Kugathasan, Umaiyal;
(2020)
Hereditary Sensory Neuropathy Type I secondary to SPTLC1/2 mutations: pathogenesis to treatment.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Hereditary Sensory Neuropathy Type I (HSN1) secondary to SPTLC1/2 mutations is a rare, slowly progressive sensory-motor neuropathy, leading to profound sensory loss and variable, but often severe, motor deficits. The genes SPTLC1/2 encode for Serine Palmitoyltransferase, an essential enzyme in de-novo sphingolipid biosynthesis. SPTLC1/2 mutations alter its substrate specificity, leading to the synthesis and accumulation of atypical metabolites, 1-deoxysphinigolipids (1-deoxySLs). 1-DeoxySLs have been postulated to be neurotoxic however the underlying pathomechanism has not been elucidated. L-serine oral supplementation is a potential therapeutic candidate but the lack of responsive outcome measures is an obstacle in carrying out a definitive clinical trial. The first objective of this thesis was to determine if 1-deoxySLs are neurotoxic and to investigate the mechanism of their toxicity using two in-vitro neuronal models: 1) mouse primary motor and DRG neurons and 2) human iPSC derived sensory neurons. The second objective was to identify a responsive outcome measure by carrying out a natural history study. 1-deoxySL treatment resulted in dose dependent neurotoxicity in both in-vitro models. Findings in the mouse in-vitro model suggest mitochondrial and ER dysfunction as possible mediators of 1-deoxySL toxicity. Probing further into ER dysfunction using SH-SY5Y cells suggests 1-deoxySLs cause early ER stress leading to the activation of the unfolded protein response. In the HSN1 iPSC derived sensory neurons there was increased production of 1-deoxySLs and early cell loss but no functional or structural ER and mitochondrial defects in these neurons at 5 months. Assessments used in the natural history study included CMT Neuropathy score version 2, nerve conduction studies, quantitative sensory testing, computerised myometry, intra-epidermal nerve fibre density (thigh), MRI determined calf intramuscular fat accumulation, plasma 1-deoxySLs and patient based questionnaires. MRI determined calf muscle fat fraction showed validity and high responsiveness over 12 months and will be useful in HSN1 clinical trials.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Hereditary Sensory Neuropathy Type I secondary to SPTLC1/2 mutations: pathogenesis to treatment |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| Keywords: | Hereditary Sensory Neuropathy, 1-Deoxysphingolipids, MRI fat fraction |
| 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-pp.ucl.ac.uk/id/eprint/10111579 |
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