Abstracts / Neuromuscular Disorders 29 (2019) S37–S208 S53 of FSHD. In spite of this, literature on ophthalmologic findings in FSHD is scarce. Here, we described the ophthalmological findings in a well- defined cohort of FSHD patients using state of the art imaging techniques. Thirty-three FSHD patients and 24 unrelated healthy controls (aged 6-68 years) underwent clinical ophthalmological examination, fundus photography, optical coherence tomography/angiography, neurological examination and genotyping. All patients had normal corrected visual acuity and normal intraocular pressure. In 27/33 patients, weakness of the orbicularis oculi was observed, leading to medical treatment in 12/33. Retinal pathology, only seen in FSHD patients and not in healthy controls, included twisting (tortuosity) of the retinal arteries in 41/60 eyes and retinal pigment epithelium defects in 5/60 eyes. Foveal hypoplasia was present in 6 eyes and exudative abnormalities were observed in 2 eyes. There was a correlation between the severity of retinal tortuosity and the D4Z4 repeat array size (R2 0.44, p<0.005). Follow-up examination in a subgroup of patients (n=6) did not show any changes after two years. In conclusion, ophthalmologic abnormalities were frequent but almost always subclinical in FSHD patients and consisted primarily of arterial tortuosity and foveal abnormalities. Retinal tortuosity was seen in the retinal arterioles and correlated with the D4Z4 repeat array size, thereby providing clinical evidence for an underlying genetic linkage between the retina and FSHD. Our data did not support a biomarker role for retinal tortuosity in FSHD. http://dx.doi.org/10.1016/j.nmd.2019.06.069 P.41 Extra-skeletal muscle manifestations of facioscapulohumeral muscular dystrophy C. Kelly, J. Saw, P. Thapa, J. Mandrekar, E. Naddaf Mayo Clinic, Rochester, USA In its classic form, FSHD is characterized by weakness predominantly affecting facial and shoulder girdle muscles. FSHD can also be associated with extra-skeletal muscle manifestations that remain poorly explored. In this study, we aimed to better characterize the spectrum of such manifestations in a large, single-center series of patients. We performed a retrospective chart review of FSHD patients seen between 2000 and 2017. We reviewed patients’ clinical information, answers to a comprehensive review of symptoms and laboratory results in the following domains: hearing loss, cardiac disease, dysphagia, ocular abnormalities and respiratory dysfunction. We identified 88 patients, 40 were females. At time of evaluation, median age was 45 years (range 1-83), and median disease duration was 9.5 years (range <1- 52). Median number of D4Z4 repeats was 6 units: 4 in early-onset FSHD before age of 10 (17 patients), and 6 in typical onset. Only 5.1% of patients were on work disability and 69% had post-graduate education. At presentation, 8% of patients reported decreased hearing and 7% were using a hearing aid. 22% reported palpitations, 9% dysphagia, 12% visual symptoms, 29% respiratory symptoms, 12% cognitive difficulties, 31% falling easily, 28% headaches and 70% any form of pain. On testing, hearing loss was present in 12/21 tested patients, abnormal ECG in 15/85, abnormal TTE in 17/46, oropharyngeal dysphagia in 9/17, abnormal vital capacity in 12/25, abnormal overnight oximetry in 17/27 and ocular abnormalities in 5/ 25 but none attributed to FSHD. A single patient had focal epilepsy. Correlation between symptoms and laboratory findings with age of onset, deletion size and disease duration will be provided at the time of the conference. Increased awareness regarding the various extra-skeletal muscle manifestations of FSHD allows timely screening, and subsequently avoiding potential complications. http://dx.doi.org/10.1016/j.nmd.2019.06.070 P.42 Discovery of novel small molecule treatment options for FSHD M. Geese 1 , M. Ermann 2 , M. Schneider 1 , S. Monecke 1 , A. Kaever 1 , S. Frankenreiter 1 , M. Bayerlova 1 , K. Schreiter 1 , A. Dickie 2 , P. Loke 2 , T. James 2 , A. Anighoro 2 , R. Hirsch 1 , S. Müller 3 , J. De Maeyer 4 1 Evotec International GmbH, Hamburg, Germany; 2 Evotec (UK) Ltd, Abingdon, Oxfordshire, UK; 3 Evotec (München) GmbH, Planegg- Martinsried, Germany; 4 Facio Therapies, Leiden, Netherlands There is wide support for the pathogenesis model in which gain- of-function of the DUX4 gene in skeletal muscle cells underlies FSHD progression. DUX4 is a transcription factor whose expression is normally restricted to early embryonic development. Expression of DUX4 in muscle tissue of FSHD patients initiates a transcription cascade ultimately resulting in overt pathology. Drug discovery efforts in FSHD have been hampered by the very low and stochastic expression of DUX4 in a small percentage of myonuclei. Because the regulatory pathways involved in the activation of DUX4 are largely unknown, we implemented a phenotypic approach to identify novel small molecules and drug targets to repress DUX4. In order to build a predictive and translatable assay, we used primary patient- derived myocytes to develop and validate a high-content screening assay allowing automated sensitive detection and quantification of endogenous, non-stimulated DUX4 protein and myotube fusion efficiency. Our assay confirmed that the expression of DUX4 is dynamically regulated during myogenic differentiation and showed that effects on fusion are associated with potentially false-positive signals on the DUX4 readout. The excellent assay performance enabled high-throughput screening, resulting in the discovery and optimization of multiple hit series with confirmed activity in secondary assays. RNA-seq studies with selected compounds revealed normalization of the FSHD transcription signature. We applied a number of chemoproteomic approaches to deconvolute the mode of action of the phenotypic hit series, resulting in the discovery of novel targets to repress DUX4. In order to support the pharmacokinetic/pharmacodynamic strategy, we developed a xenograft animal model in which we could demonstrate in vivo repression of DUX4 after oral dosing of a selected lead compound from one of the series. Together, these results form the basis for building a diverse FSHD-focused product pipeline. http://dx.doi.org/10.1016/j.nmd.2019.06.071 P.43 Targeting DUX4 expression, the root cause of FSHD: identification of a drug target and development candidate O. Wallace , A. Accorsi, R. Barnes, A. Cacace, D. Cadavid , A. Chang, D. Eyerman, R. Gould, S. Kazmirski, J. Maglio, M. Mellion, P. Rahl, A. Robertson, A. Rojas, L. Ronco, N. Shen, L. Thompson, E. Valentine Fulcrum Therapeutics, Cambridge, USA FSHD is disabling muscular dystrophy characterized by descending progressive skeletal muscle weakness affecting the face, shoulders, arms and trunk, followed by weakness of the distal lower extremities and pelvic girdle. There are currently no approved treatments for the disease. When DUX4, a homeobox transcription factor normally expressed during embryogenesis, is expressed in post-natal skeletal muscle, it results in apoptosis and replacement of the muscle by fat, leading to the clinical manifestation of disease. Using patient-derived myotubes, we employed our target identification strategies to identify p38α MAPK as a tractable target that reduces DUX4 expression. In further preclinical validation experiments using both pharmacological and genetic tools, we observed that target inhibition leads to a reduction of DUX4 mRNA and protein, expression of downstream DUX4 target genes and inhibition of apoptosis of FSHD myotubes. Moreover, reduction of DUX4 expression via p38α inhibition appears to be genotype independent, as observed by a significant effect in both FSHD1 and FSHD2 patient- derived myotubes. RNA-seq profiling indicates a selective effect on the DUX4 transcriptional program without impacting myogenesis. Supported by preclinical data and extensive human experience outside FSHD, we have