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Title: Hereditary Sensory Neuropathy Type I secondary to SPTLC1/2 mutations : pathogenesis to treatment
Author: Kugathasan, Umaiyal
ISNI:       0000 0004 9359 867X
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available