Oral Health in Hereditary Gelsolin Amyloidosis

Hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomally dominantly inherited disease, mostly found in Finland, but also with worldwide distribution. Its most characteristic clinical signs are corneal lattice dystrophy, polyneuropathy, and cutis laxa, which after onset in the thirties to forties slowly progress. AGel amyloidosis is caused by a point mutation c.640G>A/T, formerly known as c.654G>A/T, in the gene coding for both cytosolic and secretory gelsolin. Cytosolic gelsolin has many roles in cellular activities. Most importantly, it modulates actin formation and participates in cell shape alterations, motility, phagocytosis, and other functions. The c.640G>A/T gene defect causes abnormal cleavage of gelsolin and eventually leads to accumulation of aberrant secretory gelsolin as amyloid fibrils. The systemic nature of this disease has been considered to result mainly from amyloid deposits accumulating in many tissues of AGel amyloidosis patients, but the pathogenesis of the disease is not yet fully understood. Patients with AGel amyloidosis reported to their physician oral problems such as sense of dry mouth and loose or cracked teeth. This information served as a starting point for this study in which we elucidated the impact of this systemic disease on oral condition, including salivary function and periodontal health. Further, oral fibroblasts and vascular smooth muscle cells were examined in vitro to clarify whether mutated cytosolic gelsolin affects their function, thus ccontributing to the pathogenesis of AGel amyloidosis in general and/or in relation to periodontal health. Patients were invited to the study through their patient organization and forty patients volunteered. We found that patients frequently exhibit subjective mouth dryness, i.e. xerostomia, and also decreased saliva secretion, i.e. hyposalivation. The saliva composition was also altered. Especially, secretion rate of salivary IgA was decreased, further increasing the risk for oral diseases such as oral candidiasis and caries. Histopathological analyses in minor labial salivary gland (LSG) biopsies showed gelsolin amyloid deposits, as well as atrophy of the glands, and minor inflammation. These novel histopathological LSG findings could explain at least partly the alterations in saliva secretion and composition. In one case sicca symptoms (dry eyes and mouth, i.e. xerophthalmia and xerostomia, respectively) and LSG findings had misled to the diagnosis of Sjögren’s syndrome, which was later substituted with an AGel amyloidosis diagnosis. According to this study, AGel amyloidosis, on average, does not present a generally increased risk for periodontitis. However, some patients presented a high rate of disease progression, indicating that AGel amyloidosis might in some cases be associated with periodontal problems. Because both AGel amyloidosis and periodontitis progress with age, this association appears to be more common in older patients, who had lost especially their molar teeth quite commonly. In general, however, non-specific oral microbiota and common periodontal status prevail in this disease. In vitro cell studies showed that oral fibroblasts and vascular smooth muscle cells of heterozygote AGel amyloidosis patients had similar actin cytoskeleton morphology and cytosolic gelsolin distribution, migration rate, and collagen type I metabolism as control cells. Only the reaction to staurosporine, an inhibitor of protein kinases, induced minor differences in the shape change rate between the patient and control oral fibroblasts. The altered reaction of oral fibroblasts of the patients to staurosporine should be further evaluated. These results suggest that the patient oral fibroblasts and vascular smooth muscle cells mainly function normally in vitro and may not, at least via cytosolic gelsolin-associated dysfunction, contribute to the pathogenesis of AGel amyloidosis. Thus, patients with AGel amyloidosis due to their systemic disease have greater risk for oral diseases and benefit from preventive oral hygiene procedures, such as diet advice, extra fluoride, lubricants, and regular dental check-ups.