FSHD type 2 (see section on genetics below) is more complex, as it is inherited as a digenic disease (Lemmers et al., 2012b).
GENETICS FSHD was mapped to chromosome 4q35 and subsequently associated with the loss of an integral number of subtelomeric macrosatellite repeats known as D4Z4 over 20 years ago (Wijmenga et al., 1991; van Deutekom et al., 1993). Each D4Z4 repeat is 3.3 kb in size; whereas unaffected individuals have 11–100 D4Z4 repeats on chromosome 4q35, there was a contraction of repeats on one copy of 4q35 to 1–10 repeats in individuals with FSHD (van Deutekom et al., 1993). Each D4Z4 repeat contains
*Correspondence to: R. Tawil, University of Rochester Medical Center, Department of Neurology, 601 Elmwood Avenue, P.O. Box 673, Rochester, NY, 14642, United States. Tel: +1-585-275-6372, E-mail: [email protected]
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an open reading frame encoding a double homeobox gene known as DUX4 (Ding et al., 1998). However, the repeats are contained within a closed chromatin conformation (heterochromatin), suggesting the absence of transcription from within the repeats (Hewitt et al., 1994). Subsequent studies showed that repeat contraction in FSHD is associated with chromatin relaxation, raising the possibility of transcriptional activation of DUX4 (van Overveld et al., 2003). Whereas repeat contraction to 1–10 repeats was necessary for FSHD, it was not sufficient. Two distinct sequence variants are present distal to the last repeat (A or B), with FSHD occurring only with repeat contraction on the A variant (Lemmers et al., 2002). The A variant contains a polyadenylation sequence which is critical for stabilizing DUX4 mRNA (Lemmers et al., 2002, 2010). The above finding led to a unifying hypothesis for FSHD. A repeat contraction results in opening of chromatin structure and, in the setting of a permissive A background, results in the production of stable DUX4 mRNA and DUX4 protein from the distal copy of the D4Z4 repeats (Lemmers et al., 2010). In individuals with the clinical diagnosis of FSHD, about 95% have contracted repeats and are termed FSHD
type 1 or FSHD1. In the remaining patients with clinical FSHD, phenotypically indistinguishable from FSHD1, no repeat contractions is seen and yet these patients had chromatin changes at 4q35 similar to that observed in FSHD1 (de Greef et al., 2009, 2010). However, in these individuals with FSHD type 2 or FSHD2, chromatin relaxation, as measured by diminished level of DNA methylation, was noted on both D4Z4 copies, whereas hypomethylation in FSHD1 was restricted to the contracted allele. In FSHD2 as in FSHD1, at least one permissive A sequence is necessary to cause disease in addition to the open chromatin structure (de Greef et al., 2009). These findings in FSHD2 reaffirmed the importance of chromatin relaxation observed in FSHD1 in the pathophysiology of FSHD. Moreover, although FSHD1 and 2 have distinct genetic signatures, both result in the aberrant de-repression of DUX4 expression (Fig. 35.1). Whereas chromatin relaxation is the result of repeat contraction in FSHD1, the presence in FSHD2 of chromatin changes on both copies of 4q35, in the absence of repeat contraction, suggested the presence of an independent genetic factor predisposing to FSHD2. Using
Fig. 35.1. This figure shows representation of the subtelomeric region of 4q35, the site of the D4Z4 macrosatellite repeats implicated in facioscapulohumeral muscular dystrophy (FSHD). Normal: in normal individuals, both copies of 4q35 contain 11–100 D4Z4 repeats and the DNA is methylated at levels expected in transcriptionally silent heterochromatic regions. FSHD1: in FSHD1, one copy of 4q35 has a contracted number of repeats (1–10 repeats), resulting in a more permissive chromatin structure, as demonstrated by the hypomethylated DNA. FSHD2: in FSHD2, both copies of 4q35 have normal repeat numbers (11–100 repeats) but the DNA is hypomethylated due to mutations in the SMCHD1 gene, again resulting in a more permissive chromatin structure. In both FSHD1 and 2, the open chromatin structure allows the transcription of the DUX4 gene from the last D4Z4 repeat, a gene not normally expressed in somatic cells. However, stable mRNA resulting in DUX4 protein can only occur if the contracted D4Z4 allele in FSHD1 or either hypomethylated allele in FSHD2 has a polydenylation sequence distal to the last repeat, which is essential in stabilizing DUX4 mRNA.
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY exome sequencing in FSHD2 kindreds, mutations in the SMCHD1 (structural maintenance of chromosomes flexible hinge domain 1) gene were identified in about 85% of individuals with FSHD2 (Lemmers et al., 2012a). The SMCHD1 gene encodes a protein involved in X inactivation and in the expression of some autosomal genes (Mould et al., 2013). SMCHD1 mutations associated with FSHD2 may potentially result in deleterious epigenetic alterations on chromosomal regions other than 4q35 (Lemmers et al., 2012a). However, to date, based on evaluation of relatively few FSHD2 kindreds, there is no distinctive nonskeletal muscle pathology in FSHD2 compared to FSHD1 (de Greef et al., 2010).
PATHOPHYSIOLOGY The aberrant expression of DUX4 protein in somatic cells is the primary cause of disease in both FSHD1 and 2 (de Greef et al., 2010). DUX4 is a retrogene that codes for a transcriptional regulator normally expressed in the germline but whose expression is repressed in somatic tissue (Geng et al., 2012a). A relaxed D4Z4 chromatin structure allows stable DUX4 mRNA transcription from the distal copy of DUX4 when spliced to the polyadenylation signal, resulting in variegated expression of DUX4 protein in myonuclei (Fig. 35.1) (Gabriels et al., 1999; Lemmers et al., 2010; Snider et al., 2010a). The role of DUX4 in germline biology is not established (Snider et al., 2010a). Several potential mechanisms have been identified through which DUX4 expression can result in skeletal muscle pathology. DUX4 protein is highly toxic when expressed in cell lines, resulting in caspase-3-mediated apoptosis, and is known to negatively affect myogenesis (Kowaljow et al., 2007; Snider et al., 2009; Wuebbles et al., 2010). Overexpression of DUX4 in zebrafish and mice results in p53-mediated toxicity (Wallace et al., 2011). Apoptosis induced by DUX4 could be the result of expression of the germline gene program in postmitotic skeletal muscle cells (Geng et al., 2012b). DUX4 also activates a number of genes involved in atrophy, protein degradation, and innate immunity (van der Maarel et al., 2011; Geng et al., 2012b). As the germline is immuneprivileged, proteins expressed only in the germline may induce an immune response when aberrantly expressed in somatic tissue (van der Maarel et al., 2011). Such a reaction might explain the presence of inflammatory infiltrates, mostly in the perivascular regions, in up to a third of FSHD muscle biopsies (Arahata et al., 1995; Frisullo et al., 2011). In myoblast cell cultures DUX4 is expressed at high levels in very few nuclei at any time point, predominantly in differentiating myotubes (Snider et al., 2010b). The cause of the variegated DUX4 expression in myotubes is not clear.
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Understanding the factors triggering this variegated expression may help explain the regional and asymmetric involvement of muscle FSHD.
CLINICAL MANIFESTATIONS Symptoms Symptom onset in FSHD varies from infancy to late adulthood, with most patients developing symptoms in their late teens to early 20s. FSHD has a distinctive, regionally restricted onset of weakness starting rostrally in the face and the periscapular muscles and then progressing caudally to the upper arms, trunk muscles, and lower-extremity muscle. The most common initial symptoms are related to weak periscapular muscles, making it difficult to lift objects above shoulder level. Typically, facial weakness is asymptomatic but can be elicited, in hindsight; symptoms include sleeping with eyes slightly open (noted by spouse or parents), inability to whistle or difficulty drinking through a straw. However, a significant number of patients present initially with lowerextremity difficulties; nevertheless, most of the latter patients will have unnoticed or compensated facial or scapular weakness on exam. Asymmetric involvement is typical in FSHD and is more dramatic than in most other dystrophies.
Signs Recognizing the distinctive features of FSHD is crucial in making the diagnosis. In the face, the orbibularis oculi and orbicularis oris are most selectively affected. Severe orbicularis oris weakness causes difficulty in puckering of the lips that, when severe, results in everted lips. Neck extensors are more likely affected than neck flexors. The shoulders have a distinctive profile unique to FSHD. Asymmetric scapular winging is the rule with selective involvement of the lower trapezius, resulting in the upward jutting of the scapula when attempting to forward flex or abduct the shoulders. The clavicles are straight and the shoulders are rounded and slope forward. Pectoral muscle atrophy is evident with prominent axillary creases (Fig. 35.2). As the disease progresses in the upper extremities beyond the shoulder to the biceps, the deltoid remains normal or near normal in strength, a distinguishing feature from other dystrophies affecting the shoulder girdle. Involvement of the muscles of the trunk results in abdominal muscle weakness. A protuberant abdomen is often evident. Here again the asymmetric features of FSHD are evident, with selective involvement mostly of the lower abdominal muscle resulting in a positive Beevor’s sign on attempted neck flexion in the supine position (Eger et al., 2010). Progressive paraspinal
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A
C
B
D
Fig. 35.2. Typical shoulder profile of a patient with facioscapulohumeral muscular dystrophy. (A) Frontal view showing asymmetric limitation of shoulder abduction, straight clavicles, pectoral muscle atrophy with resultant prominent axillary creases, and jutting upwards of the scapula on the right on attempted shoulder abduction due to more severe involvement of the lower versus the upper trapezius. (B) Asymmetric scapular winging. (C, D) Bedside manual fixation of the scapula resulting in improved shoulder abduction from 90° (C) to about 135° (D). This bedside maneuver helps assess the degree of potential improvement in range of motion that can be expected from surgical scapular fixation. (Reproduced from Farmakidis C, Tawil R (2011) Facioscapulohumeral muscular dystrophy. In: Tawil RN, Venance S (eds) Neuromuscular disorders. Neurology in Practice Series. Oxford: Blackwell Publishing, pp. 74–79.)
muscle involvement results in an exaggerated lumbar lordosis. In the lower extremities distal weakness is typically evident first in the anterior leg muscles with later involvement in thigh and pelvic girdle muscles. Asymmetric involvement of the hip muscle can result in unilateral pelvic tilt that can be mistaken for pelvic joint pathology or leg length discrepancy. In patients with advanced disease, the distinctive regional and asymmetric involvement is less evident. Yet even in patients with severe weakness, unlike most other dystrophies, contractures are absent or minimal.
Extramuscular manifestations Respiratory involvement in FSHD is infrequent. A prospective, cross-sectional study of patients with genetically confirmed FSHD found signs of restrictive lung disease on pulmonary function testing in about 10% of patients (Scully et al., 2014). A Dutch study estimates that about 1% of patients with FSHD require ventilator support (Wohlgemuth et al., 2004). Restrictive lung disease is more common in patients with severe disease, especially those with significant trunk and hip girdle weakness and those who are wheelchairbound (Wohlgemuth et al., 2004; Scully et al., 2014). FSHD is not associated with cardiomyopathy, ventricular arrhythmias, or symptomatic conduction defects. About 5% of patients surveyed develop mild cardiac conduction abnormalities and a predilection for supraventricular arrhythmias (Laforet et al., 1998). A recent study
showed a high incidence of asymptomatic right bundle branch block in patients with FSHD (Pons van Dijk et al., 2014). Two FSHD-specific features are the occurrence of high-frequency hearing loss and retinal vascular disease that can rarely result in an exudative retinopathy, also known as Coats disease (Fitzsimons et al., 1987; Padberg et al., 1995a). The incidence of symptomatic retinal disease and hearing loss, however, is rare and limited to patients with the largest deletions in the number of D4Z4 repeats; this corresponds to a contracted 4q35 allele measuring 10–18 kb on genetic testing (see below) (Lutz et al., 2013; Statland et al., 2013b). It is estimated that about 0.6% of patients with FSHD develop Coats disease (Statland et al., 2013b).
Clinical diagnosis The availability of sensitive and specific genetic testing has facilitated the diagnosis of FSHD. Genetic testing for FSHD should be performed on patients with symptoms and signs of facial or shoulder weakness in the absence of extraocular and bulbar involvement (Padberg et al., 1991; Tawil et al., 2010a). It should be noted that facial weakness is not always evident in patients with FSHD. Consequently FSHD should be considered in patients presenting with scapular weakness and a typical shoulder profile with or without evident facial weakness. The presence of ptosis, extraocular muscle involvement, bulbar weakness, severe contractures, or symptomatic
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY respiratory insufficiency in the setting of mild weakness essentially excludes the diagnosis of FSHD. Serum creatine kinase ranges from normal to up to five times the upper limit of normal. Electromyography findings in FSHD are nonspecific with mostly show myopathic changes. Electromyography can be helpful in ruling out neurogenic causes as, for example, in a case presenting with unilateral winging or if specific changes are found (e.g., myotonic discharges), suggesting an alternative diagnosis. The differential diagnosis of FSHD includes a list of conditions that mimic some of the presentations of FSHD. These include the scapuloperoneal syndromes, limb girdle dystrophies such as calpainopathies, valosin-containing protein myopathies, inclusion body myopathy, and mitochondrial myopathies (Rowland et al., 1991; Tawil et al., 1995; Wilhelmsen et al., 1996; Sacconi et al., 2012).
Genetic testing Commercial genetic testing for FSHD1 is widely available but is much more limited for FSHD2. In FSHD1 testing, the size of the DNA fragment on 4q35 containing the D4Z4 repeat is measured. 4q35 alleles with a normal number of D4Z4 repeats (>10) measure more than 48–50 kb, whereas alleles with only 1–10 repeats, diagnostic of FSHD1, result in alleles measuring 10–38 kb. Genetic testing in a patient with features typical for FSHD showing one 4q35 allele between 10 and 38 kb is diagnostic for FSHD1. In patients in whom clinical features are consistent with FSHD, the presence of a contracted D4Z4 repeat is highly sensitive and specific (Orrell et al., 1999). In patients where the features are not typical for FSHD, it is prudent to confirm that the contracted allele is of the permissive A variant, as a contracted 4q35 allele on a B variant is not pathogenic (Lemmers et al., 2012a). FSHD1 constitutes about 95% of all patients with clinically defined FSHD. In patients with typical FSHD features and a negative FSHD1 genetic test, FSHD2 remains a possibility and testing should be pursued if available. However, even in the absence of FSHD2 testing, FSHD2 can be ruled out in some patients. As described above (in the section on genetics), a prerequisite for FSHD2 is the presence of at least one permissive A allele on 4q35 to enable the expression of DUX4 protein. Therefore the presence of two B alleles in a patient without repeat contraction rules out the possibility of FSHD2. When FSHD1 and 2 are ruled out, the next diagnostic step is a muscle biopsy. However, as muscular dystrophy diagnostics are rapidly evolving, exome sequencing may soon become the more expedient, noninvasive, and costeffective diagnostic next step in such patients.
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Disease progression and prognosis As a group, patients with FSHD progress slowly over time (FSH-DY Group, 1997; Statland et al., 2013a). However, several factors can influence both severity and rate of progression. Typically, men present earlier than women and, as a group, are more severely affected. The number of residual repeats also influences disease severity. A rare but severe form of the disease has symptom onset in infancy and early childhood; such individuals almost invariably have 1–4 residual repeats. A subgroup of such patients are disabled at a young age and are the group most likely to have extramuscular complications such as Coats disease and hearing loss (Lutz et al., 2013; Statland et al., 2013b). There is also increasing evidence that patients with the fewest number of repeats are more likely to have cognitive impairment (Funakoshi et al., 1998; Grosso et al., 2011). Another modifying factor for FSHD1 is the coexistence of an SMCHD1 mutation. In one published family, individuals with only a short repeat (FSHD1) were much less severely affected than individuals with a short repeat and an SMCHD1 mutation (FSHD1 + 2) (Sacconi et al., 2013). This finding reinforces the importance of epigenetic changes in FSHD as the combination of FSHD1 + 2 results in a more relaxed chromatin structure. In fact, a recent study shows a clear correlation between the degree of DNA hypomethylation at D4Z4 and disease severity in both FSHD1 and FSHD2 (Lemmers et al., 2015). While many patients remain asymptomatic or minimally disabled, about 20% of patients above the age of 50 become wheelchair-bound (Statland and Tawil, 2013).
MANAGEMENT There are no approved treatments that alter the course of FSHD. A number of randomized controlled clinical trials using beta agonists and MYO-029 (a myostatin inhibitor) failed to show efficacy (Tawil et al., 1997; Kissel et al., 2001; van der Kooi et al., 2004; Wagner et al., 2008). A recent randomized controlled trial of a combination of antioxidants (vitamin C and E, zinc gluconate, and selenomethionine) in FSHD was completed (Passerieux et al., 2015). While the primary outcome measure, the 2-minute walk, did not significantly change, other biomarkers showed some improvement. The clinical relevance to these changes will need further study. As FSHD is a slowly progressive disease, most patients learn to adapt to their limitations. Nevertheless, there are a number of management issues that clinicians need to be aware of. Two recent reviews produced expert opinion recommendations regarding FSHD
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(Tawil et al., 2010b; Attarian et al., 2012). Issues that are addressed include adaptation to physical limitations, management of pain, monitoring for potential extramuscular complications, and exercise. Bracing has limited utility in improving shoulder function but a variety of shoulder braces can provide temporary pain relief for patients with FSHD. In selected individuals with preserved upper-arm function, surgical scapular fixation may be an option to help improve shoulder range of motion (Orrell et al., 2010). Ankle–foot orthoses are helpful to prevent falls and improve ambulation when foot dorsiflexor weakness is significant. Some patients with combined foot dorsiflexor and knee extensor weakness may benefit from an ankle–knee–foot orthosis. There is no evidence for the need for cardiac monitoring in FSHD patients without cardiac symptoms. Regular monitoring of respiratory function is necessary only for patients with moderate to severe disease, especially those with severe truncal and hip girdle weakness or patients who are wheelchair-bound. Infantile-onset patients or adults with FSHD and large deletions (i.e., short alleles of 10–20 kb) should be screened for hearing loss and have a dilated eye exam looking for retinal vasculopathy (Tawil et al., 2010b). Early intervention with hearing aids in children is vital to prevent developmental language problems and detection and treatment of significant retinal vascular disease can prevent the occurrence of visual loss secondary to Coats disease. Recommendations regarding exercise in FSHD, as in other muscular dystrophies, are often sought by patients. Several studies have shown that aerobic exercise does not result in worsening of FSHD and should be recommended to patients (Olsen et al., 2005; Voet et al., 2010). Weight or resistance training should be limited to light weights and fewer repetitions, especially with movements requiring use of joints that are not well supported like the shoulders, because of the risk of injury.
SUMMARY FSHD is a unique muscular dystrophy in its distinctive regional involvement and mode of progression. It has also proven to be unique in its underlying genetic mechanism, which remained enigmatic for almost 20 years. Unlike most classic Mendelian disorders resulting from mutations in a gene sequence, FSHD is the result of epigenetic changes resulting in the de-repression of a gene, DUX4, normally expressed only in germline cells. The changes in the chromatin structure occur either directly as a result of contraction of the D4Z4 repeats (FSHD1) or indirectly secondary to a mutation of a gene involved
in DNA methylation (FSHD2). The recent description of a unifying mechanism for FSHD now allows for a targeted approach in the development of treatments for FSHD.
REFERENCES Arahata K, Ishihara T, Fukunaga H et al. (1995). Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve 2: S56–S66. Attarian S, Salort-Campana E, Nguyen K et al. (2012). Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011. Rev Neurol (Paris) 168: 910–918. de Greef JC, Lemmers RJ, van Engelen BG et al. (2009). Common epigenetic changes of D4Z4 in contractiondependent and contraction-independent FSHD. Hum Mutat 30: 1449–1459. de Greef JC, Lemmers RJ, Camano P et al. (2010). Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology 75: 1548–1554. Deenen JC, Arnts H, van der Maarel SM et al. (2014). Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology 83: 1056–1059. Ding H, Beckers MC, Plaisance S et al. (1998). Characterization of a double homeodomain protein (DUX1) encoded by a cDNA homologous to 3.3 kb dispersed repeated elements. Hum Mol Genet 7: 1681–1694. Eger K, Jordan B, Habermann S et al. (2010). Beevor’s sign in facioscapulohumeral muscular dystrophy: an old sign with new implications. J Neurol 257: 436–438. Fitzsimons RB, Gurwin EB, Bird AC (1987). Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy. A general association with genetic and therapeutic implications. Brain 110: 631–648. Flanigan KM, Coffeen CM, Sexton L et al. (2001). Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord 11: 525–529. Frisullo G, Frusciante R, Nociti V et al. (2011). CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol 31: 155–166. FSH-DY Group (1997). A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. Neurology 48: 38–46. Funakoshi M, Goto K, Arahata K (1998). Epilepsy and mental retardation in a subset of early onset 4q35facioscapulohumeral muscular dystrophy. Neurology 50: 1791–1794. Gabriels J, Beckers MC, Ding H et al. (1999). Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236: 25–32. Geng LN, Yao Z, Snider L et al. (2012a). DUX4 activates germline genes, retroelements, and immune mediators:
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY implications for facioscapulohumeral dystrophy. Dev Cell 22: 38–51. Geng LN, Yao Z, Snider L et al. (2012b). DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22: 38–51. Grosso S, Mostardini R, di Bartolo RM et al. (2011). Epilepsy, speech delay, and mental retardation in facioscapulohumeral muscular dystrophy. Eur J Paediatr Neurol 15: 456–460. Hewitt JE, Lyle R, Clark LN et al. (1994). Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet 3: 1287–1295. Kissel JT, McDermott MP, Mendell JR et al. (2001). Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology 57: 1434–1440. Kowaljow V, Marcowycz A, Ansseau E et al. (2007). The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord 17: 611–623. Laforet P, de Toma C, Eymard B et al. (1998). Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy. Neurology 51: 1454–1456. Lemmers RJ, de Kievit P, Sandkuijl L et al. (2002). Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet 32: 235–236. Lemmers RJ, van der Vliet PJ, Klooster R et al. (2010). A unifying genetic model for facioscapulohumeral muscular dystrophy. Science, (New York N.Y.) 329: 1650–1653. Lemmers RJ, O’Shea S, Padberg GW et al. (2012a). Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul Disord 22: 463–470. Lemmers RJ, Tawil R, Petek LM et al. (2012b). Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44: 1370–1374. Lemmers RJ, Goeman JJ, van der Vliet PJ et al. (2015). Interindividual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet 24: 659–669. Lunt PW, Harper PS (1991). Genetic counselling in facioscapulohumeral muscular dystrophy. J Med Genet 28: 655–664. Lutz KL, Holte L, Kliethermes SA et al. (2013). Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy. Neurology 81: 1374–1377. Mould AW, Pang Z, Pakusch M et al. (2013). Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. Epigenetics & Chromatin 6: 19-8935-6-19. Olsen DB, Orngreen MC, Vissing J (2005). Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology 64: 1064–1066. Orrell RW, Tawil R, Forrester J et al. (1999). Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology 52: 1822–1826.
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Orrell RW, Copeland S, Rose MR (2010). Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev 1: CD003278. Padberg GW, Lunt PW, Koch M et al. (1991). Diagnostic criteria for facioscapulohumeral muscular dystrophy. Neuromuscul Disord 1: 231–234. Padberg GW, Brouwer OF, de Keizer RJ et al. (1995a). On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve 2: S73–S80. Padberg GW, Frants RR, Brouwer OF et al. (1995b). Facioscapulohumeral muscular dystrophy in the Dutch population. Muscle Nerve Suppl 2: S81–S84. Passerieux E, Hayot M, Jaussent A et al. (2015). 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. Free Radic Biol Med 81: 158–169. Pons Van Dijk G, van der Kooi E, Behin A et al. (2014). High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms. Funct Neurol 1–7. Rowland LP, Blake DM, Hirano M et al. (1991). Clinical syndromes associated with ragged red fibers. Rev Neurol (Paris) 147: 467–473. Sacconi S, Camano P, de Greef JC et al. (2012). Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity. J Med Genet 49: 41–46. Sacconi S, Lemmers RJ, Balog J et al. (2013). The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 93: 744–751. Scully MA, Eichinger KJ, Donlin-Smith CM et al. (2014). Restrictive lung involvement in facioscapulohumeral muscular dystrophy. Muscle Nerve 50: 739–743. Snider L, Asawachaicharn A, Tyler AE et al. (2009). RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum Mol Genet 18: 2414–2430. Snider L, Geng LN, Lemmers RJ et al. (2010a). Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6: e1001181. Snider L, GENG LN, Lemmers RJ et al. (2010b). Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6: e1001181. Statland JM, Tawil R (2013). Risk of functional impairment in facioscapulohumeral muscular dystrophy. Muscle Nerve 49: 520–527. Statland JM, McDermott MP, Heatwole C (2013a). Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord 23: 306–312. Statland JM, Sacconi S, Farmakidis C et al. (2013b). Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size. Neurology 80: 1247–1250.
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Tawil R (2008). Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5: 601–606. Tawil R, Myers GJ, Weiffenbach B et al. (1995). Scapuloperoneal syndromes. Absence of linkage to the 4q35 FSHD locus. Arch Neurol 52: 1069–1072. Tawil R, McDermott MP, Pandya S et al. (1997). A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology 48: 46–49. Tawil R, van der Maarel S, Padberg GW et al. (2010a). 171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord 20: 471–475. Tawil R, van der Maarel S, Padberg GW et al. (2010b). 171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord 20: 471–475. van der Kooi EL, Vogels OJ, van Asseldonk RJ et al. (2004). Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology 63: 702–708. van der Maarel SM, Tawil R, Tapscott SJ (2011). Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 17: 252–258. van Deutekom JC, Wijmenga C, van Tienhoven EA et al. (1993). FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 2: 2037–2042. van Overveld PG, Lemmers RJ, Sandkuijl LA et al. (2003). Hypomethylation of D4Z4 in 4q-linked and non-4q-linked
facioscapulohumeral muscular dystrophy. Nat Genet 35: 315–317. Voet NB, Bleijenberg G, Padberg GW et al. (2010). Effect of aerobic exercise training and cognitive behavioural therapy on reduction of chronic fatigue in patients with facioscapulohumeral dystrophy: protocol of the FACTS-2-FSHD trial. BMC Neurology 10: 56-2377-10-56. Wagner KR, Fleckenstein JL, Amato AA et al. (2008). A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol 63: 561–571. Wallace LM, Garwick SE, Mei W et al. (2011). DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann Neurol 69: 540–552. Wijmenga C, Padberg GW, Moerer P et al. (1991). Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization. Genomics 9: 570–575. Wilhelmsen KC, Blake DM, Lynch T et al. (1996). Chromosome 12-linked autosomal dominant scapuloperoneal muscular dystrophy. Ann Neurol 39: 507–520. Wohlgemuth M, van der Kooi EL, van Kesteren RG et al. (2004). Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 63: 176–178. Wuebbles RD, Long SW, Hanel ML et al. (2010). Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol 3: 386–400.
Chapter 35
Facioscapulohumeral muscular dystrophy RABI TAWIL* Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development.
INTRODUCTION Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of its enigmatic genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. The recent description of a unifying mechanism for FSHD now allows for a targeted approach to therapeutic development.
PREVALENCE AND MODE OF INHERITANCE The prevalence of FSHD is estimated at between 1:15,000 and 1:20,000, making it the third most common form of muscular dystrophy after Duchenne dystrophy and myotonic dystrophy (Padberg et al., 1995b; Flanigan et al., 2001). A recent evaluation of the prevalence of FSHD in the Netherlands suggests a significantly higher prevalence of 2.4/20,000; confirmation of this new figure
would make the prevalence of FSHD nearly identical to that of myotonic dystrophy (Deenen et al., 2014). As life-threatening bulbar, respiratory, or cardiac involvement is rare in FSHD, life expectancy is generally unaffected (Lunt and Harper, 1991). The inheritance pattern in about 95% of patients with FSHD is autosomal dominant, with as many as a third the result of de novo mutations (Tawil, 2008). Inheritance in most of the 5% of patients who have FSHD type 2 (see section on genetics below) is more complex, as it is inherited as a digenic disease (Lemmers et al., 2012b).
GENETICS FSHD was mapped to chromosome 4q35 and subsequently associated with the loss of an integral number of subtelomeric macrosatellite repeats known as D4Z4 over 20 years ago (Wijmenga et al., 1991; van Deutekom et al., 1993). Each D4Z4 repeat is 3.3 kb in size; whereas unaffected individuals have 11–100 D4Z4 repeats on chromosome 4q35, there was a contraction of repeats on one copy of 4q35 to 1–10 repeats in individuals with FSHD (van Deutekom et al., 1993). Each D4Z4 repeat contains
*Correspondence to: R. Tawil, University of Rochester Medical Center, Department of Neurology, 601 Elmwood Avenue, P.O. Box 673, Rochester, NY, 14642, United States. Tel: +1-585-275-6372, E-mail: [email protected]
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an open reading frame encoding a double homeobox gene known as DUX4 (Ding et al., 1998). However, the repeats are contained within a closed chromatin conformation (heterochromatin), suggesting the absence of transcription from within the repeats (Hewitt et al., 1994). Subsequent studies showed that repeat contraction in FSHD is associated with chromatin relaxation, raising the possibility of transcriptional activation of DUX4 (van Overveld et al., 2003). Whereas repeat contraction to 1–10 repeats was necessary for FSHD, it was not sufficient. Two distinct sequence variants are present distal to the last repeat (A or B), with FSHD occurring only with repeat contraction on the A variant (Lemmers et al., 2002). The A variant contains a polyadenylation sequence which is critical for stabilizing DUX4 mRNA (Lemmers et al., 2002, 2010). The above finding led to a unifying hypothesis for FSHD. A repeat contraction results in opening of chromatin structure and, in the setting of a permissive A background, results in the production of stable DUX4 mRNA and DUX4 protein from the distal copy of the D4Z4 repeats (Lemmers et al., 2010). In individuals with the clinical diagnosis of FSHD, about 95% have contracted repeats and are termed FSHD
type 1 or FSHD1. In the remaining patients with clinical FSHD, phenotypically indistinguishable from FSHD1, no repeat contractions is seen and yet these patients had chromatin changes at 4q35 similar to that observed in FSHD1 (de Greef et al., 2009, 2010). However, in these individuals with FSHD type 2 or FSHD2, chromatin relaxation, as measured by diminished level of DNA methylation, was noted on both D4Z4 copies, whereas hypomethylation in FSHD1 was restricted to the contracted allele. In FSHD2 as in FSHD1, at least one permissive A sequence is necessary to cause disease in addition to the open chromatin structure (de Greef et al., 2009). These findings in FSHD2 reaffirmed the importance of chromatin relaxation observed in FSHD1 in the pathophysiology of FSHD. Moreover, although FSHD1 and 2 have distinct genetic signatures, both result in the aberrant de-repression of DUX4 expression (Fig. 35.1). Whereas chromatin relaxation is the result of repeat contraction in FSHD1, the presence in FSHD2 of chromatin changes on both copies of 4q35, in the absence of repeat contraction, suggested the presence of an independent genetic factor predisposing to FSHD2. Using
Fig. 35.1. This figure shows representation of the subtelomeric region of 4q35, the site of the D4Z4 macrosatellite repeats implicated in facioscapulohumeral muscular dystrophy (FSHD). Normal: in normal individuals, both copies of 4q35 contain 11–100 D4Z4 repeats and the DNA is methylated at levels expected in transcriptionally silent heterochromatic regions. FSHD1: in FSHD1, one copy of 4q35 has a contracted number of repeats (1–10 repeats), resulting in a more permissive chromatin structure, as demonstrated by the hypomethylated DNA. FSHD2: in FSHD2, both copies of 4q35 have normal repeat numbers (11–100 repeats) but the DNA is hypomethylated due to mutations in the SMCHD1 gene, again resulting in a more permissive chromatin structure. In both FSHD1 and 2, the open chromatin structure allows the transcription of the DUX4 gene from the last D4Z4 repeat, a gene not normally expressed in somatic cells. However, stable mRNA resulting in DUX4 protein can only occur if the contracted D4Z4 allele in FSHD1 or either hypomethylated allele in FSHD2 has a polydenylation sequence distal to the last repeat, which is essential in stabilizing DUX4 mRNA.
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY exome sequencing in FSHD2 kindreds, mutations in the SMCHD1 (structural maintenance of chromosomes flexible hinge domain 1) gene were identified in about 85% of individuals with FSHD2 (Lemmers et al., 2012a). The SMCHD1 gene encodes a protein involved in X inactivation and in the expression of some autosomal genes (Mould et al., 2013). SMCHD1 mutations associated with FSHD2 may potentially result in deleterious epigenetic alterations on chromosomal regions other than 4q35 (Lemmers et al., 2012a). However, to date, based on evaluation of relatively few FSHD2 kindreds, there is no distinctive nonskeletal muscle pathology in FSHD2 compared to FSHD1 (de Greef et al., 2010).
PATHOPHYSIOLOGY The aberrant expression of DUX4 protein in somatic cells is the primary cause of disease in both FSHD1 and 2 (de Greef et al., 2010). DUX4 is a retrogene that codes for a transcriptional regulator normally expressed in the germline but whose expression is repressed in somatic tissue (Geng et al., 2012a). A relaxed D4Z4 chromatin structure allows stable DUX4 mRNA transcription from the distal copy of DUX4 when spliced to the polyadenylation signal, resulting in variegated expression of DUX4 protein in myonuclei (Fig. 35.1) (Gabriels et al., 1999; Lemmers et al., 2010; Snider et al., 2010a). The role of DUX4 in germline biology is not established (Snider et al., 2010a). Several potential mechanisms have been identified through which DUX4 expression can result in skeletal muscle pathology. DUX4 protein is highly toxic when expressed in cell lines, resulting in caspase-3-mediated apoptosis, and is known to negatively affect myogenesis (Kowaljow et al., 2007; Snider et al., 2009; Wuebbles et al., 2010). Overexpression of DUX4 in zebrafish and mice results in p53-mediated toxicity (Wallace et al., 2011). Apoptosis induced by DUX4 could be the result of expression of the germline gene program in postmitotic skeletal muscle cells (Geng et al., 2012b). DUX4 also activates a number of genes involved in atrophy, protein degradation, and innate immunity (van der Maarel et al., 2011; Geng et al., 2012b). As the germline is immuneprivileged, proteins expressed only in the germline may induce an immune response when aberrantly expressed in somatic tissue (van der Maarel et al., 2011). Such a reaction might explain the presence of inflammatory infiltrates, mostly in the perivascular regions, in up to a third of FSHD muscle biopsies (Arahata et al., 1995; Frisullo et al., 2011). In myoblast cell cultures DUX4 is expressed at high levels in very few nuclei at any time point, predominantly in differentiating myotubes (Snider et al., 2010b). The cause of the variegated DUX4 expression in myotubes is not clear.
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Understanding the factors triggering this variegated expression may help explain the regional and asymmetric involvement of muscle FSHD.
CLINICAL MANIFESTATIONS Symptoms Symptom onset in FSHD varies from infancy to late adulthood, with most patients developing symptoms in their late teens to early 20s. FSHD has a distinctive, regionally restricted onset of weakness starting rostrally in the face and the periscapular muscles and then progressing caudally to the upper arms, trunk muscles, and lower-extremity muscle. The most common initial symptoms are related to weak periscapular muscles, making it difficult to lift objects above shoulder level. Typically, facial weakness is asymptomatic but can be elicited, in hindsight; symptoms include sleeping with eyes slightly open (noted by spouse or parents), inability to whistle or difficulty drinking through a straw. However, a significant number of patients present initially with lowerextremity difficulties; nevertheless, most of the latter patients will have unnoticed or compensated facial or scapular weakness on exam. Asymmetric involvement is typical in FSHD and is more dramatic than in most other dystrophies.
Signs Recognizing the distinctive features of FSHD is crucial in making the diagnosis. In the face, the orbibularis oculi and orbicularis oris are most selectively affected. Severe orbicularis oris weakness causes difficulty in puckering of the lips that, when severe, results in everted lips. Neck extensors are more likely affected than neck flexors. The shoulders have a distinctive profile unique to FSHD. Asymmetric scapular winging is the rule with selective involvement of the lower trapezius, resulting in the upward jutting of the scapula when attempting to forward flex or abduct the shoulders. The clavicles are straight and the shoulders are rounded and slope forward. Pectoral muscle atrophy is evident with prominent axillary creases (Fig. 35.2). As the disease progresses in the upper extremities beyond the shoulder to the biceps, the deltoid remains normal or near normal in strength, a distinguishing feature from other dystrophies affecting the shoulder girdle. Involvement of the muscles of the trunk results in abdominal muscle weakness. A protuberant abdomen is often evident. Here again the asymmetric features of FSHD are evident, with selective involvement mostly of the lower abdominal muscle resulting in a positive Beevor’s sign on attempted neck flexion in the supine position (Eger et al., 2010). Progressive paraspinal
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A
C
B
D
Fig. 35.2. Typical shoulder profile of a patient with facioscapulohumeral muscular dystrophy. (A) Frontal view showing asymmetric limitation of shoulder abduction, straight clavicles, pectoral muscle atrophy with resultant prominent axillary creases, and jutting upwards of the scapula on the right on attempted shoulder abduction due to more severe involvement of the lower versus the upper trapezius. (B) Asymmetric scapular winging. (C, D) Bedside manual fixation of the scapula resulting in improved shoulder abduction from 90° (C) to about 135° (D). This bedside maneuver helps assess the degree of potential improvement in range of motion that can be expected from surgical scapular fixation. (Reproduced from Farmakidis C, Tawil R (2011) Facioscapulohumeral muscular dystrophy. In: Tawil RN, Venance S (eds) Neuromuscular disorders. Neurology in Practice Series. Oxford: Blackwell Publishing, pp. 74–79.)
muscle involvement results in an exaggerated lumbar lordosis. In the lower extremities distal weakness is typically evident first in the anterior leg muscles with later involvement in thigh and pelvic girdle muscles. Asymmetric involvement of the hip muscle can result in unilateral pelvic tilt that can be mistaken for pelvic joint pathology or leg length discrepancy. In patients with advanced disease, the distinctive regional and asymmetric involvement is less evident. Yet even in patients with severe weakness, unlike most other dystrophies, contractures are absent or minimal.
Extramuscular manifestations Respiratory involvement in FSHD is infrequent. A prospective, cross-sectional study of patients with genetically confirmed FSHD found signs of restrictive lung disease on pulmonary function testing in about 10% of patients (Scully et al., 2014). A Dutch study estimates that about 1% of patients with FSHD require ventilator support (Wohlgemuth et al., 2004). Restrictive lung disease is more common in patients with severe disease, especially those with significant trunk and hip girdle weakness and those who are wheelchairbound (Wohlgemuth et al., 2004; Scully et al., 2014). FSHD is not associated with cardiomyopathy, ventricular arrhythmias, or symptomatic conduction defects. About 5% of patients surveyed develop mild cardiac conduction abnormalities and a predilection for supraventricular arrhythmias (Laforet et al., 1998). A recent study
showed a high incidence of asymptomatic right bundle branch block in patients with FSHD (Pons van Dijk et al., 2014). Two FSHD-specific features are the occurrence of high-frequency hearing loss and retinal vascular disease that can rarely result in an exudative retinopathy, also known as Coats disease (Fitzsimons et al., 1987; Padberg et al., 1995a). The incidence of symptomatic retinal disease and hearing loss, however, is rare and limited to patients with the largest deletions in the number of D4Z4 repeats; this corresponds to a contracted 4q35 allele measuring 10–18 kb on genetic testing (see below) (Lutz et al., 2013; Statland et al., 2013b). It is estimated that about 0.6% of patients with FSHD develop Coats disease (Statland et al., 2013b).
Clinical diagnosis The availability of sensitive and specific genetic testing has facilitated the diagnosis of FSHD. Genetic testing for FSHD should be performed on patients with symptoms and signs of facial or shoulder weakness in the absence of extraocular and bulbar involvement (Padberg et al., 1991; Tawil et al., 2010a). It should be noted that facial weakness is not always evident in patients with FSHD. Consequently FSHD should be considered in patients presenting with scapular weakness and a typical shoulder profile with or without evident facial weakness. The presence of ptosis, extraocular muscle involvement, bulbar weakness, severe contractures, or symptomatic
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY respiratory insufficiency in the setting of mild weakness essentially excludes the diagnosis of FSHD. Serum creatine kinase ranges from normal to up to five times the upper limit of normal. Electromyography findings in FSHD are nonspecific with mostly show myopathic changes. Electromyography can be helpful in ruling out neurogenic causes as, for example, in a case presenting with unilateral winging or if specific changes are found (e.g., myotonic discharges), suggesting an alternative diagnosis. The differential diagnosis of FSHD includes a list of conditions that mimic some of the presentations of FSHD. These include the scapuloperoneal syndromes, limb girdle dystrophies such as calpainopathies, valosin-containing protein myopathies, inclusion body myopathy, and mitochondrial myopathies (Rowland et al., 1991; Tawil et al., 1995; Wilhelmsen et al., 1996; Sacconi et al., 2012).
Genetic testing Commercial genetic testing for FSHD1 is widely available but is much more limited for FSHD2. In FSHD1 testing, the size of the DNA fragment on 4q35 containing the D4Z4 repeat is measured. 4q35 alleles with a normal number of D4Z4 repeats (>10) measure more than 48–50 kb, whereas alleles with only 1–10 repeats, diagnostic of FSHD1, result in alleles measuring 10–38 kb. Genetic testing in a patient with features typical for FSHD showing one 4q35 allele between 10 and 38 kb is diagnostic for FSHD1. In patients in whom clinical features are consistent with FSHD, the presence of a contracted D4Z4 repeat is highly sensitive and specific (Orrell et al., 1999). In patients where the features are not typical for FSHD, it is prudent to confirm that the contracted allele is of the permissive A variant, as a contracted 4q35 allele on a B variant is not pathogenic (Lemmers et al., 2012a). FSHD1 constitutes about 95% of all patients with clinically defined FSHD. In patients with typical FSHD features and a negative FSHD1 genetic test, FSHD2 remains a possibility and testing should be pursued if available. However, even in the absence of FSHD2 testing, FSHD2 can be ruled out in some patients. As described above (in the section on genetics), a prerequisite for FSHD2 is the presence of at least one permissive A allele on 4q35 to enable the expression of DUX4 protein. Therefore the presence of two B alleles in a patient without repeat contraction rules out the possibility of FSHD2. When FSHD1 and 2 are ruled out, the next diagnostic step is a muscle biopsy. However, as muscular dystrophy diagnostics are rapidly evolving, exome sequencing may soon become the more expedient, noninvasive, and costeffective diagnostic next step in such patients.
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Disease progression and prognosis As a group, patients with FSHD progress slowly over time (FSH-DY Group, 1997; Statland et al., 2013a). However, several factors can influence both severity and rate of progression. Typically, men present earlier than women and, as a group, are more severely affected. The number of residual repeats also influences disease severity. A rare but severe form of the disease has symptom onset in infancy and early childhood; such individuals almost invariably have 1–4 residual repeats. A subgroup of such patients are disabled at a young age and are the group most likely to have extramuscular complications such as Coats disease and hearing loss (Lutz et al., 2013; Statland et al., 2013b). There is also increasing evidence that patients with the fewest number of repeats are more likely to have cognitive impairment (Funakoshi et al., 1998; Grosso et al., 2011). Another modifying factor for FSHD1 is the coexistence of an SMCHD1 mutation. In one published family, individuals with only a short repeat (FSHD1) were much less severely affected than individuals with a short repeat and an SMCHD1 mutation (FSHD1 + 2) (Sacconi et al., 2013). This finding reinforces the importance of epigenetic changes in FSHD as the combination of FSHD1 + 2 results in a more relaxed chromatin structure. In fact, a recent study shows a clear correlation between the degree of DNA hypomethylation at D4Z4 and disease severity in both FSHD1 and FSHD2 (Lemmers et al., 2015). While many patients remain asymptomatic or minimally disabled, about 20% of patients above the age of 50 become wheelchair-bound (Statland and Tawil, 2013).
MANAGEMENT There are no approved treatments that alter the course of FSHD. A number of randomized controlled clinical trials using beta agonists and MYO-029 (a myostatin inhibitor) failed to show efficacy (Tawil et al., 1997; Kissel et al., 2001; van der Kooi et al., 2004; Wagner et al., 2008). A recent randomized controlled trial of a combination of antioxidants (vitamin C and E, zinc gluconate, and selenomethionine) in FSHD was completed (Passerieux et al., 2015). While the primary outcome measure, the 2-minute walk, did not significantly change, other biomarkers showed some improvement. The clinical relevance to these changes will need further study. As FSHD is a slowly progressive disease, most patients learn to adapt to their limitations. Nevertheless, there are a number of management issues that clinicians need to be aware of. Two recent reviews produced expert opinion recommendations regarding FSHD
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(Tawil et al., 2010b; Attarian et al., 2012). Issues that are addressed include adaptation to physical limitations, management of pain, monitoring for potential extramuscular complications, and exercise. Bracing has limited utility in improving shoulder function but a variety of shoulder braces can provide temporary pain relief for patients with FSHD. In selected individuals with preserved upper-arm function, surgical scapular fixation may be an option to help improve shoulder range of motion (Orrell et al., 2010). Ankle–foot orthoses are helpful to prevent falls and improve ambulation when foot dorsiflexor weakness is significant. Some patients with combined foot dorsiflexor and knee extensor weakness may benefit from an ankle–knee–foot orthosis. There is no evidence for the need for cardiac monitoring in FSHD patients without cardiac symptoms. Regular monitoring of respiratory function is necessary only for patients with moderate to severe disease, especially those with severe truncal and hip girdle weakness or patients who are wheelchair-bound. Infantile-onset patients or adults with FSHD and large deletions (i.e., short alleles of 10–20 kb) should be screened for hearing loss and have a dilated eye exam looking for retinal vasculopathy (Tawil et al., 2010b). Early intervention with hearing aids in children is vital to prevent developmental language problems and detection and treatment of significant retinal vascular disease can prevent the occurrence of visual loss secondary to Coats disease. Recommendations regarding exercise in FSHD, as in other muscular dystrophies, are often sought by patients. Several studies have shown that aerobic exercise does not result in worsening of FSHD and should be recommended to patients (Olsen et al., 2005; Voet et al., 2010). Weight or resistance training should be limited to light weights and fewer repetitions, especially with movements requiring use of joints that are not well supported like the shoulders, because of the risk of injury.
SUMMARY FSHD is a unique muscular dystrophy in its distinctive regional involvement and mode of progression. It has also proven to be unique in its underlying genetic mechanism, which remained enigmatic for almost 20 years. Unlike most classic Mendelian disorders resulting from mutations in a gene sequence, FSHD is the result of epigenetic changes resulting in the de-repression of a gene, DUX4, normally expressed only in germline cells. The changes in the chromatin structure occur either directly as a result of contraction of the D4Z4 repeats (FSHD1) or indirectly secondary to a mutation of a gene involved
in DNA methylation (FSHD2). The recent description of a unifying mechanism for FSHD now allows for a targeted approach in the development of treatments for FSHD.
REFERENCES Arahata K, Ishihara T, Fukunaga H et al. (1995). Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve 2: S56–S66. Attarian S, Salort-Campana E, Nguyen K et al. (2012). Recommendations for the management of facioscapulohumeral muscular dystrophy in 2011. Rev Neurol (Paris) 168: 910–918. de Greef JC, Lemmers RJ, van Engelen BG et al. (2009). Common epigenetic changes of D4Z4 in contractiondependent and contraction-independent FSHD. Hum Mutat 30: 1449–1459. de Greef JC, Lemmers RJ, Camano P et al. (2010). Clinical features of facioscapulohumeral muscular dystrophy 2. Neurology 75: 1548–1554. Deenen JC, Arnts H, van der Maarel SM et al. (2014). Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology 83: 1056–1059. Ding H, Beckers MC, Plaisance S et al. (1998). Characterization of a double homeodomain protein (DUX1) encoded by a cDNA homologous to 3.3 kb dispersed repeated elements. Hum Mol Genet 7: 1681–1694. Eger K, Jordan B, Habermann S et al. (2010). Beevor’s sign in facioscapulohumeral muscular dystrophy: an old sign with new implications. J Neurol 257: 436–438. Fitzsimons RB, Gurwin EB, Bird AC (1987). Retinal vascular abnormalities in facioscapulohumeral muscular dystrophy. A general association with genetic and therapeutic implications. Brain 110: 631–648. Flanigan KM, Coffeen CM, Sexton L et al. (2001). Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord 11: 525–529. Frisullo G, Frusciante R, Nociti V et al. (2011). CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol 31: 155–166. FSH-DY Group (1997). A prospective, quantitative study of the natural history of facioscapulohumeral muscular dystrophy (FSHD): implications for therapeutic trials. Neurology 48: 38–46. Funakoshi M, Goto K, Arahata K (1998). Epilepsy and mental retardation in a subset of early onset 4q35facioscapulohumeral muscular dystrophy. Neurology 50: 1791–1794. Gabriels J, Beckers MC, Ding H et al. (1999). Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236: 25–32. Geng LN, Yao Z, Snider L et al. (2012a). DUX4 activates germline genes, retroelements, and immune mediators:
FACIOSCAPULOHUMERAL MUSCULAR DYSTROPHY implications for facioscapulohumeral dystrophy. Dev Cell 22: 38–51. Geng LN, Yao Z, Snider L et al. (2012b). DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22: 38–51. Grosso S, Mostardini R, di Bartolo RM et al. (2011). Epilepsy, speech delay, and mental retardation in facioscapulohumeral muscular dystrophy. Eur J Paediatr Neurol 15: 456–460. Hewitt JE, Lyle R, Clark LN et al. (1994). Analysis of the tandem repeat locus D4Z4 associated with facioscapulohumeral muscular dystrophy. Hum Mol Genet 3: 1287–1295. Kissel JT, McDermott MP, Mendell JR et al. (2001). Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology 57: 1434–1440. Kowaljow V, Marcowycz A, Ansseau E et al. (2007). The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord 17: 611–623. Laforet P, de Toma C, Eymard B et al. (1998). Cardiac involvement in genetically confirmed facioscapulohumeral muscular dystrophy. Neurology 51: 1454–1456. Lemmers RJ, de Kievit P, Sandkuijl L et al. (2002). Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet 32: 235–236. Lemmers RJ, van der Vliet PJ, Klooster R et al. (2010). A unifying genetic model for facioscapulohumeral muscular dystrophy. Science, (New York N.Y.) 329: 1650–1653. Lemmers RJ, O’Shea S, Padberg GW et al. (2012a). Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul Disord 22: 463–470. Lemmers RJ, Tawil R, Petek LM et al. (2012b). Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44: 1370–1374. Lemmers RJ, Goeman JJ, van der Vliet PJ et al. (2015). Interindividual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet 24: 659–669. Lunt PW, Harper PS (1991). Genetic counselling in facioscapulohumeral muscular dystrophy. J Med Genet 28: 655–664. Lutz KL, Holte L, Kliethermes SA et al. (2013). Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy. Neurology 81: 1374–1377. Mould AW, Pang Z, Pakusch M et al. (2013). Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. Epigenetics & Chromatin 6: 19-8935-6-19. Olsen DB, Orngreen MC, Vissing J (2005). Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology 64: 1064–1066. Orrell RW, Tawil R, Forrester J et al. (1999). Definitive molecular diagnosis of facioscapulohumeral dystrophy. Neurology 52: 1822–1826.
547
Orrell RW, Copeland S, Rose MR (2010). Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev 1: CD003278. Padberg GW, Lunt PW, Koch M et al. (1991). Diagnostic criteria for facioscapulohumeral muscular dystrophy. Neuromuscul Disord 1: 231–234. Padberg GW, Brouwer OF, de Keizer RJ et al. (1995a). On the significance of retinal vascular disease and hearing loss in facioscapulohumeral muscular dystrophy. Muscle Nerve 2: S73–S80. Padberg GW, Frants RR, Brouwer OF et al. (1995b). Facioscapulohumeral muscular dystrophy in the Dutch population. Muscle Nerve Suppl 2: S81–S84. Passerieux E, Hayot M, Jaussent A et al. (2015). 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. Free Radic Biol Med 81: 158–169. Pons Van Dijk G, van der Kooi E, Behin A et al. (2014). High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms. Funct Neurol 1–7. Rowland LP, Blake DM, Hirano M et al. (1991). Clinical syndromes associated with ragged red fibers. Rev Neurol (Paris) 147: 467–473. Sacconi S, Camano P, de Greef JC et al. (2012). Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity. J Med Genet 49: 41–46. Sacconi S, Lemmers RJ, Balog J et al. (2013). The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet 93: 744–751. Scully MA, Eichinger KJ, Donlin-Smith CM et al. (2014). Restrictive lung involvement in facioscapulohumeral muscular dystrophy. Muscle Nerve 50: 739–743. Snider L, Asawachaicharn A, Tyler AE et al. (2009). RNA transcripts, miRNA-sized fragments and proteins produced from D4Z4 units: new candidates for the pathophysiology of facioscapulohumeral dystrophy. Hum Mol Genet 18: 2414–2430. Snider L, Geng LN, Lemmers RJ et al. (2010a). Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6: e1001181. Snider L, GENG LN, Lemmers RJ et al. (2010b). Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6: e1001181. Statland JM, Tawil R (2013). Risk of functional impairment in facioscapulohumeral muscular dystrophy. Muscle Nerve 49: 520–527. Statland JM, McDermott MP, Heatwole C (2013a). Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord 23: 306–312. Statland JM, Sacconi S, Farmakidis C et al. (2013b). Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size. Neurology 80: 1247–1250.
548
R. TAWIL
Tawil R (2008). Facioscapulohumeral muscular dystrophy. Neurotherapeutics 5: 601–606. Tawil R, Myers GJ, Weiffenbach B et al. (1995). Scapuloperoneal syndromes. Absence of linkage to the 4q35 FSHD locus. Arch Neurol 52: 1069–1072. Tawil R, McDermott MP, Pandya S et al. (1997). A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology 48: 46–49. Tawil R, van der Maarel S, Padberg GW et al. (2010a). 171st ENMC international workshop: standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord 20: 471–475. Tawil R, van der Maarel S, Padberg GW et al. (2010b). 171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord 20: 471–475. van der Kooi EL, Vogels OJ, van Asseldonk RJ et al. (2004). Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology 63: 702–708. van der Maarel SM, Tawil R, Tapscott SJ (2011). Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med 17: 252–258. van Deutekom JC, Wijmenga C, van Tienhoven EA et al. (1993). FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet 2: 2037–2042. van Overveld PG, Lemmers RJ, Sandkuijl LA et al. (2003). Hypomethylation of D4Z4 in 4q-linked and non-4q-linked
facioscapulohumeral muscular dystrophy. Nat Genet 35: 315–317. Voet NB, Bleijenberg G, Padberg GW et al. (2010). Effect of aerobic exercise training and cognitive behavioural therapy on reduction of chronic fatigue in patients with facioscapulohumeral dystrophy: protocol of the FACTS-2-FSHD trial. BMC Neurology 10: 56-2377-10-56. Wagner KR, Fleckenstein JL, Amato AA et al. (2008). A phase I/II trial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol 63: 561–571. Wallace LM, Garwick SE, Mei W et al. (2011). DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann Neurol 69: 540–552. Wijmenga C, Padberg GW, Moerer P et al. (1991). Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization. Genomics 9: 570–575. Wilhelmsen KC, Blake DM, Lynch T et al. (1996). Chromosome 12-linked autosomal dominant scapuloperoneal muscular dystrophy. Ann Neurol 39: 507–520. Wohlgemuth M, van der Kooi EL, van Kesteren RG et al. (2004). Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology 63: 176–178. Wuebbles RD, Long SW, Hanel ML et al. (2010). Testing the effects of FSHD candidate gene expression in vertebrate muscle development. Int J Clin Exp Pathol 3: 386–400.