Characterization of genetic markers for sporadic amyotrophic lateral sclerosis

Frances Theunissen

Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease, is a devastating and fatal neurodegenerative condition. ALS is a heterogeneous disease with variable symptom presentation between patients. It is characterized by progressive motor deficits that occur over weeks or months, affecting most voluntary muscles in the body. The heterogeneous clinical presentation and diverse speed of progression makes this disease challenging to diagnose. Currently, there is no effective treatment for ALS and at present there are no methods to determine which patients are more likely to respond to novel or existing ALS therapeutics (riluzole, edaravone and recently approved relyvrio). Over the past 20 years, more than 70 controlled trials of putative ALS therapeutics have failed to demonstrate clinical efficacy for ALS. This high failure rate is likely the result of the heterogenous nature of ALS, and a lack of understanding the patho-genetic mechanism(s) that drive disease. Therefore, there is an urgent need to characterize novel genetic loci that may underpin risk of disease or be linked to ALS disease modification. The aim of this thesis is to investigate if novel genetic markers can offer insight into disease mechanisms for sporadic ALS (sALS). This thesis focuses on candidate genes involved in cytoskeletal integrity, which are known to be disrupted in ALS pathophysiology. These genetic markers will help to understand the involvement of cytoskeletal genes in sALS and focus future studies on genetic mechanisms that may contribute to axonal dysfunction. Each candidate gene (NEFH, STMN2 and KIF5A) was screened using a short structural variant selection algorithm to identify variable candidate genetic loci. Candidate structural variants were subsequently investigated in case-control association studies using multiple sALS cohorts. This was to determine each variants potential contribution to sALS disease risk or influence on ALS phenotype, including age of onset, site of onset, survival time and disease progression. Firstly, we report an intronic tetranucleotide (TTTA) variant in NEFH that may have a protective advantage for lowering the risk of sALS and delaying the age of disease onset. Secondly, we report the first genetic association between STMN2 and sALS, with the intronic dinucleotide (CA) variant also having disease modifying effects including, earlier age of disease onset, reduced survival in bulbar onset patients and faster disease progression. Finally, we report a novel intronic dinucleotide (TC) variant in KIF5A that can stratify disease progression and survival of spinal onset sALS patients. While validation in additional patient cohorts in needed, the novel genetic markers explored in this thesis provides the initial characterization of novel loci that may help to sub-phenotype sALS patients. These genetic markers may be useful tools in future clinical trials with the potential to stratify patient response or be used as a tool to enrich patient populations for individuals more likely to respond to novel ALS therapies. With the urgent need to improve the success rate of ALS clinical trials, this thesis provides the first step towards identifying novel genetic markers with clinical utility.

Characterization of genetic markers for sporadic amyotrophic lateral sclerosis

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