The clinical characterisation and genetic epidemiology of familial ALS in Ireland

THESIS 10220The overall objective of this thesis is to collate the existing literature on familial ALS and to address shortcomings in the research, to investigate aggregation of ALS and other conditions among relatives of patients with ALS, to characterise the C9orf72 phenotype, and to identify possible candidates for future genetic studies. This is done through a comprehensive epidemiological characterisation of the Irish ALS population with a particular focus on familial ALS, and through a detailed family aggregation study of ALS patients and their relatives. The Irish ALS register is used to characterise the Irish ALS population with the aim of identifying subgroups of patients with familial disease who may share individual genes. A detailed chapter describes the phenotype associated with the C9orf72 repeat expansion. Results from this thesis include estimation of the rate of FALS; through a systematic review and meta-analysis, the population-based rate is estimated to be 5.1%, however this is subsequently refuted by the findings from the family aggregation study, containing almost 10,000 relatives of ALS patients and controls, which demonstrates that the rate of familial ALS is closer to 16%. Assessment of the risk of developing ALS estimates that relatives of ALS patients with the C9orf72 repeat expansion have a HR of 34, and relatives of ALS patients without the C9orf72 repeat expansion have a HR of 2, compared to relatives of controls.The aggregation of schizophrenia and suicide is also elevated in the relatives of ALS patients compared to relatives of controls. In the final section, findings generated from this thesis are used to propose future research projects, and candidates for future genetic studies are considered