Introduction: Myasthenia gravis (MG) is an immune-mediated disorder affecting the neuromuscular junction. Weakness of the extraocular muscles (EOMs) occurs frequently in MG and typically responds to immune therapies similarly to the non-ocular muscles. Susceptible individuals with the ophthalmoplegic subphenotype of MG (OP-MG), which occurs almost exclusively in acetylcholine receptor positive MG (AChR-MG), may manifest treatmentresistant extraocular muscle weakness despite the use of standard immune therapies. The pathogenetic mechanisms involved in the development of treatment-resistant ophthalmoplegia in MG are still unknown and no effective treatment currently exists. Aim: To investigate the molecular-genetic pathogenesis of the OP-MG subphenotype. Methods: Triangulation of data from clinical observations, review of MG muscle biopsy histopathology, gene expression studies in OP-MG patient-derived orbital muscles (AChR-MG) and bioenergetic studies in highly specialised perimysial ocular fibroblasts of these OP-MG cases was used to identify the underlying pathogenetic mechanisms of OP-MG and to verify previous hypotheses generated by next generation sequencing studies. Results: Myasthenic ophthalmoparesis may persist despite immune therapies in 40% of cases in the first year of immune treatment. Delay to diagnosis of MG and therefore initiation of treatment (>1 year) was an unfavourable prognostic factor for resolution of ophthalmoparesis and suggested that with prolonged weakness, pathological changes may occur at the level of the muscle. Review of the literature documenting histopathology in MG muscle biopsies showed that neurogenic atrophy and features of mitochondrial stress, which may be secondary consequences of functional denervation and reduced contractility, are frequently observed in MG muscle biopsies and the EOMs may be particularly susceptible, demonstrating features of fatty and fibrocellular replacement of myofibres. Gene expression studies performed in the orbital muscles of OP-MG and non-MG control cases supported the hypotheses of previous unbiased genomic studies showing that genes harbouring OP-MG associated gene variants may be involved in a dysregulated network of genes including genes in pathways involved in atrophy signalling, muscle contractility and mitochondrial homeostasis. Several genes were significantly downregulated in the OP-MG orbital muscles compared with controls. MicroRNAs which are biological regulators of gene expression, were hypothesized to be a potential pathogenetic mechanism causing downregulation of these genes in OP-MG orbital muscles and several microRNAs highly expressed in EOMs were associated with the significantly repressed genes in OP-MG orbital muscle using available data in public microRNA databases. Preliminary dynamic bioenergetic assays in perimysial ocular fibroblasts derived from the EOM myotendons of OP-MG and non-MG control cases suggested that regulation of mitochondrial homeostasis may be altered in the context of MG. Conclusion: Gene expression analyses in patient-derived orbital muscles support the hypotheses of previous genomic studies suggesting that pathogenetic mechanisms involving pathways relating to muscle atrophy, contractility and mitochondrial homeostasis may by triggered in the EOMs in the context of MG. Dysregulation of these pathways is likely to impact EOM regeneration in the context of MG-induced complement-mediated attack as well as contractility in this specialized muscle allotype with a high firing rate. These complex aberrant molecular-genetic interactions may contribute to persistent ophthalmoplegia despite adequate immune therapies in OP-MG cases.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:uct/oai:localhost:11427/38478 |
| Date | 08 September 2023 |
| Creators | Europa, Tarin |
| Contributors | Heckmann, Jeanine, Nel Melissa |
| Publisher | Faculty of Health Sciences, Department of Medicine |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Doctoral Thesis, Doctoral, PhD |
| Format | application/pdf |
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