225th ENMC international workshop:: A global FSHD registry framework, 18–20 November 2016, Heemskerk, The Netherlands

Abstract

•The workshop focused on patient registries for facioscapulohumeral muscular dystrophy.•The core dataset for international FSHD registries was updated.•The foundation was created on which to establish a global registry for FSHD. On 18–20 November 2016, the 225th ENMC Workshop on ‘A global FSHD Registry framework’ took place in Heemskerk, the Netherlands. Twenty-two participants from 11 different countries gathered, including clinicians, researchers, policy makers and representatives from patient advocacy groups and industry. Facioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disorder, characterized by weakness of the facial and shoulder girdle muscles followed by the leg and trunk muscles [1Padberg G.W. Facioscapulohumeral disease.1982Google Scholar, 2Mul K. Lassche S. Voermans N.C. Padberg G.W. Horlings C.G. van Engelen B.G. What's in a name? The clinical features of facioscapulohumeral muscular dystrophy.Pract Neurol. 2016; 16: 201-207Crossref PubMed Scopus (63) Google Scholar]. There is a large variability in the severity of symptoms, ranging from asymptomatic to wheelchair bound individuals. Approximately 95% of FSHD patients carry one allele with a reduced number (1–10) of D4Z4 repeat units on chromosome 4q35 associated with specific haplotypes (FSHD1) [[3]Lemmers R.J. van der Vliet P.J. Klooster R. Sacconi S. Camaño P. Dauwerse J.G. et al.A unifying genetic model for facioscapulohumeral muscular dystrophy.Science. 2010; 329: 1650-1653Crossref PubMed Scopus (521) Google Scholar]. Of the remaining 5% of patients with FSHD phenotype (FSHD2), most cases have been explained by heterozygous mutations in the SMCHD1 (Structural Maintenance of Chromosomes flexible Hinge Domain containing-1) gene [[4]Lemmers R.J. Tawil R. Petek L.M. Balog J. Block G.J. Santen G.W. et al.Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2.Nat Genet. 2012; 44: 1370-1374Crossref PubMed Scopus (414) Google Scholar]. These two different (epi)genetic mechanisms lead to chromatin relaxation of the D4Z4 repeat in somatic tissue and subsequent expression of the DUX4 gene in myogenic cells. DUX4 is thought to be the major contributor to FSHD pathology, although the exact pathophysiological mechanism is still largely unknown [[5]Ricci G. Zatz M. Tupler R. Facioscapulohumeral muscular dystrophy: more complex than it appears.Curr Mol Med. 2014; 14: 1052-1068Crossref PubMed Scopus (21) Google Scholar]. Expansion of our knowledge on the (epi)genetic mechanism underlying FSHD has led to advances in identifying (targeted) therapeutic strategies. Consequently it is now important to develop a ‘clinical trial toolbox’, consisting of patient registries, biomarkers and clinical outcome measures to ensure resources are utilized effectively [[6]Tawil R. Padberg G.W. Shaw D.W. van der Maarel S.M. Tapscott S.J. Participants F.W. Clinical trial preparedness in facioscapulohumeral muscular dystrophy: clinical, tissue, and imaging outcome measures 29–30 May 2015, Rochester, New York.Neuromuscul Disord. 2016; 26: 181-186Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. The wide phenotypic expression in rare diseases, such as FSHD, means that patient registries are particularly important for clinical trial readiness. The aims of this workshop were to analyze the experience and results of the existing FSHD patient registries, update the Treat-NMD recommended dataset for FSHD, increase collaboration among established research groups and patient advocacy organizations and create the foundation on which to establish a global registry for FSHD. Rossella Tupler started with an overview on the adult FSHD phenotype. The first description of FSHD was of an infantile onset case in 1884 by Landouzy and Dejerine. Even in this first report, the wide spectrum of clinical presentation was evident, describing familial cases with later onset and without facial weakness. Phenotypic variability was further expanded upon in a case report of a large family in Utah in the 1950s that included the observation of minimally affected individuals. In the 1980s, Padberg examined multiple large FSHD families and established diagnostic criteria for individuals to be included in linkage analyses (Table 1), setting the gold standard for FSHD [1Padberg G.W. Facioscapulohumeral disease.1982Google Scholar, 7Padberg G.W. Lunt P.W. Koch M. Fardeau M. Diagnostic criteria for facioscapulohumeral muscular dystrophy.Neuromuscul Disord. 1991; 1: 231-234Abstract Full Text PDF PubMed Scopus (188) Google Scholar]. This led to the discovery of the D4Z4 repeat contraction as the cause of FSHD1 in 1992, enabling highly sensitive and specific genetic testing for FSHD [[8]Wijmenga C. Hewitt J.E. Sandkuijl L.A. Clark L.N. Wright T.J. Dauwerse H.G. et al.Chromosome 4q DNA rearrangements associated with facioscapulohumeral muscular dystrophy.Nat Genet. 1992; 2: 26-30Crossref PubMed Scopus (547) Google Scholar]. A rough inverse correlation between the number of D4Z4 repeat units (1–10) and clinical severity has been proposed [[9]Tawil R. Forrester J. Griggs R.C. Mendell J. Kissel J. McDermott M. et al.Evidence for anticipation and association of deletion size with severity in facioscapulohumeral muscular dystrophy. The FSH-DY Group.Ann Neurol. 1996; 39: 744-748Crossref PubMed Scopus (167) Google Scholar].Table 1Padberg and Brouwer clinical criteria for diagnosing (infantile) FSHD.Main criteria for clinical diagnosis of FSHD by Padberg et al.1. Onset of the disease in facial or shoulder girdle muscles; sparing of the extra-ocular, pharyngeal and lingual muscles and the myocardium2. Facial weakness in more than 50% of the affected family members3. Autosomal dominant inheritance in familial cases4. Evidence of myopathic disease in EMG and muscle biopsy in at least one affected member without biopsy features specific to alternative diagnosisMain criteria for clinical diagnosis of infantile FSHD by Brouwer et al.1. Signs and symptoms of facial weakness by the age of five2. Shoulder girdle weakness by the age of ten Open table in a new tab In recent studies on patients included in the Italian FSHD registries, again wide variability in disease severity, including among members of the same family, has been demonstrated. The ‘comprehensive clinical evaluation form’ was introduced as a novel tool for categorizing patients and their relatives based on typical and/or atypical features for the FSHD phenotype [[10]Ricci G. Ruggiero L. Vercelli L. Sera F. Nikolic A. Govi M. et al.A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes.J Neurol. 2016; 263: 1204-1214Crossref PubMed Scopus (38) Google Scholar]. A number of videos with examples of different FSHD phenotypes were shown during the presentation. In the first workshop discussion session, it was agreed to first focus on discriminating typical from atypical phenotypes, because this distinction seems most relevant for future clinical trials on therapeutic approaches. Additionally, atypical phenotypes are rare and potential modifiers of the phenotype are still largely unknown. Angela Berardinelli presented an overview of the infantile form of FSHD, starting with the criteria for infantile FSHD set by Brouwer and Padberg: signs and symptoms of facial weakness by the age of five and shoulder girdle weakness by the age of ten (Table 1) [[11]Brouwer O.F. Padberg G.W. Wijmenga C. Frants R.R. Facioscapulohumeral muscular dystrophy in early childhood.Arch Neurol. 1994; 51: 387-394Crossref PubMed Scopus (95) Google Scholar]. In the literature, the infantile form is considered a very severe and rapid form of FSHD. It makes up a small proportion (around 4%) of the total FSHD population [[11]Brouwer O.F. Padberg G.W. Wijmenga C. Frants R.R. Facioscapulohumeral muscular dystrophy in early childhood.Arch Neurol. 1994; 51: 387-394Crossref PubMed Scopus (95) Google Scholar]. Within this group, disease course is reported to be more homogeneous. One remarkable characteristic of this group is that the onset of pelvic girdle weakness can occasionally precede the shoulder girdle weakness by 1.5–2 years. The infantile form is also more frequently associated with extra-muscular manifestations such as mental retardation, epilepsy, severe exudative retinopathy, hearing loss and severe respiratory problems in some cases requiring (non-invasive) ventilation. This severe form is often associated with very short D4Z4 repeat fragments of 1–3 repeat units. Results were shown of a multicenter retrospective study aiming to investigate the prognostic significance of very short 4q35 alleles of 1–3 repeat units [[12]Nikolic A. Ricci G. Sera F. Bucci E. Govi M. Mele F. 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: e007798Crossref Scopus (53) Google Scholar]. A total of 66 index cases (40 de novo and 26 familial cases) were included through the Italian National Consortium for FSHD. In this cohort of patients carrying 1–3 repeat units, there was wide clinical variability in the severity of symptoms. Additionally, infantile onset of symptoms did not always predict a very severe clinical outcome. In this retrospective study, no evidence of pre- or perinatal onset of the disease was found. The results indicate that the presence of a very short repeat fragment does not always associate with a severe phenotype, thus supporting the hypothesis that additional factors other than the repeat size must contribute to FSHD disease severity. In the workshop discussion that followed, other clinicians noted that in their experience young onset FSHD is not necessarily predictive of a very severe disease course. In retrospect, quite a proportion of FSHD patients may have had unnoticed mild facial weakness at young age. Nicole Voet presented the results of a clinical trial on aerobic exercise and cognitive behavioral therapy to reduce chronic fatigue in FSHD through tackling fatigue perpetuating factors [[13]Voet N. Bleijenberg G. Hendriks J. de Groot I. Padberg G. van Engelen B. et al.Both aerobic exercise and cognitive-behavioral therapy reduce chronic fatigue in FSHD: an RCT.Neurology. 2014; 83: 1914-1922Crossref PubMed Scopus (92) Google Scholar]. After 16 weeks of intervention and 12 weeks of follow-up, both treatments were effective in reducing chronic fatigue. Additionally, MRI imaging of the upper leg muscles showed a significantly smaller increase in the percentage of fatty infiltration in the muscles of patients in the intervention groups compared to a control group [[14]Janssen B. Voet N. Geurts A. van Engelen B. Heerschap A. Quantitative MRI reveals decelerated fatty infiltration in muscles of active FSHD patients.Neurology. 2016; 86: 1700-1707Crossref PubMed Scopus (48) Google Scholar]. In the workshop discussion that followed, it was agreed that physical activity or exercise could potentially be a modifier of disease severity, which may be of particular relevance in the design of future clinical trials. Silvère van der Maarel summarized what is currently known on FSHD on a molecular level and elucidated current knowledge in the context of his extensive experience in the molecular characterization of the disease. Briefly, 95% of all FSHD patients carry a repeat contraction of the D4Z4 repeat on chromosome 4q35, whereas most of the other 5% have a mutation in the SMCHD1 gene. Both mechanisms result in chromatin relaxation of the D4Z4 repeat in somatic tissue and subsequent expression of the DUX4 transcription factor in skeletal muscle. Only specific 4qA haplotypes provide the necessary polyadenylation signal to stabilize the DUX4 transcript and are thus disease-permissive. An exception is the 4qA166 haplotype, which for unknown reasons appears to be less likely to be disease-causing than other 4qA haplotypes. DUX4 is a transcription factor normally expressed in the luminal cells of the testis and suppressed in somatic cells. The exact pathways by which DUX4 expression leads to muscle weakness is currently unknown, but it is believed to influence, amongst others, pathways involved in apoptosis, expression of stem cell genes, alterations of RNA processing in muscle atrophy and inhibition of muscle regeneration. Because of the observation that in individuals with shorter repeat sizes, the disease is more likely to be symptomatic, an oligogenic model is proposed in which individuals with longer repeat sizes are more dependent on additional modifiers for the disease to become symptomatic. This oligogenic model could also explain the variability in onset and progression of FSHD and the high frequency of non-penetrant mutation carriers in the population. Modifiers could be environmental factors or (epigenetic) factors working in cis, such as the repeat length or the polyadenylation signal, or in trans, like SMCHD1. Recently, a new trans-acting factor was found through the identification of two FSHD families with a mutation in the DNMT3B gene [[15]van den Boogaard M.L. Lemmers R.J. Balog J. Wohlgemuth M. Auranen M. Mitsuhashi S. et al.Mutations in DNMT3B modify epigenetic repression of the D4Z4 repeat and the penetrance of facioscapulohumeral dystrophy.Am J Hum Genet. 2016; 98: 1020-1029Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar]. Research continues on finding additional modifiers. Betsy Bogard introduced different registry models from the perspective of the industry as well as from patient advocacy groups. She explained the “original” registry model in rare diseases: a longitudinal registry focused on one disease and owned by a drug company. These registries have historically been clinician-centered, with data input only through clinicians and no or limited feedback directly to the participating patients. Over the last 5–7 years ‘patient-driven’ registries have evolved. These are more frequently cross-sectional, patient-reported and provide direct feedback to patients. An example of a global ‘one registry’ for fibrodysplasia ossificans progressiva (FOP) was shown. In this registry example, there is input by both clinicians and patients through different portals of the same registry. In general, it was pointed out to be aware of de-centralized registry ownership, because it can lead to registry fragmentation and thus complicate data consolidation. Although registries provide valuable information, no registry could replace natural history studies and clinical trials. Armelle Richiardi outlined the relevance of patient registries for the industry. From an industry perspective, registries are mostly used in the setting of clinical trials for obtaining disease knowledge (clinical trial endpoints, long term disease progression, treatment impact) and patient knowledge (patient profile and identification for clinical trials, post marketing surveillance). An example of a successful collaboration of the industry with a registry was given: a registry and natural history study for early onset FSHD including patients from twelve different hospitals worldwide. Longitudinal data on this cohort will be collected in the upcoming years. June Kinoshita presented an overview of the existing FSHD patient registries from an international perspective. Currently, there are FSHD registries in 13 different countries comprising data on over 3000 patients. While the current registries include a large number of patients, this is still only a fraction of the total number of FSHD patients worldwide. Furthermore, of those registered, data are not uniformly collected and is consequently difficult to aggregate or compare. Therefore, it is critical for the FSHD community to establish a global core dataset that collects patient-reported information in a way that it can be anonymized, aggregated and analyzed. There are still a number of logistic issues to be solved before establishing a global federated registry. Five different national FSHD registries and their results so far were discussed. Baziel van Engelen presented the Dutch FSHD registry, a patient-centered online registry that currently contains 275 participants. Patients register themselves online, sign an informed consent form to collect genetic data and then fill out online questionnaires. In addition to the standardized and internationally agreed Treat-NMD core data set (Table 2), a number of validated questionnaires are included, for example on fatigue, depression, pain and quality of life. These additional questionnaires serve as patient reported outcome measures (PROMS) to enable researchers to learn more about the impact of the disease.Table 2Updated treat-NMD core dataset for FSHD.ItemSelf-report exampleMandatory items1a.Personal dataBiological sex at birthFirst nameMiddle nameLast nameDate of birthCity of birthCountry of birthCurrent Address Zip/post code CountryTelephoneEmailYour* personal dataBiological sex at birthFirst nameMiddle nameLast nameDate of birthCity of birthCountry of birthCurrent Address Zip/post codeCountryTelephoneEmail*Or FSHD patient's, if you are a parent/guardian or caregiver registering on behalf of a patient1b.Alternative contactNext of kinFirst nameLast nameCurrent addressZip/post codeCountryTelephoneEmailAlternative contact should you be unavailableNext of kinFirst nameLast nameCurrent addressZip/post codeCountryTelephoneEmail1c.Diagnosing physicianFirst nameLast nameMedical institutionAddressZip/post codeCountryTelephoneEmailPhysician who diagnosed you with FSHDFirst nameLast nameMedical institutionAddressZip/post codeCountryTelephoneEmail2.Genetic test result○ Confirmed FSHD1 (D4Z4 contraction 1–10 repeats + 4qA)○ FSHD2 (no contraction + 4qA + SMCHD1 mutation)○ Not FSHD (homozygous for 4qB)○ Result pending○ Not testedWhat is your genetic test result?○ I have been told I have genetically confirmed FSHD and I can provide a copy of my genetic test result [UPLOAD]○ I have been told I have genetically confirmed FSHD but I do not have my genetic test result. [FOLLOW-UP: OBTAIN GENETIC TEST REPORT FROM DIAGNOSING PHYSICIAN]○ I have been tested but I haven't received the result yet○ I have not been tested but wish to be tested○ I have not been tested and do not wish to be tested3.Clinical diagnosis○ Facial weakness○ Periscapular shoulder weakness○ Foot dorsiflexor weakness○ Hip girdle weakness○ Asymptomatic (patients has no complaints, but physician detects signs)○ Non-penetrant (no signs)Which of these symptoms do you have? (Select all that apply)○ Facial weakness(weakness of muscles in the face causing e.g. inability to smile, to whistle, or to close your eyes fully at night)○ Shoulder weakness(weakness of the muscles around the shoulder blades causinge.g. shoulder blades to protrude; inability to raise your arms sideways above the level of your shoulder).○ Foot or ankle weakness(weakness of the muscles that help you lift your feet up, causing e.g. foot drop (where the foot tends to hang with the toes pointing down), steppage gait (lifting the feet high when walking), or frequent tripping)○ Hip girdle weakness(weakness of the muscles of the pelvis and top of the legs, causing e.g. difficulties in going up stairs or ladders, rising from a chair or getting up from the floor)○ I have none of the signs or symptoms described above4.Current best motor function○ Ambulatory (unassisted)○ Ambulatory (assisted)○ Non-ambulatoryWhich of the following options describes the best motor function you are currently able to achieve?○ I can walk unaided always○ I can walk unaided most of the time○ I can walk with an assistive device for some distance○ I can walk with an assistive device for a short distance○ I cannot walk5.Wheelchair use○ No○ Part-time (start date year)○ Full-time (start date year)Do you use a wheelchair? (please select all that apply)○ I don't use a wheelchair.○ I started using an assistive device from [YEAR]○ I started using a wheelchair part-time from [YEAR]○ I use a wheelchair all the time since [YEAR]6a.Pulmonary function test○ No○ YesHas your respiratory capacity ever been evaluated (for example pulmonary function testing)?○ No○ Yes○ I don't know6b.Non-invasive ventilation○ None○ Part-time (start date year)○ Full-time (start date year)Do you regularly use a non-invasive (mask) ventilation device?○ No, never○ Yes, but only part-time, e.g. at night, since [YEAR])○ Yes, all day since [YEAR]6c.Invasive ventilationo Noneo Part-time (start date year)o Full-time (start date year)Do you use invasive ventilation (requiring surgery, e.g. tracheostomy)?○ No○ Yes, part-time since [YEAR]○ Yes, full-time since [YEAR]7.Age of onset for selected FSHD symptoms (taken from question 3)○ Facial weakness (start date year)○ Periscapular shoulder weakness (start date year)○ Foot dorsiflexor weakness (start date year)○ Hip girdle weakness (start date year)At what age did you first notice symptoms related to your FSHD? Give approximate year for all that apply○ Facial weakness, first occurred in [YEAR]○ Shoulder weakness, first occurred in [YEAR]○ Ankle/foot weakness, first occurred in [YEAR]○ Hip girdle weakness, first occurred in [YEAR]8.Retinal vascular disease attributable to FSHD○ No○ Yes (start date year)○ UnknownHave you been diagnosed with retinal problems or abnormal blood vessels at the back of your eye that your doctors think may be related to your FSHD? (“Coat's disease,” retinal vascular disease)○ No○ Yes, first occurred in [YEAR], but with no visual impairment○ Yes, first occurred in [YEAR], and has caused visual impairment○ I don't know9.Hearing loss○ No○ Yes (start date year)○ UnknownDo you have hearing loss?○ No○ Yes, first occurred in [YEAR], but I don't use a hearing aid○ Yes, first occurred in [YEAR], and I use a hearing aid○ I don't know10.Scapular fixation○ No○ Yes, unilateral (surgery date year)○ Yes, bilateral (surgery dates year)Have you had scapular fixation (an operation to fix your shoulder blade to your ribcage)?○ No○ Yes, in one shoulder [LEFT/RIGHT], operated in [YEAR]○ Yes, both shoulders, operated in [YEAR] and [YEAR]11.Pregnancy (only females)○ No○ Yes○ Number of pregnancies(For women only) Have you ever been pregnant? Select all that apply.○ No○ Yes, ____ time(s) in [YEARS]12.Family history○ Affected mother○ Affected father○ Affected offspring○ Affected sibling(s)○ Other affected relative○ No○ UnknownHas anybody else in your family been diagnosed with FSHD (select all that apply)?○ Yes, mother○ Yes, father○ Yes, one or more children○ Yes, one or several of my siblings (brothers and sisters)○ Yes, further relatives (other than parents and siblings)○ No○ I don't know13.Epilepsy○ No○ YesDo you have a history of seizures/convulsions?○ No○ Yes14.Mental retardation○ No○ YesDo you have a history of delayed cognitive development or cognitive impairment?○ No○ YesNon-mandatory15.Ethnic origin○ Pulldown menu [SPECIFIC TO EACH COUNTRY'S REQUIREMENTS]○ Other○ Declined to answerHow would you describe your ethnic origin?○ Pulldown menu [SPECIFIC TO EACH COUNTRY'S REQUIREMENTS]○ Other○ I choose not to answer this question16.Other registry○ Yes (specify)○ No○ UnknownHave you signed up for any other FSHD registry or studies?○ Yes (if yes, please specify: PULLDOWN MENU or OTHER)○ No○ I don't know Open table in a new tab The Dutch registry envisions a two-way registry, in which patients not only provide input but also receive feedback about their successive data over time or in comparison to the total group. Additionally, the registry is structured to enable participants to make suggestions with regard to researched items. This registry has already proven useful in the recruitment of patients for a recent clinical trial. Teresinha Evangelista presented the UK (United Kingdom) FSHD patient registry. The UK FSHD Patient Registry is an online patient-initiated registry combining patient reported outcomes with clinically verified details [[16]Evangelista T. Wood L. Fernandez-Torron R. Williams M. Smith D. Lunt P. et al.Design, set-up and utility of the UK facioscapulohumeral muscular dystrophy patient registry.J Neurol. 2016; 263: 1401-1408Crossref PubMed Scopus (23) Google Scholar]. Genetic confirmation is obtained through a clinician specialist or directly from the laboratory that is performing the test. The registry contains the Treat-NMD core data set and a set of additional questionnaires, for example on pain, quality of life and scapular fixation. Since 2013 over 700 participants have registered, 576 of whom have a confirmed genetic diagnosis. Longitudinal data are collected through annual updates. The registry has proven its utility with the recruitment of patients for a natural history study of infantile onset FSHD and the validation of a newly developed Rasch-built patient reported outcome measure. The US (United States) National Patient Registry was presented by Rabi Tawil. It is the oldest FSHD registry established in 2000 as a combined registry for FSHD and myotonic dystrophy [[17]Hilbert J.E. Kissel J.T. Luebbe E.A. Martens W.B. McDermott M.P. Sanders D.B. et al.If you build a rare disease registry, will they enroll and will they use it? Methods and data from the National Registry of Myotonic Dystrophy (DM) and Facioscapulohumeral Muscular Dystrophy (FSHD).Contemp Clin Trials. 2012; 33: 302-311Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar]. Participants sign a consent form that allows the registry to obtain medical records for review. There are currently 876 patients registered and 88 unaffected family members. Paper questionnaires are filled out by the participants and all medical records are reviewed by one clinician and participants are categorized by diagnostic certainty. All data are then entered into an electronic data base. About 60% of all participants are genetically confirmed. There is a yearly follow-up to track disease progression and longitudinal data up to 14 years is available. The registry captures hard endpoints such as age at first use of assistive devices and use of wheelchair and includes a functional questionnaire that allows tracking of disease progression [[18]Statland J.M. Tawil R. Risk of functional impairment in facioscapulohumeral muscular dystrophy.Muscle Nerve. 2013; 49: 520-527Crossref Scopus (56) Google Scholar]. Newsletters and recruitment letters about studies are sent out regularly by the registry to participants. Researchers utilize the registry to either to help recruit patients for clinical studies or to analyze anonymized data. To date, the registry has received application for 19 applications. Rossella Tupler presented the Italian FSHD registry; it is a multi-center clinician reported registry. Fourteen neuromuscular clinics and two diagnostic laboratories participate in the ‘Italian National Registry for FSHD’. The registry includes a standardized clinical examination and molecular testing of index cases and relatives. The registry now includes 1093 index cases with 2131 D4Z4 carrier relatives and 399 single cases. The patients are categorized based on the phenotype into classical and atypical or complex phenotypes [[10]Ricci G. Ruggiero L. Vercelli L. Sera F. Nikolic A. Govi M. et al.A novel clinical tool to classify facioscapulohumeral muscular dystrophy phenotypes.J Neurol. 2016; 263: 1204-1214Crossref PubMed Scopus (38) Google Scholar]. The registry has been used for a prospective observational study of 246 subjects with a follow-up period of five years. Over those five years, the mean FSHD score [[19]Lamperti C. Fabbri G. Vercelli L. et al.A standardized clinical evaluation of patients affected by facioscapulohumeral muscular dystrophy: the FSHD clinical score.Muscle Nerve. 2010; 42: 213-217Crossref PubMed Scopus (93) Google Scholar] increased from 4.4 ± 3.7 SD to 5.6 ± 4.3 SD and 4% of patients lost ambulation. Approximately a quarter of the 45% asymptomatic relatives became symptomatic during the five years of follow-up, decreasing the percentage of asymptomatic relatives to 34%. Sabrina Sacconi introduced the French FSHD registry, which includes a total of 682 patients. It is a combined patient- and doctor-reported registry with a self-reported form and a clinical evaluation form respectively. Patients and doctors can view data for a specific patient online by using a personal patient identification number. More recently, the motor function measure has been included as an outcome measure in the registry. After these five registries were presented, the workshop participants discussed some of the challenges faced by current registries. The proportion of registered patients is still low compared to the total number of potential participants. The inclusion rates could be improved by actively involving patients and patient advocacy groups, improving accessibility of the registries and actively inviting patients to be involved, for example at the time of diagnosis. Since no registry will be able to capture data on every aspect of the disease, a core dataset with optional additional data collection on specified topics is desired. Data collection needs to be standardized to enable assembly of data globally. Additionally, different topics could be addressed in different registries to complement one another. Hugh Dawkins shared the experiences from the federated global registry for Duchenne muscular dystrophy (DMD). The Duchenne Foundation, in close partnership with Australian umbrella neuromuscular disease patient organizations, initiated a nationwide campaign for a National DMD Registry to collate clinical and genetic data. Patients and patient advocacy groups have been involved in the development of the registry throughout the entire process. This ‘patient voice’ has helped to get policymakers engaged and thus accelerate