Facioscapulohumeral dystrophy in children: design of a prospective, observational study on natural history, predictors and clinical impact (iFocus FSHD)

Rianne J M Goselink, Tim H A Schreuder, Karlien Mul, Nicol C Voermans, Maaike Pelsma, Imelda J M de Groot, Nens van Alfen, Bas Franck, Thomas Theelen, Richard J Lemmers, Jean K Mah, Silvère M van der Maarel, Baziel G van Engelen, Corrie E Erasmus, Rianne J M Goselink, Tim H A Schreuder, Karlien Mul, Nicol C Voermans, Maaike Pelsma, Imelda J M de Groot, Nens van Alfen, Bas Franck, Thomas Theelen, Richard J Lemmers, Jean K Mah, Silvère M van der Maarel, Baziel G van Engelen, Corrie E Erasmus

Abstract

Background: Facioscapulohumeral muscular dystrophy (FSHD; OMIM 158900 & 158901) is a progressive skeletal muscle dystrophy, characterized by an autosomal dominant inheritance pattern. One of the major unsolved questions in FSHD is the marked clinical heterogeneity, ranging from asymptomatic individuals to severely affected patients with an early onset. An estimated 10% of FSHD patients have an early onset (onset before 10 years of age) and are traditionally classified as infantile FSHD. This subgroup is regarded as severely affected and extra-muscular symptoms, such as hearing loss and retinopathy, are frequently described. However, information on the prevalence, natural history and clinical management of early onset FSHD is currently lacking, thereby hampering adequate patient counselling and management. Therefore, a population-based prospective cohort study on FSHD in children is highly needed.

Methods/design: This explorative study aims to recruit all children (aged 0-17 years) with a genetically confirmed diagnosis of FSHD in The Netherlands. The children will be assessed at baseline and at 2-year follow-up. The general aim of the study is the description of the clinical features and genetic characteristics of this paediatric cohort. The primary outcome is the motor function as measured by the Motor Function Measure. Secondary outcomes include quantitative and qualitative description of the clinical phenotype, muscle imaging, genotyping and prevalence estimations. The ultimate objective will be a thorough description of the natural history, predictors of disease severity and quality of life in children with FSHD.

Discussion: The results of this population-based study are vital for adequate patient management and clinical trial-readiness. Furthermore, this study is expected to provide additional insight in the epigenetic and environmental disease modifying factors. In addition to improve counselling, this could contribute to unravelling the aetiology of FSHD.

Trial registration: clinicaltrials.gov NCT02625662.

Keywords: Facioscapulohumeral dystrophy; Muscular dystrophies; Neuromuscular diseases; Observational study; Paediatrics.

Figures

Fig. 1
Fig. 1
Flow chart of inclusion

References

    1. Padberg GW. Facioscapulohumeral dystrophy. 1982.
    1. Tawil R, Van Der Maarel SM. Facioscapulohumeral muscular dystrophy. Muscle Nerve. 2006;34(1):1–15. doi: 10.1002/mus.20522.
    1. Mul K, Lassche S, Voermans NC, Padberg GW, Horlings CG, van Engelen BG. What’s in a name? The clinical features of facioscapulohumeral muscular dystrophy. Pract Neurol. 2016;16(3):201–7. doi:10.1136/practneurol-2015-001353. Epub 2016 Feb 9. Review.
    1. Deenen JC, Arnts H, van der Maarel SM, Padberg GW, Verschuuren JJ, Bakker E, Weinreich SS, Verbeek AL, van Engelen BG. Population-based incidence and prevalence of facioscapulohumeral dystrophy. Neurology. 2014;83(12):1056–1059. doi: 10.1212/WNL.0000000000000797.
    1. Gaillard MC, Roche S, Dion C, Tasmadjian A, Bouget G, Salort-Campana E, Vovan C, Chaix C, Broucqsault N, Morere J, et al. Differential DNA methylation of the D4Z4 repeat in patients with FSHD and asymptomatic carriers. Neurology. 2014;83(8):733–742. doi: 10.1212/WNL.0000000000000708.
    1. Tonini MM, Pavanello RC, Gurgel-Giannetti J, Lemmers RJ, van der Maarel SM, Frants RR, Zatz M. Homozygosity for autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) does not result in a more severe phenotype. J Med Genet. 2004;41(2):e17. doi: 10.1136/jmg.2003.010637.
    1. Richard JLF, Lemmers P, Daniel G, Miller MD, van der Maarel SM. Facioscapulohumeral Muscular Dystrophy. 2014.
    1. Brooke MH. Clinical examination of patients with neuromuscular disease. Adv Neurol. 1977;17:25–39.
    1. Brouwer OF, Padberg GW, Wijmenga C, Frants RR. Facioscapulohumeral muscular dystrophy in early childhood. Arch Neurol. 1994;51(4):387–394. doi: 10.1001/archneur.1994.00540160085011.
    1. Trevisan CP, Pastorello E, Tomelleri G, Vercelli L, Bruno C, Scapolan S, Siciliano G, Comacchio F. Facioscapulohumeral muscular dystrophy: hearing loss and other atypical features of patients with large 4q35 deletions. Eur J Neurol. 2008;15(12):1353–1358. doi: 10.1111/j.1468-1331.2008.02314.x.
    1. Chen TH, Lai YH, Lee PL, Hsu JH, Goto K, Hayashi YK, Nishino I, Lin CW, Shih HH, Huang CC, et al. Infantile facioscapulohumeral muscular dystrophy revisited: Expansion of clinical phenotypes in patients with a very short EcoRI fragment. Neuromuscul Disord. 2013;23(4):298–305. doi: 10.1016/j.nmd.2013.01.005.
    1. Nikolic A, Ricci G, Sera F, Bucci E, Govi M, Mele F, Rossi M, Ruggiero L, Vercelli L, Ravaglia S, et al. Clinical expression of facioscapulohumeral muscular dystrophy in carriers of 1-3 D4Z4 reduced alleles: experience of the FSHD Italian National Registry. BMJ Open. 2016;6(1):e007798. doi: 10.1136/bmjopen-2015-007798.
    1. Sacconi S, Lemmers RJ, Balog J, van der Vliet PJ, Lahaut P, van Nieuwenhuizen MP, Straasheijm KR, Debipersad RD, Vos-Versteeg M, Salviati L, 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. doi: 10.1016/j.ajhg.2013.08.004.
    1. Lemmers RJ, Goeman JJ, van der Vliet PJ, van Nieuwenhuizen MP, Balog J, Vos-Versteeg M, Camano P, Ramos Arroyo MA, Jerico I, Rogers MT, 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. doi: 10.1093/hmg/ddu486.
    1. Himeda CL, Debarnot C, Homma S, Beermann ML, Miller JB, Jones PL, Jones TI. Myogenic enhancers regulate expression of the facioscapulohumeral muscular dystrophy-associated DUX4 gene. Mol Cell Biol. 2014;34(11):1942–1955. doi: 10.1128/MCB.00149-14.
    1. Dorobek M, van der Maarel SM, Lemmers RJ, Ryniewicz B, Kabzinska D, Frants RR, Gawel M, Walecki J, Hausmanowa-Petrusewicz I. Early-onset facioscapulohumeral muscular dystrophy type 1 with some atypical features. J Child Neurol. 2015;30(5):580–587. doi: 10.1177/0883073814528281.
    1. Klinge L, Eagle M, Haggerty ID, Roberts CE, Straub V, Bushby KM. Severe phenotype in infantile facioscapulohumeral muscular dystrophy. Neuromuscul Disord. 2006;16(9-10):553–558. doi: 10.1016/j.nmd.2006.06.008.
    1. Funakoshi M, Goto K, Arahata K. Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy. Neurology. 1998;50(6):1791–1794. doi: 10.1212/WNL.50.6.1791.
    1. Lutz KL, Holte L, Kliethermes SA, Stephan C, Mathews KD. Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy. Neurology. 2013;81(16):1374–1377. doi: 10.1212/WNL.0b013e3182a84140.
    1. Wijmenga C, Frants RR, Brouwer OF, Moerer P, Weber JL, Padberg GW. Location of facioscapulohumeral muscular dystrophy gene on chromosome 4. Lancet. 1990;336(8716):651–653. doi: 10.1016/0140-6736(90)92148-B.
    1. Lemmers RJ, de Kievit P, Sandkuijl L, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM. Facioscapulohumeral muscular dystrophy is uniquely associated with one of the two variants of the 4q subtelomere. Nat Genet. 2002;32(2):235–236. doi: 10.1038/ng999.
    1. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camano P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, et al. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010;329(5999):1650–1653. doi: 10.1126/science.1189044.
    1. Lunt PW, Jardine PE, Koch MC, Maynard J, Osborn M, Williams M, Harper PS, Upadhyaya M. Correlation between fragment size at D4F104S1 and age at onset or at wheelchair use, with a possible generational effect, accounts for much phenotypic variation in 4q35-facioscapulohumeral muscular dystrophy (FSHD) Hum Mol Genet. 1995;4(5):951–958. doi: 10.1093/hmg/4.5.951.
    1. Tawil R, Forrester J, Griggs RC, Mendell J, Kissel J, McDermott M, King W, Weiffenbach B, Figlewicz D. Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group. Ann Neurol. 1996;39(6):744–748. doi: 10.1002/ana.410390610.
    1. Himeda CL, Jones TI, Jones PL. Facioscapulohumeral muscular dystrophy as a model for epigenetic regulation and disease. Antioxid Redox Signal. 2015;22(16):1463–1482. doi: 10.1089/ars.2014.6090.
    1. van Overveld PG, Lemmers RJ, Sandkuijl LA, Enthoven L, Winokur ST, Bakels F, Padberg GW, van Ommen GJ, Frants RR, van der Maarel SM. Hypomethylation of D4Z4 in 4q-linked and non-4q-linked facioscapulohumeral muscular dystrophy. Nat Genet. 2003;35(4):315–317. doi: 10.1038/ng1262.
    1. Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW, Amell AM, van der Vliet PJ, Almomani R, Straasheijm KR, 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. doi: 10.1038/ng.2454.
    1. Tawil R, Kissel JT, Heatwole C, Pandya S, Gronseth G, Benatar M, Guideline Development D, Implementation Subcommittee of the American Academy of N, Practice Issues Review Panel of the American Association of N, Electrodiagnostic M 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. doi: 10.1212/WNL.0000000000001783.
    1. Tawil R, Padberg GW, Shaw DW, van der Maarel SM, Tapscott SJ, Participants FW. 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. doi: 10.1016/j.nmd.2015.10.005.
    1. Passerieux E, Hayot M, Jaussent A, Carnac G, Gouzi F, Pillard F, Picot MC, Bocker K, Hugon G, Pincemail J, 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. doi: 10.1016/j.freeradbiomed.2014.09.014.
    1. Voet N, Bleijenberg G, Hendriks J, de Groot I, Padberg G, van Engelen B, Geurts A. Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT. Neurology. 2014;83(21):1914–1922. doi: 10.1212/WNL.0000000000001008.
    1. Blackburn K. In.; 2016: .
    1. Tawil R, van der Maarel SM, Tapscott SJ. Facioscapulohumeral dystrophy: the path to consensus on pathophysiology. Skelet Muscle. 2014;4:12. doi: 10.1186/2044-5040-4-12.
    1. Spierziekten Nederland []. Accessed 8 Nov 2016.
    1. van Engelen BG, van Veenendaal H, van Doorn PA, Faber CG, van der Hoeven JH, Janssen NG, Notermans NC, van Schaik IN, Visser LH, Verschuuren JJ. The Dutch neuromuscular database CRAMP (Computer Registry of All Myopathies and Polyneuropathies): development and preliminary data. Neuromuscul Disord. 2007;17(1):33–37. doi: 10.1016/j.nmd.2006.09.017.
    1. WHO . ICF : International classification of functioning, disability and health / World Health Organization. 2015.
    1. Berard C, Payan C, Hodgkinson I, Fermanian J, Group MFMCS A motor function measure for neuromuscular diseases. Construction and validation study. Neuromuscul Disord. 2005;15(7):463–470. doi: 10.1016/j.nmd.2005.03.004.
    1. de Lattre C, Payan C, Vuillerot C, Rippert P, de Castro D, Berard C, Poirot I, Group MFMS. Motor function measure: validation of a short form for young children with neuromuscular diseases. Arch Phys Med Rehabil. 2013;94(11):2218–2226. doi: 10.1016/j.apmr.2013.04.001.
    1. Pillen S, Verrips A, van Alfen N, Arts IM, Sie LT, Zwarts MJ. Quantitative skeletal muscle ultrasound: diagnostic value in childhood neuromuscular disease. Neuromuscul Disord. NMD 2007;17(7):509–16. Epub 2007 May 29.
    1. van den Engel-Hoek L, Erasmus CE, Hendriks JC, Geurts AC, Klein WM, Pillen S, Sie LT, de Swart BJ, de Groot IJ. Oral muscles are progressively affected in Duchenne muscular dystrophy: implications for dysphagia treatment. J Neurol. 2013;260(5):1295–1303. doi: 10.1007/s00415-012-6793-y.
    1. Janssen BH, Pillen S, Voet NB, Heerschap A, van Engelen BG, van Alfen N. Quantitative muscle ultrasound versus quantitative magnetic resonance imaging in facioscapulohumeral dystrophy. Muscle Nerve. 2014;50(6):968–975. doi: 10.1002/mus.24247.
    1. Alfen NV, Gilhuis HJ, Keijzers JP, Pillen S, Van Dijk JP. Quantitative facial muscle ultrasound: feasibility and reproducibility. Muscle Nerve. 2013;48(3):375–380. doi: 10.1002/mus.23769.
    1. Janssen BH, Voet NB, Nabuurs CI, Kan HE, de Rooy JW, Geurts AC, Padberg GW, van Engelen BG, Heerschap A. Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration. PLoS One. 2014;9(1):e85416. doi: 10.1371/journal.pone.0085416.
    1. Tasca G, Monforte M, Iannaccone E, Laschena F, Ottaviani P, Leoncini E, Boccia S, Galluzzi G, Pelliccioni M, Masciullo M, et al. Upper girdle imaging in facioscapulohumeral muscular dystrophy. PLoS One. 2014;9(6):e100292. doi: 10.1371/journal.pone.0100292.
    1. Statland JM, Sacconi S, Farmakidis C, Donlin-Smith CM, Chung M, Tawil R. Coats syndrome in facioscapulohumeral dystrophy type 1: frequency and D4Z4 contraction size. Neurology. 2013;80(13):1247–1250. doi: 10.1212/WNL.0b013e3182897116.
    1. Deenen JC. In. . Accessed 8 Dec 2016.
    1. CastorEDC []
    1. Davignon AP RE, Boisselle F. Normal ECG standards for infants and children. Pediatr Cardiol. 1979;1:123–31.
    1. Frankenburg WK, Dodds J, Archer P, Shapiro H, Bresnick B. The Denver II: a major revision and restandardization of the Denver Developmental Screening Test. Pediatrics. 1992;89(1):91–97.
    1. Hicks CL, von Baeyer CL, Spafford PA, van Korlaar I, Goodenough B. The Faces Pain Scale-Revised: toward a common metric in pediatric pain measurement. Pain. 2001;93(2):173–183. doi: 10.1016/S0304-3959(01)00314-1.
    1. van Dijk GP, van der Kooi E, Behin A, Smeets J, Timmermans J, van der Maarel S, Padberg G, Voermans N, van Engelen B. High prevalence of incomplete right bundle branch block in facioscapulohumeral muscular dystrophy without cardiac symptoms. Funct Neurol. 2014;29(3):159–165.
    1. Laboratories ATSCoPSfCPF ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. 2002;166(1):111–117. doi: 10.1164/ajrccm.166.1.at1102.
    1. McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, Atkinson L, Reha A, Hirawat S, Miller LL. The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010;41(4):500–510. doi: 10.1002/mus.21544.
    1. Gordijn M, Cremers EM, Kaspers GJ, Gemke RJ. Fatigue in children: reliability and validity of the Dutch PedsQL Multidimensional Fatigue Scale. Qual Life Res. 2011;20(7):1103–1108. doi: 10.1007/s11136-010-9836-9.
    1. Jat KR. Spirometry in children. Prim Care Respir J. 2013;22(2):221–229. doi: 10.4104/pcrj.2013.00042.
    1. Huckabee ML, McIntosh T, Apperley O. Quantitative Assessment of Oral Phase Efficiency: TOMASS Norms and Preliminary Validation. Nashville, TN, USA: Dysphagia Research Society Annual Scientific Meeting, 5-8 Mar 2014; 2014.
    1. Wada A, Kawakami M, Liu M, Otaka E, Nishimura A, Liu F, Otsuka T. Development of a new scale for dysphagia in patients with progressive neuromuscular diseases: the Neuromuscular Disease Swallowing Status Scale (NdSSS). J Neurol. 2015.
    1. van den Engel-Hoek L, Erasmus CE, van Bruggen HW, de Swart BJ, Sie LT, Steenks MH, de Groot IJ. Dysphagia in spinal muscular atrophy type II: more than a bulbar problem? Neurology. 2009;73(21):1787–1791. doi: 10.1212/WNL.0b013e3181c34aa6.
    1. Vanhoutte EK, Faber CG, van Nes SI, Jacobs BC, van Doorn PA, van Koningsveld R, Cornblath DR, van der Kooi AJ, Cats EA, van den Berg LH, et al. Modifying the Medical Research Council grading system through Rasch analyses. Brain. 2012;135(Pt 5):1639–1649. doi: 10.1093/brain/awr318.
    1. Ricci E, Galluzzi G, Deidda G, Cacurri S, Colantoni L, Merico B, Piazzo N, Servidei S, Vigneti E, Pasceri V, et al. Progress in the molecular diagnosis of facioscapulohumeral muscular dystrophy and correlation between the number of KpnI repeats at the 4q35 locus and clinical phenotype. Ann Neurol. 1999;45(6):751–757. doi: 10.1002/1531-8249(199906)45:6<751::AID-ANA9>;2-M.
    1. van Overveld PG, Enthoven L, Ricci E, Rossi M, Felicetti L, Jeanpierre M, Winokur ST, Frants RR, Padberg GW, van der Maarel SM. Variable hypomethylation of D4Z4 in facioscapulohumeral muscular dystrophy. Ann Neurol. 2005;58(4):569–576. doi: 10.1002/ana.20625.
    1. Lamperti C, Fabbri G, Vercelli L, D’Amico R, Frusciante R, Bonifazi E, Fiorillo C, Borsato C, Cao M, Servida M, et al. A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: the FSHD clinical score. Muscle Nerve. 2010;42(2):213–217. doi: 10.1002/mus.21671.
    1. Ploeg PDEMSePDJDvd: Sociaal-Emotionele Vragenlijst (SEV): Houten: Springer Media; 2015. .
    1. Ravens-Sieberer U, Gosch A, Rajmil L, Erhart M, Bruil J, Duer W, Auquier P, Power M, Abel T, Czemy L, et al. KIDSCREEN-52 quality-of-life measure for children and adolescents. Expert Rev Pharmacoecon Outcomes Res. 2005;5(3):353–364. doi: 10.1586/14737167.5.3.353.

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