Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.791023
Title: Understanding the phenotype and preparing for therapeutics in Bardet-Biedl syndrome
Author: Forsythe, Elizabeth
ISNI:       0000 0004 8500 5037
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2019
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Abstract:
Bardet-Biedl syndrome (BBS) is a rare pleiotropic ciliopathy characterised by rod-cone dystrophy, renal dysplasia, obesity, polydactyly, intellectual disability and hypogenitalism. This thesis explores the phenotype, natural history and therapeutic potential of BBS through the priorities of those who understand it best: the patients and carers. The UK national BBS clinics provide the largest reported number of patients with BBS worldwide. I utilised this cohort to explore kidney disease, visual decline, obesity, morbidity and mortality in BBS as well as potential for testing pharmacological and lifestyle interventions. I discovered that although renal dysplasia is common in this patient population, end stage renal failure occurs infrequently, usually in early childhood, and is almost unheard of in patients with the common BBS1 p.Met390Arg mutation. Visual decline is genotype and mutation type dependent and patients with BBS1 p.Met390Arg typically develop visual deterioration at a later age than other patients and progress more slowly. Although most patients with BBS experience severe obesity and elevated cardiometabolic risk, those carrying BBS1 p.Met390Arg mutations remain at lower risk. The number of attendances at the paediatric national BBS clinics correlate positively with reduction in standardised body mass index (BMI-SDS). In keeping with the hypomorphic p.Met390Arg clinical phenotype, exploration of the cellular phenotype revealed that fibroblasts from patients with BBS1 mutations had a hypomorphic proliferation phenotype similar to control cells. As a stepping stone to therapies, I demonstrate the effect of an exercise intervention on cognition and hippocampal neuroplasticity in BBS. Despite starting with a genetically pre-determined hippocampal volume deficit, it is possible to generate a hippocampal volume increase through physical activity. My findings serve to highlight the clinical and cellular hypomorphic phenotype associated with the common BBS1 p.Met390Arg mutation, the natural history of BBS as well as the potential effects of lifestyle intervention. Although our understanding of this highly complex condition remains imperfect, I hope this work will help move BBS to the forefront for rare disease therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.791023  DOI: Not available
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