Investigating the pathological mechanism of neuropathy in POEMS syndrome

POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, Skin disorder) is a rare disease characterised by an inflammatory polyneuropathy an a monoclonal plasma cell dyscrasia. POEMS syndrome causes some of the most significant disability and mortality of any inflammatory neuropathy. The pathophysiology is unknown but recognised to be cytokine mediated, notably driven by vascular endothelial growth factor, however little is known about the other mediators at play. This thesis collates clinical data from the largest POEMS cohorti in Europe in order to study the characteristic disease features, optimise therapies and identify factors that influence outcome. Utilising our POEMS sample biobank, we carry out highly sensitive immunoassays to study the cytokines released in POEMS syndrome, and whether they correlate with disease activity. We go on to study the proteome of POEMS syndrome through mass spectrometry, to uncover the biological pathway involved and identify a number of novel, potentially pathogenic molecules. Fluid biomarkers of neuropathy in POEMS syndrome and related neuropathies are additionally explored. The development and optimisation of a homebrew immunoassay for peripherin, a peripheral nerve specific biomarker is detailed. The potential clinical utility of this biomarker is compared against that of serum neurofilament light. Finally, we attempt to model the neuropathogenesis of POEMS neuropathy in vitro using a novel human induced pleuripotent stem cell derived neuronal culture system