UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Understanding the phenotype and preparing for therapeutics in Bardet-Biedl syndrome

Forsythe, Elizabeth; (2019) Understanding the phenotype and preparing for therapeutics in Bardet-Biedl syndrome. Doctoral thesis (Ph.D), UCL (University College London). Green open access

[thumbnail of Forsythe_10081917_Thesis_redacted.pdf]
Preview
Text
Forsythe_10081917_Thesis_redacted.pdf

Download (4MB) | Preview

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.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Understanding the phenotype and preparing for therapeutics in Bardet-Biedl syndrome
Event: UCL (University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. 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.
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 Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10081917
Downloads since deposit
53Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item