Abstracts / Neuromuscular Disorders 29 (2019) S37–S208 S79 Indeed specific muscle isoforms are expressed during muscle maturation and in adulthood, through alternative splicing. A single intraperitoneal injection of 25mg/kg of antisense oligonucleotides targeting the total pool of Dnm2 increased the lifespan, whole body strength, and reduced disease severity in Mtm1KO mice, however a single injection alone was not sufficient to rescue the disease for the lifespan of the mice. Repeated injections of ASO was able to revert the disease phenotype in mice within 2 weeks, and the effects lasted several months after the final injection. ASO was still detected in skeletal muscles at this time point, but not in key tissues such as the liver, which may explain in part the longterm improvement in the myopathic phenotype. New ligand-conjugated antisense (LICA) oligonucleotides targeting Dnm2 are now being tested in Mtm1KO mice for potency and efficacy. ASO-mediated Dnm2 knockdown can efficiently correct skeletal muscle defects due to loss of MTM1, providing an attractive therapeutic strategy for this disease. Effective muscle targeting will be an important step in translation of this approach to the clinic for patients. http://dx.doi.org/10.1016/j.nmd.2019.06.160 P.105 INCEPTUS pre-phase 1, prospective, non-interventional, natural history run-in study to evaluate subjects aged 4 years and younger with X-linked myotubular myopathy (XLMTM) L. Servais 1 , P. Shieh 2 , J. Dowling 3 , N. Kuntz 4 , W. Müller-Felber 5 , B. Smith 6 , C. Bönnemann 7 , F. Muntoni 8 , D. Bilder 9 , T. Duong 10 , R. Graham 11 , M. Jain 12 , M. Lawlor 13 , V. MacBean 14 , M. Noursalehi 15 , T. Pitts 16 , G. Rafferty 17 , S. Rico 15 , S. Prasad 15 1 Hôpital Armand Trousseau, Paris, France; 2 University of California, Los Angeles, USA; 3 Hospital for Sick Children, Toronto, Canada; 4 Lurie Children’s Hospital, Chicago, USA; 5 Klinikum der Universität, Munich, Germany; 6 University of Florida, Gainesville, USA; 7 NIH Porter Neuroscience RC, Bethesda, USA; 8 Great Ormond Street Hospital, London, UK; 9 University of Utah, Salt Lake City, USA; 10 Stanford University, Palo Alto, USA; 11 Children’s Hospital, Boston, USA; 12 NIH Hatfield Clinical RC, Bethesda, USA; 13 Medical College of Wisconsin, Milwaukee, USA; 14 Brunel University London, London, UK; 15 Audentes Therapeutics, San Francisco, USA; 16 University of Louisville, Louisville, USA; 17 King’s College London, London, UK XLMTM is a rare disease caused by mutations in the MTM1 gene, leading to profound muscle weakness, respiratory failure and early death. INCEPTUS (NCT02704273) is a prospective, non-interventional study in patients (pts) ≤4 years old to characterize the course and natural history of XLMTM using neuromuscular and respiratory assessments and to identify adverse events (AEs). INCEPTUS will generate within-pt control data to support a Phase 1/2 gene therapy clinical trial (ASPIRO). As of 22MAR19, 32 male pts (0.3-4.6 years of age) have been enrolled and assessed every 3 months for up to 24 months. There were 3 deaths and 61 serious AEs, mainly due to respiratory tract infections. neuromuscular function is severely compromised. Children’s Hospital of Philadelphia Infant test of neuromuscular disorders (CHOP INTEND) was performed in all pts. Mean CHOP INTEND scores show a 2.7-point annual decline from baseline (mean [SD, min-max]= 33.3 [8.1, 17-52]) to month 12 (30.6 [5.8, 19-40]). A healthy pt may score a maximum of 64 points. Developmental milestones (per Bayley-III scales) were evaluated if pts scored >45 points on the CHOP INTEND or if they were able to sit. In INCEPTUS, 27 pts (87%) have no or very poor head control, a motor milestone typically reached by 4 months of age in healthy pts. Similarly, while healthy pts can roll by 5 months, none of the INCEPTUS pts achieved this milestone. Only 3 pts (9%) in INCEPTUS were able to sit without assistance >30 seconds. Most pts (n=24, 75%) require invasive ventilatory support; 21 pts for 24h/day. Respiratory muscle strength measured as maximum inspiratory pressure (MIP, cmH2O) is very low at baseline (34.5 [12.2, 17.6-64.5]) and declines by 6.3 cmH2O over 12 months’ follow-up (28.3 [7.9, 15.1-41.4]). INCEPTUS prospectively demonstrates that neuromuscular and respiratory functions are severely impaired and slowly worsen over time in pts ≤4 years old, reinforcing that XLMTM is a severe, life-threatening childhood disorder. http://dx.doi.org/10.1016/j.nmd.2019.06.161 P.106 Mutation-specific therapy for X-linked myotubular myopathy S. Hayashi 1 , S. Noguchi 1 , T. Kumutpongpanich 1 , A. Iida 1 , M. Okubo 1 , M. Matsuo 2 , I. Nishino 1 1 NCNP, Tokyo, Japan; 2 Kobe Gakuin University, Kobe, Japan X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy due to mutations in MTM1 encoding a 3-phosphoinositides phosphatase myotubularin. XLMTM patients display severe generalized hypotonia at birth accompanied by respiratory insufficiency and pathologically show small-size fibers with peripheral halo, centrally located nuclei, disorganized perinuclear organelles in the muscle. Among 78 patients with pathologically diagnosed as XLMTM in our cohort, causative mutations were not identified in 20 cases by targeted re-sequencing panel for congenital myopathy, MTM1 Sanger sequencing nor Whole-exome sequencing. In order to validate deep intronic mutations and aberrant splicing events, we performed RNA-seq analysis on 14 cases who had unreported variants or no-mutations in exonic regions of MTM1. Sashimi plot revealed retentions of intronic sequence in patient1 (between exon 5 and 6) and patient 2 (between exon 11 and 12), respectively. In patient 3, exon 4 skipping was observed due to a synonymous mutation in exon 4. These aberrant splicing were predicted to cause frameshift and subsequently create premature stop codon in these patients. The in vitro splicing experiments with artificial hybrid minigene constructs confirmed those mutations exclusively produced abnormal splicing products. Lastly, Myoblasts from patient 2 showed perinuclear distribution of mitochondria in addition to the abnormal splicing, and treatment with antisense morpholino oligonucleotides rescued those phenotypes. In conclusion, RNA-seq analysis can uncover deep intronic mutations and synonymous mutations which lead abnormal splicing events as the cause of muscle diseases such as XLMTM. We propose that antisense therapy is potentially practical for diseases arising from this type of mutation. http://dx.doi.org/10.1016/j.nmd.2019.06.162 P.107 Clinical changes over time in patients with centronuclear myopathy due to mutations in DNM2 gene enrolled in a European prospective natural history study M. Annoussamy 1 , J. Baets 2 , W. De Ridder 2 , D. Duchêne 1 , A. Grangé 1 , C. Lilien 1 , V. Chê 1 , T. Gidaro 1 , A. Seferian 1 , A. Behin 3 , N. Voermans 4 , M. Bitoun 5 , J. Hogrel 1 , C. Freitag 6 , K. Paradis 6 , L. Thielemans 6 , S. Van Rooijen 6 , L. Servais 1 1 Institute of Myology, Paris, France; 2 Antwerp University Hospital, Antwerpen, Belgium; 3 APHP- GH Pitié-Salpétrière, Paris, France; 4 Radboud Univ Medical Center, Nijmegen, Netherlands; 5 Sorbonne Univ, INSERM, AIM, Paris, France; 6 Dynacure, Ilkirch-Graffenstaden, France Centronuclear myopathy (CNM) is an inherited neuromuscular disorder characterized by the presence of hypotrophic myofibers with centrally placed nuclei on muscle biopsies. CNM exists in 3 forms: i) X-linked recessive caused by mutations in the MTM gene encoding for the myotubularin protein (OMIM 310400), ii) autosomal dominant caused by mutations in the DNM2 gene encoding for the dynamin 2 protein (OMIM 160150) and iii) autosomal recessive form due to mutations in the BIN1 gene encoding for the amphyphysin 2 protein (OMIM 255200). The classic form of dominant CNM due to DNM2 mutations has been described as following a mild clinical course with the onset in adolescence and a slow progression. Nevertheless, the form with muscle hypertrophy may be present at a younger age and has