Rowczenio, DM; (2015) Genetic Analyses and Phenotypic Studies in Hereditary Systemic Amyloidosis and Autoinflammatory Syndromes. Doctoral thesis , UCL (University College London).

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Abstract

Background Amyloidosis is a rare heterogeneous disease in which proteins undergo conformational change and are deposited as amyloid fibrils. Hereditary amyloidosis (HA) is caused by deposition of genetically variant proteins, whereas AA amyloidosis results from abnormally increased synthesis of the plasma protein SAA in response to inflammation. AA amyloidosis has long been recognised as one of the most serious complications of hereditary autoinflammatory diseases (AIDs). Aims To perform molecular investigations in patients with features suggestive of HA and AIDs; to assess genotype-phenotype relationship in these diseases and to create the first online registry for mutations associated with HA. Results Analysis of genes associated with HA resulted in discovery of 13 novel amyloidogenic mutations comprising six in APOA1, six in TTR and one in GSN. Investigations in AIDs identified the following: mosaic mutations in the NLRP3 and TNFRSF1A genes in patients with late onset CAPS and TRAPS; 21 patients with an autosomal dominant form of FMF caused by the MEFV M694del mutation, who were found to share an identical disease haplotype that emerged approximately 550 years ago; and genetic variants in 24 (43%) of 56 patients with AA amyloidosis of undetermined aetiology in whom the AIDs genes were screened speculatively . Conclusions This research into HA and AIDs has enabled a deeper understanding of genotype-phenotype correlations in these very rare diseases, which has proved to be much more varied than previously reported suggesting that other genetic and environmental factors may be involved in their pathogenesis. Discovery of novel gene variants in HA, along with the lack of centralised repository for collecting information on new and known mutations in this disease inspired me to create an online registry, with the aim of making this resource openly accessible to the scientific community. Most importantly, discoveries made in these rare syndromes guided the introduction of very effective treatment, underscoring the value of genetic analysis.

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