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Publicatie

Tackling etiologically unsolved progressive muscle disorders

Boek - Dissertatie

Ondertitel:from rare inherited myopathies to sporadic inclusion body myositis
Primary muscle disorders comprise a large group of inherited and acquired diseases that affect muscle structure, metabolism, or the function of muscle ion channels. Muscle disorders presenting with slowly progressive muscle weakness constitute a group of disorders eminently suited for a multi-level pattern recognition approach, clinically as well as biologically. Given that only very few acquired muscle disorders present with slowly progressive muscular weakness, an inherited muscle disorder (IMD) is typically suspected in case of this clinical presentation. IMD constitute a clinically, genetically and histopathologically very heterogeneous group of rare diseases with more than 160 genetically distinct entities identified, rendering the diagnostic process complex. Sporadic inclusion body myositis (sIBM) constitutes a very relevant, clinically recognizable differential diagnosis in patients over 50 years of age. A few other atypically presenting acquired muscle disorders might also present slowly progressive muscle weakness, particularly idiopathic inflammatory myopathies (IIM) with anti-HMGCR antibodies and the enigmatic, supposedly very rare, putatively immune-mediated acquired myopathy, called sporadic late-onset nemaline myopathy (SLONM). The ultimate aim of this PhD thesis was to gain insights in pathomechanisms of both inherited and acquired muscle disorders, clinically characterized by slowly progressive muscle weakness and biologically ultimately by muscle degeneration. In this thesis I particularly capitalized on ongoing revolutions in 1) genetics of IMD to identify patients with very rare IMD and to study genotype-phenotype correlations and disease mechanisms of these disorders; 2) proteomic studies of muscle, allowing an unbiased dissection of disease signatures in both acquired and inherited muscle disorders. This resulted in: 1) the identification of patients with rare IMD due to mutations in TRIM32, BVES, VCP and other (novel) genes, and the further unraveling of pathomechanisms of these disorders; 2) unprecedented insights in the muscle proteome and disease patterns of sIBM and VCP-related myopathy. Furthermore, we highlight the unexpectedly high prevalence of patients with slowly progressing SLONM in whole exome sequencing unsolved suspected IMD patient cohorts. This PhD thesis nicely illustrates the relevance of studying both inherited and acquired muscle disorders characterized by slowly progressive muscular weakness. We are on the verge of fascinating and exciting times in myology research and clinical myology. Diagnosing patients with rare IMD and dissecting disease mechanisms of muscle disorders will remain highly relevant with regard to rapid translation of therapies to the clinics.
Aantal pagina's: 199
Jaar van publicatie:2020
Trefwoorden:Doctoral thesis
Toegankelijkheid:Open