Rossor, AM;
(2014)
A Clinical and In Vitro Study of the Distal Hereditary Motor Neuropathies (n/a, , Trans.).
Doctoral thesis , UCL (University College London).
Abstract
The hereditary motor neuropathies (HMN) encompass diseases of motor axons and neurons and range from the progressive, length dependent distal hereditary motor neuropathies (dHMN) to the developmental, non-progressive dominant congenital spinal muscular atrophies (DCSMA). In this Thesis I have investigated the pathomechanisms of HMN and undertaken a natural history study of patients with dHMN. In Chapter 2 I investigated the pathomechanism of dHMN due to homozygous mutations in the heat shock protein HSJ1, using primary motor neurons (MNs) from HSJ1 knockout mice. Using live cell confocal imaging I examined mitochondrial axonal transport and ER calcium levels, but found no evidence of axonal transport deficits or ER stress. In Chapter 3 I examined the pathomechanism of dHMN due to a novel mutation in FBXO38. FBXO38 modulates the transcriptional activity of KLF7; a transcription factor with a role in neuronal development and repair. I therefore examined neurite outgrowth in lentivirus-infected primary MNs and demonstrated a reduction in neurite outgrowth in mutant FBXO38 infected MNs. In Chapter 4, I identified a mutation in a new disease gene, BICD2, in a family with a form of DCSMA termed lower extremity dominant SMA. BICD2 is a dynein adaptor protein and using immunoprecipitation I found that two disease mutations in BICD2 increase dynein binding affinity. In Chapter 5, I performed a genetic study of the HMNs and showed that mutations in HSPB1 are the most common cause of dHMN. I also evaluated plasma neurofilament heavy chain (NFH) as a biomarker of disease activity in the inherited neuropathies but was unable to detect a difference between patients and healthy volunteers. This would suggest that plasma NFH levels are not a suitable biomarker of disease activity in the inherited neuropathies.
| Type: | Thesis (Doctoral) |
|---|---|
| Title: | A Clinical and In Vitro Study of the Distal Hereditary Motor Neuropathies |
| Language: | English |
| Additional information: | Permission for digitisation not received. |
| Keywords: | peripheral neuropathy |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1426967 |
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