AGel amyloidosis: Genetic background and natural history

Eeva-Kaisa Schmidt

Tutkimustuotos: OpinnäyteVäitöskirjaArtikkelikokoelma


Amyloidosis is a disease that results from systemic or localised deposition of amyloid fibrils in organs and tissues causing disruption to their normal function. Gelsolin (AGel) amyloidosis is a monogenic, autosomal dominantly inherited disorder that was described for the first time by the Finnish ophthalmologist Jouko Meretoja in 1969 (Meretoja, 1969). Most AGel amyloidosis patients have been reported in Finland. To date, four different gelsolin gene variants have been associated with amyloidosis, c.640G > A being the most common and the only so far reported mutation in Finland. The characteristic triad of progressive ophthalmological, neurological and dermatological manifestations is known to be frequent in AGel amyloidosis patients. The purpose of this study was to investigate and broaden the knowledge on the genetic background and natural course of AGel amyloidosis. Firstly, we aimed to identify Finnish AGel amyloidosis patients and families, and to create a national patient registry of Finnish AGel amyloidosis patients. Based on information from the patient registry, we wanted to describe and verify the characteristic natural course of AGel amyloidosis in a representative patient group. Through conducting a haplotype analysis, we aimed to answer the question of whether all the Finnish AGel amyloidosis patients share the same gelsolin gene variant associated haplotype and thus possibly have a common ancestor. We pursued investigating the severity and frequency of pathological inner organ, especially cardiac, involvement in AGel amyloidosis. A further goal of this study was to recognise the causes of death of AGel amyloidosis patients, compare them with those of the normal Finnish population, and increase understanding of the disease’s influence on patients’ lifespan. As part of this study, we founded and later updated the National Finnish Gelsolin Amyloidosis Patient Registry (FIN-GAR). In the first phase, a total of 227 AGel amyloidosis patients were included in the FIN-GAR registry, and five years later the registry was updated to include 261 patients, that is approximately 25-40% of all Finnish patients. Based on the FIN-GAR registry and genealogical study, we identified 62 Finnish AGel amyloidosis families and conducted a haplotype analysis. Further, we collected and systematically analysed autopsy reports and tissue samples of 25 deceased patients to better understand the inner organ involvement of the disease. Finally, we collected the death certificates of 272 deceased patients and investigated their causes of death. The life span of the patients was calculated both based on the data from the death certificates and utilising the relative-survival method. The study confirmed that the 62 studied Finnish AGel amyloidosis families share a gelsolin gene variant c.640G > A associated haplotype that is not otherwise common in the Finnish population, implicating that all the Finnish patients are likely to descend from a common ancestor. The natural course of AGel amyloidosis was fortified and it was shown that the prevalence of a variety of symptoms belonging to the characteristic triad of ophthalmological, dermatological and neurological symptoms is high. A significant portion of patients need repeated plastic surgery as symptomatic treatment, and the incidence of cataract and carpal tunnel syndrome operations is high. Amyloid deposits in the myocardium and cardiac blood vessels are common in middle-aged and elderly patients, possibly leading to clinical cardiac manifestations. As it is a systemic disease, amyloid deposits are also frequently found in the kidneys, lungs, thyroid gland, liver, spleen and pancreas. AGel amyloidosis was demonstrated to be the underlying cause of death in 20% of the patients, underlining the severity of the disease. Renal diseases may prove lethal, even in heterozygotes, even though renal manifestations are usually mild. Interestingly, for an unknown reason, malignancies were significantly less common as causes of death in AGel amyloidosis patients than in the general Finnish population. Even though the disease burden, visible in the high prevalence of diverse symptoms and high number of operations, is significant, the life span is comparable with that of the normal population, and patients do not seem to retire earlier than the general population.
  • Atula, Sari, Valvoja
  • Kiuru-Enari, Sari Maaret Kristiina, Valvoja
Painoksen ISBN978-951-51-6179-6
Sähköinen ISBN978-951-51-6180-2
TilaJulkaistu - 2020
OKM-julkaisutyyppiG5 Tohtorinväitöskirja (artikkeli)


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