Congenital myopathies: Puzzling it out

Congenital myopathies (CMs) conform a large group of heterogeneous NMD with an ever-growing genotypic-phenotypic spectrum. CMs are caused by variants in at least 27 genes that code mostly for muscle proteins. The prevalence of CMs is 1.5 per 100,000, while the prevalence in the child population is higher. CMs are characterized at a clinical level by neonatal onset with severe hypotonia, muscle weakness and developmental delay. However, recent advances in diagnostic techniques have expanded the CM phenotypic spectrum and many forms of late onset CMs have been identified. They are often considered milder with slower progression, variable clinical presentations and different modes of inheritance. The underlying pathomechanism of how variants in sarcomeric, is still unravelling, and to date, no therapies are available for CMs. This thesis sheds light on two main topics: 1) Unravelling function of sarcomeric proteins in disease, and 2) therapeutic intervention in different types of congenital myopathies. In this thesis I show that variants in sarcomeric genes result in highly heterogeneous pathological phenotypes with different levels of muscle involvement observed in mouse models but also in human skeletal muscle fibers. I show that variants in sarcomeric genes alpha skeletal actin (acta1), slow skeletal muscle myosin binding protein c (mybpc1) and kelch and BTB-domain containing protein 13 (kbtbd13) significantly affect normal muscle function. In this thesis, I show that the use of small molecules that activate or inhibit sarcomere function can be used to improve sarcomere function in skeletal muscles of an animal model and human muscle fibers harboring variants in acta1 and mybpc1, respectively. Furthermore, A main focus of this thesis was to develop a gene therapy approach to prevent and revert phenotype development in a rare type of nemaline myopathy, i.e. nemaline myopathy type 6 due to a Dutch founder variant in kbtbd13. The exciting findings of this project highlight the promise of using viral vectors to deliver genome modulation or genome correction tools that can potentially improve the quality of life of affected individuals. Altogether, this thesis contributes to the field of therapy in CMs. The development of novel small molecules that improve sarcomere function and recent advances in delivery methods such as myotropic AAVs and gene editing tools, have opened a bright future in the field of therapeutic treatments for rare muscle disorde