Available online at www.sciencedirect.com Neuromuscular Disorders 29 (2019) 811–817 www.elsevier.com/locate/nmd Research conference report 26th Annual Facioscapulohumeral Dystrophy International Research Congress Marseille, France, 19–20 June 2019 a b, ∗ c June Kinoshita , Frédérique Magdinier , George W. Padberg a FSHD Society, 450 Bedford Street, Lexington, MA, USA b Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics, Marseille, France c Radboud UMC, Nijmegen, The Netherlands Received 2 August 2019 1. Introduction In the welcome session, Mark Stone, CEO of the FSHD Society, summarized the international patient advocacy group Research in Facioscapulohumeral Muscular Dystrophy meeting that was held on the previous day (June 18), which (FSHD) has reached the stage where we are seeing the gathered representatives of patients associations from six first drug trials aiming at reduction of its pathological gene European countries as well as Brazil, China, Israel, Japan, product DUX4. Driven by this development and by increased and the United States. international collaboration on translational research and trial preparedness, the FSHD Society has decided to hold its 2. Plenary and keynote lectures annual International Research Conference (IRC) alternating between the USA and in Europe, beginning this year with the The meeting opened with a plenary session aimed at 26th IRC held in Marseille, France. The meeting occurred on presenting the condition from the point of view of affected 19–20 June, 2019, at the Palais du Pharo, a historical palace individuals. A 10-min video gave an intimate look into the built in the second half of the 19th century by Napoleon III life of Pierre Laurian. Afterward, Pierre Laurian and Marie for his wife, the empress Eugenie. Martine Fleck discussed the impact of FSHD on their daily In a full program of two days, 52 podium talks and 35 lives. posters were presented, offering inspiration and collaboration Jamshid Arjomand, CSO of the FSHD Society, presented among the 180 participants. The program committee made an overview of a recent Industry Collaborative meeting special efforts to attract clinical researchers, as advancement the Society hosted in March of 2019 (available at www. of drug development brings greater urgency to improving fshdsociety.org ) aimed at identifying gaps in FSHD clinical our understanding of the clinical features of FSHD, trial readiness. These gaps included issues with genetic genotype-phenotype correlations, natural history, and optimal testing, lack of molecular or validated imaging biomarkers ways to measure disease progression. With the recent and a need for a more comprehensive understating of the advances in FSHD studies now including large sets of natural history of FSHD that might be obtained by the data, greater availability of biomaterials from multiple large integration of data from the existing registries. To address research initiatives, and the rapid approach of more clinical these gaps, he highlighted the FSHD Society’s launch of trials, the FSHD IRC is more relevant than ever to ensure the Therapeutic Accelerator Initiative and a set of prioritized dissemination of the latest research findings, set needs and activities, involving all stakeholders, to help expedite their priorities, and encourage collaboration to speed up progress resolution. toward delivering effective treatments to patients and families. Three keynote lectures opened the first and second day scientific sessions. The first keynote lecture was given by Michel Fardeau, founder of the Institut de Myologie in ∗ Corresponding author. Paris and curator of the archives of Professor Dejerine. He E-mail address: [email protected] (F. Magdinier). presented the first description and illustration of FSHD by https://doi.org/10.1016/j.nmd.2019.08.015 0960-8966 812 J. Kinoshita, F. Magdinier and G.W. Padberg / Neuromuscular Disorders 29 (2019) 811–817 Duchenne in his famous book on the “electrisation localisée,” damage to DUX4 regulation and whether DNA damage and dwelled on the lives of the two authors who gave activates DUX4 in FSHD patient-derived iPS cells and muscle FSHD its eponym – Landouzy and Dejerine – and on their cells. relationships with various famous neurologists active in the Session 1: The FSHD clinical phenotype . Co-chairs, medical circles of Paris at the end of the 19th century [1] . George Padberg and Peter Lunt. Professor Fardeau also reviewed postmortem muscle samples The first talk, by Nicol Voermans (Radboud UMC, of Dejerine’s patients proving that FSHD is a myopathy. Nijmegen, The Netherlands), discussed the clinical Pathology slides of the facial muscles showed in one case characteristics of childhood FSHD and the implications fatty degeneration and in another normal muscle, leaving for trial-readiness [10] . She presented the data on the natural open the discussion whether the facial muscle involvement history in 32 children with FSHD. FSHD in childhood in FSHD is more a hypoplastic or a dystrophic process. consisted of facial weakness with normal or only mildly Next, Nicolas Levy, head of the Department of Medical affected motor performance, decreased functional exercise Genetics at Aix-Marseille University, summarized the genetic capacity, pain and fatigue, decreased quality of life, lumbar features of FSHD, from the early identification of the locus hyperlordosis, and abnormalities on muscle ultrasound. in 1990 to the latest improvements [2,3] . He presented an Systemic features such as hearing loss, retinal, and cardiac overview of the different regions of the 4q35 locus associated abnormalities were infrequent and often subclinical. Patients with the disease including the D4Z4 repeat array, the DUX4 had a mean D4Z4 repeat array of 5 units (range 2–9 units) gene with its polyA addition signal on the permissive type and 14% of the mutations were de novo . FSHD in childhood A telomeric allele and the proximal SSLP of still unknown is more prevalent than previously known and has a broader significance in the pathogenesis [4,5] . He then summarized phenotype than early-onset FSHD. It resembles classic FSHD the recent findings related to the discovery of mutations in both genetically and clinically. the SMCHD1 gene. This gene is mutated in FSHD2 patients In the second presentation, Jos IJspeert (Radboud UMC, presenting with clinical FSHD but in the absence of D4Z4 Nijmegen, The Netherlands), showed videos of FSHD patients array shortening, but also in patients with Bosma arhinia with various degrees of scapular dyskinesis and demonstrated microphthalmia syndrome, an unrelated disease without any how to discriminate dyskinesis due to loss of muscle strength clear sign of muscular dystrophy [6,7] . Dr. Levy also from dyskinesis due to loss of motor control and suggested presented the molecular combing technique allowing a direct that FSHD patients with the latter condition might benefit visualization of D4Z4-associated alleles (4q35 and 10q26) from scapular coordination training. and the recent identification of recurrent cis duplication of Ceren Hangül (Akdeniz University, Antalya, Turkey) the 4q35 region in a number of patients and other complex discussed endocrinological parameters in FSHD. She tested rearrangements of the FSHD locus [8] . Dr.Levy concluded the effects of estradiol and other hormones on severity, his talk by underlining the remaining difficulties for by using facial 3D morphology scan (f3D) as an genotype-phenotype correlations and prediction of the course indicator of facial severity and the clinical severity score or onset of the disease in the majority of patients. (CSS) as an indicator of total severity. Neutral (fN), On the second day, Bradley R. Cairns of the Huntsman eyebrow elevation (fEE), maximal closing of the eyes Cancer Institute at the University of Utah gave a keynote (fCE), maximal showing of the teeth (fST), whistling address on the role of DUX4 in development. He summarized (fW) and maximal compression of teeth (fCT) were his published work showing that human DUX4 and mouse measured. fCE and fW were significantly different in Dux are transiently expressed at the onset of gene expression FSHD compared to the control group. fW correlated with in the early cleavage stage embryo, where DUX4/Dux drive free-testosterone, total-testosterone, estradiol, progesterone, expression of a large component of the initial wave of zygotic estradiol/free-testosterone ratio, estradiol/total-testosterone gene activation [9] . He then discussed new work from his ratio in 11 FSHD patients. CSS correlated with estradiol, lab led by postdoctoral fellow Edward Grow on the signaling progesterone, testosterone estradiol/free-testosterone ratio, pathways and transcription factors that activate Dux in mouse estradiol/total-testosterone ratio in 38 FSHD patients. The embryos and DUX4 in human embryos. Both Dux and DUX4 correlation was significant after menopause in 15 females as display a brief burst of expression in embryos, limited to well as in 23 males before the age of thirty. These results less than one cell cycle and coincident with zygotic genome suggest that there is a correlation between hormone levels activation (ZGA). Cairns described his unpublished work in and disease severity and that fW could be used as a specific embryonic stem cell lines showing that both Dux and DUX4 indicator of facial severity in FSHD. are activated by DNA damage, utilizing components of the The last presentation in this session was by Sabrina canonical signaling pathway. Prior