Multifocal motor neuropathy: Clinical, genetic, and immunological studies

Abstract

Multifocal motor neuropathy (MMN) is a very rare inflammatory neuropathy that leads to muscle weakness in mainly the hands and feet. IgM antibodies directed against the ganglioside GM1 can be found in at least 50% of patients with MMN, which upon binding to neurons activate the classical pathway of the complement cascade, leading to motor neuron damage. MMN is treatable with intravenous immunoglobulins (IVIg), but its efficacy is usually partial, and many patients will follow a steadily progressive disease course. Therefore, identifying new and more effective treatment strategies for patients with MMN remains important. To achieve this, we need to improve our detailed understanding of the immunopathology underlying MMN. In this thesis, we performed clinical, genetic, and immunological studies in MMN. We showed that despite treatment with IVIg, deterioration of muscle weakness over time is the rule rather than the exception, and identified factors associated with worse disease outcome. Next, we found that MMN is associated with two HLA class II genotypes, and with a polymorphism in the promotor region of the complement regulator CD55, demonstrating genetic susceptibility underlying MMN. We demonstrated that, next to anti-GM1 IgM antibodies, anti-GM2 IgM antibodies are found in a subgroup of patients, extending the repertoire of antibodies associated with MMN. These antibodies specifically bind to Schwann cells, also activate complement, and are associated with an earlier onset of muscle weakness. Finally, we found that MMN is associated with an altered composition of bacteria that constitute the gut microbiome, and found certain alterations to be specifically associated with anti-GM1 IgM antibodies. Together, the studies in this thesis significantly improve our understanding of the immunopathogenesis of MMN, which may hopefully form a basis for the development of novel treatment strategies.