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Published in: Neurotherapeutics 4/2018

01-10-2018 | Review

Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments

Authors: Johanna Hamel, Rabi Tawil

Published in: Neurotherapeutics | Issue 4/2018

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Abstract

A reliable model of a disease pathomechanism is the first step to develop targeted treatment. In facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy, recent advances in understanding the complex genetics and epigenetics have led to the identification of a disease mechanism, moving the field towards targeted therapy development. FSHD is caused by expression of DUX4, a retrogene located on the D4Z4 macrosatellite repeat array on chromosome 4q35, a gene expressed in the germline but typically repressed in somatic tissue. DUX4 derepression results from opening of the chromatin structure either by contraction of the number of repeats (FSHD1) or by chromatin hypomethylation of the D4Z4 repeats resulting from mutations in SMCHD1, a gene involved in chromatin methylation (FSHD2). The resulting expression of DUX4, a transcriptional regulator, and its target genes is toxic to skeletal muscle. Efforts for targeted treatment currently focus on disrupting DUX4 expression or blocking 1 or more of several downstream effects of DUX4. This review article focuses on the underlying FSHD genetics, current understanding of the pathomechanism, and potential treatment strategies in FSHD. In addition, recent advances in the development of new clinical outcome measures as well as biomarkers, critical for the success of future clinical trials, are reviewed.
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Literature
1.
go back to reference Flanigan KM, Coffeen CM, Sexton L, et al. Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord. 2001;11(6–7):525–529.CrossRefPubMed Flanigan KM, Coffeen CM, Sexton L, et al. Genetic characterization of a large, historically significant Utah kindred with facioscapulohumeral dystrophy. Neuromuscul Disord. 2001;11(6–7):525–529.CrossRefPubMed
3.
go back to reference Deenen JC, Arnts H, van der Maarel SM, et al. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology. 2014;83(12):1056–1059.CrossRefPubMedPubMedCentral Deenen JC, Arnts H, van der Maarel SM, et al. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology. 2014;83(12):1056–1059.CrossRefPubMedPubMedCentral
4.
go back to reference van der Maarel SM, Deidda G, Lemmers RJ, et al. De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet. 2000;66(1):26–35.CrossRefPubMed van der Maarel SM, Deidda G, Lemmers RJ, et al. De novo facioscapulohumeral muscular dystrophy: frequent somatic mosaicism, sex-dependent phenotype, and the role of mitotic transchromosomal repeat interaction between chromosomes 4 and 10. Am J Hum Genet. 2000;66(1):26–35.CrossRefPubMed
5.
go back to reference Statland JM, McDermott MP, Heatwole C, et al. Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2013;23(4):306–312.CrossRefPubMedPubMedCentral Statland JM, McDermott MP, Heatwole C, et al. Reevaluating measures of disease progression in facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2013;23(4):306–312.CrossRefPubMedPubMedCentral
6.
go back to reference Wijmenga C, Frants RR, Brouwer OF, et al. Location of facioscapulohumeral muscular dystrophy gene on chromosome 4. Lancet. 1990;336(8716):651–653.CrossRefPubMed Wijmenga C, Frants RR, Brouwer OF, et al. Location of facioscapulohumeral muscular dystrophy gene on chromosome 4. Lancet. 1990;336(8716):651–653.CrossRefPubMed
7.
go back to reference Wijmenga C, Padberg GW, Moerer P, et al. Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization. Genomics. 1991;9(4):570–575.CrossRefPubMed Wijmenga C, Padberg GW, Moerer P, et al. Mapping of facioscapulohumeral muscular dystrophy gene to chromosome 4q35-qter by multipoint linkage analysis and in situ hybridization. Genomics. 1991;9(4):570–575.CrossRefPubMed
8.
go back to reference van Deutekom JC, Wijmenga C, van Tienhoven EA, et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet. 1993;2(12):2037–2042.CrossRefPubMed van Deutekom JC, Wijmenga C, van Tienhoven EA, et al. FSHD associated DNA rearrangements are due to deletions of integral copies of a 3.2 kb tandemly repeated unit. Hum Mol Genet. 1993;2(12):2037–2042.CrossRefPubMed
9.
10.
go back to reference Lemmers RJ, de Kievit P, Sandkuijl L, et al. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002;32(2):235–236.CrossRefPubMed Lemmers RJ, de Kievit P, Sandkuijl L, et al. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002;32(2):235–236.CrossRefPubMed
11.
go back to reference Lemmers RJ, Wohlgemuth M, van der Gaag KJ, et al. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2007;81(5):884–894.CrossRefPubMedPubMedCentral Lemmers RJ, Wohlgemuth M, van der Gaag KJ, et al. Specific sequence variations within the 4q35 region are associated with facioscapulohumeral muscular dystrophy. Am J Hum Genet. 2007;81(5):884–894.CrossRefPubMedPubMedCentral
12.
go back to reference Lemmers RJ, van der Vliet PJ, Klooster R, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010;329(5999):1650–1653.CrossRefPubMedPubMedCentral Lemmers RJ, van der Vliet PJ, Klooster R, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010;329(5999):1650–1653.CrossRefPubMedPubMedCentral
13.
go back to reference van Overveld PG, Lemmers RJ, Sandkuijl LA, et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35(4):315–317.CrossRefPubMed van Overveld PG, Lemmers RJ, Sandkuijl LA, et al. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35(4):315–317.CrossRefPubMed
14.
15.
go back to reference Lemmers RJ, Goeman JJ, van der Vliet PJ, et al. Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet. 2015;24(3):659–669.CrossRefPubMed Lemmers RJ, Goeman JJ, van der Vliet PJ, et al. Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2. Hum Mol Genet. 2015;24(3):659–669.CrossRefPubMed
16.
go back to reference Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012;44(12):1370–1374.CrossRefPubMedPubMedCentral Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. 2012;44(12):1370–1374.CrossRefPubMedPubMedCentral
17.
go back to reference van den Boogaard ML, Lemmers R, Balog J, et al. Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. Am J Hum Genet. 2016;98(5):1020–1029.CrossRefPubMedPubMedCentral van den Boogaard ML, Lemmers R, Balog J, et al. Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy. Am J Hum Genet. 2016;98(5):1020–1029.CrossRefPubMedPubMedCentral
19.
go back to reference Ricci G, Scionti I, Sera F, et al. Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. Brain. 2013;136(Pt 11):3408–3417.CrossRefPubMedPubMedCentral Ricci G, Scionti I, Sera F, et al. Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. Brain. 2013;136(Pt 11):3408–3417.CrossRefPubMedPubMedCentral
20.
go back to reference Sacconi S, Lemmers RJ, Balog J, et al. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. 2013;93(4):744–751.CrossRefPubMedPubMedCentral Sacconi S, Lemmers RJ, Balog J, et al. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. 2013;93(4):744–751.CrossRefPubMedPubMedCentral
21.
go back to reference Larsen M, Rost S, El Hajj N, et al. Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. Eur J Hum Genet. 2015;23(6):808–816.CrossRefPubMed Larsen M, Rost S, El Hajj N, et al. Diagnostic approach for FSHD revisited: SMCHD1 mutations cause FSHD2 and act as modifiers of disease severity in FSHD1. Eur J Hum Genet. 2015;23(6):808–816.CrossRefPubMed
22.
go back to reference de Greef JC, Krom YD, den Hamer B, et al. Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model. Hum Mol Genet. 2018;27(4):716–731.CrossRefPubMed de Greef JC, Krom YD, den Hamer B, et al. Smchd1 haploinsufficiency exacerbates the phenotype of a transgenic FSHD1 mouse model. Hum Mol Genet. 2018;27(4):716–731.CrossRefPubMed
23.
go back to reference Park HJ, Lee W, Kim SH, et al. FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1. Yonsei Med J. 2018;59(2):337–340.CrossRefPubMed Park HJ, Lee W, Kim SH, et al. FAT1 Gene Alteration in Facioscapulohumeral Muscular Dystrophy Type 1. Yonsei Med J. 2018;59(2):337–340.CrossRefPubMed
24.
go back to reference Mariot V, Roche S, Hourde C, et al. Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. Ann Neurol. 2015;78(3):387–400.CrossRefPubMed Mariot V, Roche S, Hourde C, et al. Correlation between low FAT1 expression and early affected muscle in facioscapulohumeral muscular dystrophy. Ann Neurol. 2015;78(3):387–400.CrossRefPubMed
25.
go back to reference Snider L, Geng LN, Lemmers RJ, et al. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet. 2010;6(10):e1001181.CrossRefPubMedPubMedCentral Snider L, Geng LN, Lemmers RJ, et al. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet. 2010;6(10):e1001181.CrossRefPubMedPubMedCentral
26.
go back to reference Bosnakovski D, Chan SSK, Recht OO, et al. Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nat Commun. 2017;8(1):550.CrossRefPubMedPubMedCentral Bosnakovski D, Chan SSK, Recht OO, et al. Muscle pathology from stochastic low level DUX4 expression in an FSHD mouse model. Nat Commun. 2017;8(1):550.CrossRefPubMedPubMedCentral
27.
go back to reference Gannon OM, Merida de Long L, Saunders NA. DUX4 Is Derepressed in Late-Differentiating Keratinocytes in Conjunction with Loss of H3K9me3 Epigenetic Repression. J Invest Dermatol. 2016;136(6):1299–1302.CrossRefPubMed Gannon OM, Merida de Long L, Saunders NA. DUX4 Is Derepressed in Late-Differentiating Keratinocytes in Conjunction with Loss of H3K9me3 Epigenetic Repression. J Invest Dermatol. 2016;136(6):1299–1302.CrossRefPubMed
28.
go back to reference De Iaco A, Planet E, Coluccio A, et al. DUX-family transcription factors regulate zygotic genome activation in placental mammals. Nat Genet. 2017;49(6):941–945.CrossRefPubMedPubMedCentral De Iaco A, Planet E, Coluccio A, et al. DUX-family transcription factors regulate zygotic genome activation in placental mammals. Nat Genet. 2017;49(6):941–945.CrossRefPubMedPubMedCentral
29.
go back to reference Geng LN, Yao Z, Snider L, et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012;22(1):38–51.CrossRefPubMed Geng LN, Yao Z, Snider L, et al. DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell. 2012;22(1):38–51.CrossRefPubMed
30.
go back to reference Feng Q, Snider L, Jagannathan S, et al. A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. Elife. 2015;4. Feng Q, Snider L, Jagannathan S, et al. A feedback loop between nonsense-mediated decay and the retrogene DUX4 in facioscapulohumeral muscular dystrophy. Elife. 2015;4.
31.
go back to reference Shadle SC, Zhong JW, Campbell AE, et al. DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS Genet. 2017;13(3):e1006658.CrossRefPubMedPubMedCentral Shadle SC, Zhong JW, Campbell AE, et al. DUX4-induced dsRNA and MYC mRNA stabilization activate apoptotic pathways in human cell models of facioscapulohumeral dystrophy. PLoS Genet. 2017;13(3):e1006658.CrossRefPubMedPubMedCentral
32.
go back to reference Kowaljow V, Marcowycz A, Ansseau E, et al. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord. 2007;17(8):611–623.CrossRefPubMed Kowaljow V, Marcowycz A, Ansseau E, et al. The DUX4 gene at the FSHD1A locus encodes a pro-apoptotic protein. Neuromuscul Disord. 2007;17(8):611–623.CrossRefPubMed
33.
go back to reference Wallace LM, Garwick SE, Mei W, et al. DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann Neurol. 2011;69(3):540–552.CrossRefPubMed Wallace LM, Garwick SE, Mei W, et al. DUX4, a candidate gene for facioscapulohumeral muscular dystrophy, causes p53-dependent myopathy in vivo. Ann Neurol. 2011;69(3):540–552.CrossRefPubMed
34.
go back to reference Campbell AE, Shadle SC, Jagannathan S, et al. NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. Elife. 2018;7. Campbell AE, Shadle SC, Jagannathan S, et al. NuRD and CAF-1-mediated silencing of the D4Z4 array is modulated by DUX4-induced MBD3L proteins. Elife. 2018;7.
35.
go back to reference Jones TI, Chen JC, Rahimov F, et al. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum Mol Genet. 2012;21(20):4419–4430.CrossRefPubMedPubMedCentral Jones TI, Chen JC, Rahimov F, et al. Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis. Hum Mol Genet. 2012;21(20):4419–4430.CrossRefPubMedPubMedCentral
36.
go back to reference Balog J, Thijssen PE, Shadle S, et al. Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics. 2015;10(12):1133–1142.CrossRefPubMedPubMedCentral Balog J, Thijssen PE, Shadle S, et al. Increased DUX4 expression during muscle differentiation correlates with decreased SMCHD1 protein levels at D4Z4. Epigenetics. 2015;10(12):1133–1142.CrossRefPubMedPubMedCentral
37.
go back to reference Jones TI, King OD, Himeda CL, et al. Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin Epigenetics. 2015;7:37.CrossRefPubMedPubMedCentral Jones TI, King OD, Himeda CL, et al. Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin Epigenetics. 2015;7:37.CrossRefPubMedPubMedCentral
38.
go back to reference Jones T, Jones PL. A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PLoS One. 2018;13(2):e0192657.CrossRefPubMedPubMedCentral Jones T, Jones PL. A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PLoS One. 2018;13(2):e0192657.CrossRefPubMedPubMedCentral
39.
go back to reference Moris G, Wood L, FernaNdez-Torron R, et al. Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2018;57(3):380–387.CrossRefPubMed Moris G, Wood L, FernaNdez-Torron R, et al. Chronic pain has a strong impact on quality of life in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2018;57(3):380–387.CrossRefPubMed
40.
go back to reference Ghosh PS, Milone M. Camptocormia as presenting manifestation of a spectrum of myopathic disorders. Muscle Nerve. 2015;52(6):1008–1012.CrossRefPubMed Ghosh PS, Milone M. Camptocormia as presenting manifestation of a spectrum of myopathic disorders. Muscle Nerve. 2015;52(6):1008–1012.CrossRefPubMed
41.
go back to reference Jordan B, Eger K, Koesling S, Zierz S. Camptocormia phenotype of FSHD: a clinical and MRI study on six patients. J Neurol. 2011;258(5):866–873.CrossRefPubMed Jordan B, Eger K, Koesling S, Zierz S. Camptocormia phenotype of FSHD: a clinical and MRI study on six patients. J Neurol. 2011;258(5):866–873.CrossRefPubMed
42.
go back to reference Scully MA, Eichinger KJ, Donlin-Smith CM, Tawil R, Statland JM. Restrictive lung involvement in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2014;50(5):739–743.CrossRefPubMedPubMedCentral Scully MA, Eichinger KJ, Donlin-Smith CM, Tawil R, Statland JM. Restrictive lung involvement in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2014;50(5):739–743.CrossRefPubMedPubMedCentral
43.
go back to reference Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology. 2004;63(1):176–178.CrossRefPubMed Wohlgemuth M, van der Kooi EL, van Kesteren RG, van der Maarel SM, Padberg GW. Ventilatory support in facioscapulohumeral muscular dystrophy. Neurology. 2004;63(1):176–178.CrossRefPubMed
44.
go back to reference Moreira S, Wood L, Smith D, et al. Respiratory involvement in ambulant and non-ambulant patients with facioscapulohumeral muscular dystrophy. J Neurol. 2017;264(6):1271–1280.CrossRefPubMedPubMedCentral Moreira S, Wood L, Smith D, et al. Respiratory involvement in ambulant and non-ambulant patients with facioscapulohumeral muscular dystrophy. J Neurol. 2017;264(6):1271–1280.CrossRefPubMedPubMedCentral
45.
go back to reference Wohlgemuth M, Horlings CGC, van der Kooi EL, et al. Respiratory function in facioscapulohumeral muscular dystrophy 1. Neuromuscul Disord. 2017;27(6):526–530.CrossRefPubMed Wohlgemuth M, Horlings CGC, van der Kooi EL, et al. Respiratory function in facioscapulohumeral muscular dystrophy 1. Neuromuscul Disord. 2017;27(6):526–530.CrossRefPubMed
46.
go back to reference van Dijk GP, van der Kooi E, Behin A, et al. High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms. Funct Neurol. 2014;29(3):159–165.PubMedPubMedCentral van Dijk GP, van der Kooi E, Behin A, et al. High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms. Funct Neurol. 2014;29(3):159–165.PubMedPubMedCentral
47.
go back to reference Statland JM, Sacconi S, Farmakidis C, et al. Coats syndrome in facioscapulohumeral dystrophy type 1 Frequency and D4Z4 contraction size. Neurology. 2013;80(13):1247–1250.CrossRefPubMedPubMedCentral Statland JM, Sacconi S, Farmakidis C, et al. Coats syndrome in facioscapulohumeral dystrophy type 1 Frequency and D4Z4 contraction size. Neurology. 2013;80(13):1247–1250.CrossRefPubMedPubMedCentral
48.
go back to reference Mah JK, Feng J, Jacobs MB, et al. A multinational study on motor function in early-onset FSHD. Neurology. 2018. Mah JK, Feng J, Jacobs MB, et al. A multinational study on motor function in early-onset FSHD. Neurology. 2018.
49.
go back to reference Goselink RJM, Voermans NC, Okkersen K, et al. Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data. Neuromuscul Disord. 2017;27(12):1077–1083.CrossRefPubMed Goselink RJM, Voermans NC, Okkersen K, et al. Early onset facioscapulohumeral dystrophy - a systematic review using individual patient data. Neuromuscul Disord. 2017;27(12):1077–1083.CrossRefPubMed
50.
go back to reference Tonini MM, Passos-Bueno MR, Cerqueira A, et al. Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord. 2004;14(1):33–38.CrossRefPubMed Tonini MM, Passos-Bueno MR, Cerqueira A, et al. Asymptomatic carriers and gender differences in facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord. 2004;14(1):33–38.CrossRefPubMed
51.
go back to reference Teveroni E, Pellegrino M, Sacconi S, et al. Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity. J Clin Invest. 2017;127(4):1531–1545.CrossRefPubMedPubMedCentral Teveroni E, Pellegrino M, Sacconi S, et al. Estrogens enhance myoblast differentiation in facioscapulohumeral muscular dystrophy by antagonizing DUX4 activity. J Clin Invest. 2017;127(4):1531–1545.CrossRefPubMedPubMedCentral
52.
go back to reference Tawil R, McDermott MP, Pandya S, et al. A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology. 1997;48(1):46–49.CrossRefPubMed Tawil R, McDermott MP, Pandya S, et al. A pilot trial of prednisone in facioscapulohumeral muscular dystrophy. FSH-DY Group. Neurology. 1997;48(1):46–49.CrossRefPubMed
53.
go back to reference Kissel JT, McDermott MP, Mendell JR, et al. Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology. 2001;57(8):1434–1440.CrossRefPubMed Kissel JT, McDermott MP, Mendell JR, et al. Randomized, double-blind, placebo-controlled trial of albuterol in facioscapulohumeral dystrophy. Neurology. 2001;57(8):1434–1440.CrossRefPubMed
54.
go back to reference van der Kooi EL, Vogels OJ, van Asseldonk RJ, et al. Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology. 2004;63(4):702–708.CrossRefPubMed van der Kooi EL, Vogels OJ, van Asseldonk RJ, et al. Strength training and albuterol in facioscapulohumeral muscular dystrophy. Neurology. 2004;63(4):702–708.CrossRefPubMed
55.
go back to reference Payan CA, Hogrel JY, Hammouda EH, et al. Periodic Salbutamol in Facioscapulohumeral Muscular Dystrophy: A Randomized Controlled Trial. Archives of Physical Medicine and Rehabilitation. 2009;90(7):1094–1101.CrossRefPubMed Payan CA, Hogrel JY, Hammouda EH, et al. Periodic Salbutamol in Facioscapulohumeral Muscular Dystrophy: A Randomized Controlled Trial. Archives of Physical Medicine and Rehabilitation. 2009;90(7):1094–1101.CrossRefPubMed
56.
go back to reference van der Kooi EL, Kalkman JS, Lindeman E, et al. Effects of training and albuterol on pain and fatigue in facioscapulohumeral muscular dystrophy. J Neurol. 2007;254(7):931–940.CrossRefPubMedPubMedCentral van der Kooi EL, Kalkman JS, Lindeman E, et al. Effects of training and albuterol on pain and fatigue in facioscapulohumeral muscular dystrophy. J Neurol. 2007;254(7):931–940.CrossRefPubMedPubMedCentral
57.
go back to reference Campbell AE, Oliva J, Yates MP, et al. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet Muscle. 2017;7(1):16.CrossRefPubMedPubMedCentral Campbell AE, Oliva J, Yates MP, et al. BET bromodomain inhibitors and agonists of the beta-2 adrenergic receptor identified in screens for compounds that inhibit DUX4 expression in FSHD muscle cells. Skelet Muscle. 2017;7(1):16.CrossRefPubMedPubMedCentral
58.
go back to reference Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63(5):561–571.CrossRefPubMed Wagner KR, Fleckenstein JL, Amato AA, et al. A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008;63(5):561–571.CrossRefPubMed
59.
go back to reference Elsheikh BH, Bollman E, Peruggia M, et al. Pilot trial of diltiazem in facioscapulohumeral muscular dystrophy. Neurology. 2007;68(17):1428–1429.CrossRefPubMed Elsheikh BH, Bollman E, Peruggia M, et al. Pilot trial of diltiazem in facioscapulohumeral muscular dystrophy. Neurology. 2007;68(17):1428–1429.CrossRefPubMed
60.
go back to reference Bosnakovski D, Xu Z, Gang EJ, et al. An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. EMBO J. 2008;27(20):2766–2779.CrossRefPubMedPubMedCentral Bosnakovski D, Xu Z, Gang EJ, et al. An isogenetic myoblast expression screen identifies DUX4-mediated FSHD-associated molecular pathologies. EMBO J. 2008;27(20):2766–2779.CrossRefPubMedPubMedCentral
61.
go back to reference Dmitriev P, Bou Saada Y, Dib C, et al. DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients. Free Radical Biology and Medicine. 2016;99:244–258.CrossRefPubMed Dmitriev P, Bou Saada Y, Dib C, et al. DUX4-induced constitutive DNA damage and oxidative stress contribute to aberrant differentiation of myoblasts from FSHD patients. Free Radical Biology and Medicine. 2016;99:244–258.CrossRefPubMed
62.
go back to reference 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. Free Radic Biol Med. 2015;81:158–169.CrossRefPubMed 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. Free Radic Biol Med. 2015;81:158–169.CrossRefPubMed
63.
go back to reference Tawil R, Kissel JT, Heatwole C, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;85(4):357–364.CrossRefPubMedPubMedCentral Tawil R, Kissel JT, Heatwole C, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. 2015;85(4):357–364.CrossRefPubMedPubMedCentral
64.
go back to reference Le Hanneur M, Saint-Cast Y. Long-term results of Letournel scapulothoracic fusion in facioscapulohumeral muscular dystrophy: A retrospective study of eight cases. Orthop Traumatol Surg Res. 2017;103(3):421–425.CrossRefPubMed Le Hanneur M, Saint-Cast Y. Long-term results of Letournel scapulothoracic fusion in facioscapulohumeral muscular dystrophy: A retrospective study of eight cases. Orthop Traumatol Surg Res. 2017;103(3):421–425.CrossRefPubMed
65.
go back to reference Cooney AD, Gill I, Stuart PR. The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy. J Shoulder Elbow Surg. 2014;23(1):e8–e13.CrossRefPubMed Cooney AD, Gill I, Stuart PR. The outcome of scapulothoracic arthrodesis using cerclage wires, plates, and allograft for facioscapulohumeral dystrophy. J Shoulder Elbow Surg. 2014;23(1):e8–e13.CrossRefPubMed
66.
go back to reference Orrell RW, Copeland S, Rose MR. Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev. 2010(1):CD003278. Orrell RW, Copeland S, Rose MR. Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev. 2010(1):CD003278.
67.
go back to reference Olsen DB, Orngreen MC, Vissing J. Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology. 2005;64(6):1064–1066.CrossRefPubMed Olsen DB, Orngreen MC, Vissing J. Aerobic training improves exercise performance in facioscapulohumeral muscular dystrophy. Neurology. 2005;64(6):1064–1066.CrossRefPubMed
68.
go back to reference Voet N, Bleijenberg G, Hendriks J, et al. Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT. Neurology. 2014;83(21):1914–1922.CrossRefPubMed Voet N, Bleijenberg G, Hendriks J, et al. Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT. Neurology. 2014;83(21):1914–1922.CrossRefPubMed
69.
go back to reference Wallace LM, Saad NY, Pyne NK, et al. Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD. Mol Ther Methods Clin Dev. 2018;8:121–130.CrossRefPubMed Wallace LM, Saad NY, Pyne NK, et al. Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD. Mol Ther Methods Clin Dev. 2018;8:121–130.CrossRefPubMed
70.
go back to reference Chen JC, King OD, Zhang Y, et al. Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther. 2016;24(8):1405–1411.CrossRefPubMedPubMedCentral Chen JC, King OD, Zhang Y, et al. Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther. 2016;24(8):1405–1411.CrossRefPubMedPubMedCentral
71.
go back to reference Tawil R, Shaw DW, van der Maarel SM, Tapscott SJ. Clinical trial preparedness in facioscapulohumeral dystrophy: outcome measures and patient access: 8–9 April 2013, Leiden, The Netherlands. Neuromuscul Disord. 2014;24(1):79–85. Tawil R, Shaw DW, van der Maarel SM, Tapscott SJ. Clinical trial preparedness in facioscapulohumeral dystrophy: outcome measures and patient access: 8–9 April 2013, Leiden, The Netherlands. Neuromuscul Disord. 2014;24(1):79–85.
72.
go back to reference Tawil R, Padberg GW, Shaw DW, et al. Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York. Neuromuscul Disord. 2016;26(2):181–186.CrossRefPubMed Tawil R, Padberg GW, Shaw DW, et al. Clinical trial preparedness in facioscapulohumeral muscular dystrophy: Clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York. Neuromuscul Disord. 2016;26(2):181–186.CrossRefPubMed
73.
go back to reference Yao Z, Snider L, Balog J, et al. DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet. 2014;23(20):5342–5352.CrossRefPubMedPubMedCentral Yao Z, Snider L, Balog J, et al. DUX4-induced gene expression is the major molecular signature in FSHD skeletal muscle. Hum Mol Genet. 2014;23(20):5342–5352.CrossRefPubMedPubMedCentral
74.
go back to reference Petek LM, Rickard AM, Budech C, et al. A cross sectional study of two independent cohorts identifies serum biomarkers for facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord. 2016;26(7):405–413.CrossRefPubMedPubMedCentral Petek LM, Rickard AM, Budech C, et al. A cross sectional study of two independent cohorts identifies serum biomarkers for facioscapulohumeral muscular dystrophy (FSHD). Neuromuscul Disord. 2016;26(7):405–413.CrossRefPubMedPubMedCentral
75.
go back to reference Statland J, Donlin-Smith CM, Tapscott SJ, van der Maarel S, Tawil R. Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy. J Neuromuscul Dis. 2014;1(2):181–190. Statland J, Donlin-Smith CM, Tapscott SJ, van der Maarel S, Tawil R. Multiplex Screen of Serum Biomarkers in Facioscapulohumeral Muscular Dystrophy. J Neuromuscul Dis. 2014;1(2):181–190.
76.
77.
go back to reference Frisullo G, Frusciante R, Nociti V, et al. CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol. 2011;31(2):155–166.CrossRefPubMed Frisullo G, Frusciante R, Nociti V, et al. CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol. 2011;31(2):155–166.CrossRefPubMed
78.
go back to reference Statland JM, Heatwole C, Eichinger K, et al. Electrical impedance myography in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2016;54(4):696–701.CrossRefPubMedPubMedCentral Statland JM, Heatwole C, Eichinger K, et al. Electrical impedance myography in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2016;54(4):696–701.CrossRefPubMedPubMedCentral
79.
go back to reference Mul K, Heatwole C, Eichinger K, et al. Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1-year follow-up study. Muscle Nerve. 2018. Mul K, Heatwole C, Eichinger K, et al. Electrical impedance myography in facioscapulohumeral muscular dystrophy: A 1-year follow-up study. Muscle Nerve. 2018.
80.
go back to reference Eichinger K, Heatwole C, Iyadurai S, et al. Facioscapulohumeral muscular dystrophy functional composite outcome measure. Muscle Nerve. 2018. Eichinger K, Heatwole C, Iyadurai S, et al. Facioscapulohumeral muscular dystrophy functional composite outcome measure. Muscle Nerve. 2018.
81.
go back to reference Johnson NE, Quinn C, Eastwood E, Tawil R, Heatwole CR. Patient-identified disease burden in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2012;46(6):951–953.CrossRefPubMedPubMedCentral Johnson NE, Quinn C, Eastwood E, Tawil R, Heatwole CR. Patient-identified disease burden in facioscapulohumeral muscular dystrophy. Muscle Nerve. 2012;46(6):951–953.CrossRefPubMedPubMedCentral
Metadata
Title
Facioscapulohumeral Muscular Dystrophy: Update on Pathogenesis and Future Treatments
Authors
Johanna Hamel
Rabi Tawil
Publication date
01-10-2018
Publisher
Springer International Publishing
Published in
Neurotherapeutics / Issue 4/2018
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI
https://doi.org/10.1007/s13311-018-00675-3

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