Abstract
The aim of this thesis was to test the hypothesis that there are genetic risk factors other than mutations in the Cu/Zn superoxide dismutase gene which can lead to ALS or modify phenotype, in sporadic and familial disease, in a population which was well defined clinically.Amyotrophic lateral sclerosis (ALS) a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within three to five years. About 5-10% of cases are familial, usually with a history suggesting autosomal dominant inheritance, and about 20% of these cases and 2% of sporadic cases have mutations in the gene for Cu/Zn superoxide dismutase, SOD1. For the remaining 98% of patients, genetic risk factors, if any, have been difficult to determine. Clinical and genetic data on 452 patients with ALS attending a specialist clinic were collected and a statistical analysis performed to determine the clinical factors affecting prognosis and phenotype. Genes identified as being likely to be involved in ALS were studied within this defined population, specifically, the genes for apolipoprotein E, neurofilament H and Cu/Zn superoxide dismutase. The apolipoprotein (APOE) ε4 allele was shown to be significantly associated with bulbar onset ALS, with a trend to worsening survival. Four new mutations associated with ALS were identified in the heavy neurofilament subunit (NFH) tail. There was evidence of a protective genetic factor tightly linked to the SOD1 locus in families with the Asp90Ala mutation who share a common founder about 43 generations ago. These findings indicate that there are genetic risk factors other than mutations in the Cu/Zn superoxide dismutase gene which can lead to ALS or modify phenotype, in sporadic and familial disease.
| Date of Award | 1999 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Nigel Leigh (Supervisor) & John Powell (Supervisor) |