S118 Abstracts / Neuromuscular Disorders 29 (2019) S37–S208 continuously regenerate, may contribute to loss of muscle tissue and function. Proteostasis is disrupted in muscle during neuromuscular disease progression and often accompanied by the accumulation of irreversible protein aggregates in the cytoplasm, which are considered cytotoxic. Tar DNA binding Protein 43 (TDP-43), is a common component of these cytotoxic cytoplasmic cellular aggregates, even though TDP-43 is often not mutated. Unexpectedly, we observed cytoplasmic TDP-43 in amyloid assemblies or myo-granules during muscle regeneration following an induced muscle injury in normal mice. Myo-granules appear following an induced injury and dissipate during muscle regeneration. In regenerating muscle, TDP-43 is associated with transcripts encoding sarcomeric structural proteins as well as vasolin containing protein. We propose that cytoplasmic TDP-43-containing assemblies are not cytotoxic but are required for muscle formation, providing protection, transport and localized translation for TDP-43-associated transcripts. The relationship of cytoplasmic TDP-43-containing aggregates in diseased skeletal muscle to myo-granules in normal muscle is not known, however, myo-granules can seed the formation of insoluble amyloid fibrils. Thus, the formation of insoluble cytoplasmic aggregates occurring in progressive neuromuscular diseases may arise from altered myo-granule composition or from aberrant formation or clearance of myo-granules during continuous regeneration occurring in diseased muscle. Determining the relationship between cytotoxic TDP-43-containing cytoplasmic aggregates and myo-granules is essential to better understand disease progression and for the development of new therapies aimed at eliminating or preventing the accumulation of insoluble cytoplasmic aggregates arising during the progression of neuromuscular diseases. http://dx.doi.org/10.1016/j.nmd.2019.06.291 EXTRA-MUSCULAR MANIFESTATIONS IN NMD O.12 Contribution of cardiac defects to spinal muscular atrophy pathology: a human tissue study C. Alves, R. Garner, F. Nery, J. Siranosian, A. Johnstone, K. Swoboda Massachusetts General Hospital, Boston, USA Spinal muscular atrophy (SMA) subjects develop severe muscle weakness as a primary manifestation of motor neuron disease. However, given that SMA patients have decreased survival motor neuron (SMN) protein in peripheral tissues, and the administration of the only approved SMA therapy is limited to central nervous system, systemic abnormalities may require coadjuvant therapies. For instance, structural cardiac defects have been observed in SMA subjects. Here, we investigated heart samples from SMA type 1 infants and children (n = 7) in comparison with age- and sex-matched control subjects (n = 7). Gross examination of heart in our autopsy series revealed collagen accumulation in several specimens. Using RT-qPCR, we found significantly higher mRNA expression of genes commonly upregulated in heart failure patients, including the latent-transforming growth factor betabinding protein 1 (LTBP1; +240%; p = 0.03), hemoglobin subunit alpha 2 (HBA2; +186%; p = 0.02), and heme oxygenase 1 (HMOX1; + 88%; p = 0.04). Moreover, a PCR array revealed multiple differentially expressed genes and molecular pathways associated to cardiovascular disease in the heart of SMA type 1 subjects. From 84 genes tested in this PCR array, 25 genes were differentially expressed in SMA type 1 subjects compared to controls (p < 0.05). These novel data demonstrate that heart from SMA type 1 subjects have a different gene profile. Currently, we are running an unbiased proteomic screening to determine the main pathways affected in the heart of these SMA type 1 subjects. In future experiments, we will use cardiomyocytes derived from induced pluripotent stem cells to investigate the changes observed in the heart and determine whether they are primary consequences of reduced SMN protein or a secondary consequence of muscle atrophy. . http://dx.doi.org/10.1016/j.nmd.2019.06.292 O.13 Nemaline myopathy patients with mutations in KBTBD13 display a cardiac phenotype J. de Winter 1, K. Bouman 2, M. van den Berg 3, J. Strohm 4, J. Jongbloed 3, W. van der Roest 3, J. van Wijngaarden 5, J. Timmermans 2, E. Kamsteeg 2, B. Van Engelen 2, R. Van der Pijl 4, H. Granzier 4, K. van SpaendonckZwarts 6, N. Voermans 2, C. Ottenheijm 7 1 Amsterdam UMC, Location VUmc, 1081 HV, Netherlands; 2 Radboud Univ Medical Centre, Nijmegen, Netherlands; 3 UMC Groningen, Groningen, Netherlands; 4 University of Arizona, Tucson, USA; 5 Deventer Hospital, Deventer, Netherlands; 6 Amsterdam UMC, locatie AMC, Amsterdam, Netherlands; 7 Amsterdam UMC, Location VUmc, Amsterdam, Netherlands Nemaline myopathy due to mutations in KBTBD13 (NEM6) is characterized by mild proximal weakness and a peculiar slowness of muscle relaxation. KBTBD13 is also expressed in cardiac muscle. However, a cardiac phenotype in NEM6 has not been reported yet. A member of a large family with the NEM6 Dutch founder mutation KBTBD13R408C visited our cardiogenetic outpatient clinic because of dilated cardiomyopathy. Hence, we aimed to elucidate the consequences of KBTBD13-mutations on cardiac function. A pedigree was constructed, medical reports on cardiac characteristics were collected and cardiological evaluation (ECG, echocardiography, ultrasound and MRI on indication) was performed. We engineered a Kbtbd13-knockout mouse model and performed echocardiography at rest and during acute stress (i.e. administration of dobutamine) in nine month old mice. Forty-two NEM6 patients harboring the Dutch founder mutation KBTBD13R408C underwent cardiological evaluation. Thirty-seven patients (88%) displayed a cardiac phenotype: eighteen patients revealed (mild) left ventricular dysfunction and twenty-one patients showed rhythm disorders. Recently, two patients with rhythm disorders received an implantable cardioverter-defibrillator (ICD). Pedigree analysis revealed four cases of sudden cardiac death. Functional evaluation by echocardiography revealed that upon dobutamine administration Kbtbd13-knockout mice had a blunted increase in heart rate (P-interaction < 0.01) and fractional shortening (P-interaction < 0.05). No changes in diastolic parameters (i.e. E/A ratio, E/E’ ratio) were observed. Thus Kbtbd13-deficiency causes an impaired response upon acute cardiac stress. On the basis of these findings, we recommend cardiological evaluation of families with a mutation in KBTBD13. The Kbtbd13-knockout mouse model enables us to further decipher the pathomechanism underlying cardiac dysfunction upon Kbtbd13-deficiency. http://dx.doi.org/10.1016/j.nmd.2019.06.293 O.14 B3GNT4 deficiency: a new α-dystroglycanopathy causing late-onset progressive brain atrophy and muscular dystrophy J. Vissing 1, A. Töpf 2, V. Straub 2, T. Krag 3 1 Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; 2 Walton MD Research Ctr, Newcastle, UK; 3 Rigshospitalet, Copenhagen, Denmark Defects of α-dystroglycan glycosylation (dystroglycanopathies) account for 20 disorders presenting with either early onset brain and muscular dystrophy phenotype, or late onset purer muscular dystrophy. Here, we report a new dystroglycanopathy with an atypical phenotype of late-onset,