Exploring neurodegeneration in Ataxia-Telangiectasia

Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive DNA repair disorder. The condition is characterised by a progressive neurodegenerative disorder. Cancer predisposition, immunodeficiency and respiratory disease can result in premature death. The life expectancy of a patient with A-T is 30 years old. The phenotype is highly heterogeneous when partially functioning ATM protein and kinase are present. The exact mechanism for disease causation and associated phenotype is unclear. It is also unknown why the cerebellum is so vulnerable in this condition. There are increasing reports of the association of mitochondrial dysfunction in A-T but how this is associated with DNA repair is unknown. The current lack of precise disease phenotyping, and metabolic and imaging biomarkers limits the progress of developing curative treatments and successful clinical trials for this disease. This study focuses on trial readiness and exploring the neurodegenerative process in A-T. I have focused on the development of a longitudinal study to effectively study the natural history of A-T and evaluated white matter hyperintensities, cerebral microbleeds and cognitive phenotype in adult A-T patients. I have also evaluated potential MRI and serum biomarkers. Finally, I have explored mitochondrial dysfunction and response to mitochondrial DNA depletion in human A-T fibroblasts. In this study, I have identified a cerebellar cognitive affective syndrome in A-T patients with executive and motor language dysfunction. Serum fibroblast growth factor 21 and dentate nuclei hypointensity could serve as potential molecular and imaging biomarkers. Finally, I have found a potential association of A-T with mitochondrial respiratory chain dysfunction and alterations of mitochondrial DNA replication.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Tiet, May Yung

Advisor dc:contributor.advisor

• Hovarth, Rita

• Ataxia Telangiectasia

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/a78d99e8-d998-47d3-883f-6002363bd42d/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.112012

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/373678