Meretojan taudista uutta tietoa kansallisen potilasrekisterin avulla

Tiedot Meretojan taudin eli suomalaisen perinnöllisen gelsoliiniamyloidoosin taudinkulusta ovat tähän saakka perustuneet suhteellisen pieniin potilassarjoihin. Uuden kansallisen FIN-GAR-potilasrekisterin avulla voidaan paremmin kartoittaa taudin oireita ja niiden yleisyyttä sekä sen luonnollista kulkua. Potilasrekisteriin on tähän mennessä kerätty tiedot 235 potilaasta, ja siihen toivotaan edelleen täydennystä. Rekisterin mukaan ensioireet alkavat yleensä silmistä. Taudin ensisijainen diagnostinen löydös on potilaalle tyypillisesti jo 20–30-vuotiaana kehittyvä sarveiskalvon verkkomainen rappeuma. Muut oireet ja löydökset kehittyvät suurin piirtein samanaikaisesti, mediaanien osuessa 50 ja 60 ikävuoden välille. Naisilla oireet kehittyvät keskimäärin aiemmin ja erityisesti silmäoireet ovat yleisempiä kuin miehillä. Rannekanavaoireyhtymä, sydämentahdistin ja munuaisensiirrot ovat rekisterin potilailla huomattavasti yleisempiä kuin normaaliväestössä. Näiden tarkkaa patologista yhteyttä Meretojan tautiin tutkitaan ­parhaillaan.Peer reviewe

Common origin of the gelsolin gene variant in 62 Finnish AGel amyloidosis families

Finnish gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominantly inherited systemic disorder with ophthalmologic, neurologic and dermatologic symptoms. Only the gelsolin (GSN) c.640G>A variant has been found in the Finnish patients thus far. The purpose of this study was to examine whether the Finnish patients have a common ancestor or whether multiple mutation events have occurred at c.640G, which is a known mutational hot spot. A total of 79 Finnish AGel amyloidosis families including 707 patients were first discovered by means of patient interviews, genealogic studies and civil and parish registers. From each family 1-2 index patients were chosen. Blood samples were available from 71 index patients representing 64 families. After quality control, SNP array genotype data were available from 68 patients from 62 nuclear families. All the index patients had the same c.640G>A variant (rs121909715). Genotyping was performed using the Illumina CoreExome SNP array. The homozygosity haplotype method was used to analyse shared haplotypes. Haplotype analysis identified a shared haplotype, common to all studied patients. This shared haplotype included 17 markers and was 361 kb in length (GRCh37 coordinates 9:124003326–124364349) and this level of haplotype sharing was found to occur highly unlikely by chance. This GSN haplotype ranked as the largest shared haplotype in the 68 patients in a genome-wide analysis of haplotype block lengths. These results provide strong evidence that although there is a known mutational hot spot at GSN c.640G, all of the studied 62 Finnish AGel amyloidosis families are genetically linked to a common ancestor.Peer reviewe

Natural course of Finnish gelsolin amyloidosis

Background: Finnish type of hereditary gelsolin amyloidosis (FGA) is one of the most common diseases of Finnish disease heritage. Existing FGA knowledge is based only on smaller patient series, so our aim was to elucidate the natural course of the disease in a comprehensive sample of patients and to build up a national FGA patient registry. Methods: An inquiry about the known and suspected signs of FGA, sent to the members of Finnish Amyloidosis Association, telephone contacts and hospital records were utilised to create the registry. Results: A total of 227 patients were entered to the database. The first symptom was ophthalmological for 167 patients (73.6%) at the mean age of 39 years. Corneal lattice dystrophy (CLD) was reported at the mean age of 43 years. Impaired vision, polyneuropathy, facial nerve paresis and cutis laxa appeared on average between 52 and 57 years. Carpaltunnel syndrome (CTS) was reported by 86 patients (37.9%). Nine patients (4.0%) had a pacemaker and 12 (6.1%) had cardiomyopathy. Conclusions: The first symptom was ophthalmological in most cases. Except for CLD, no prominent difference in the age of appearance was found between the major symptoms. CTS, cardiac pacemakers and cardiomyopathy were remarkably more common compared to the general population

Causes of death and life span in Finnish gelsolin amyloidosis

Background: Finnish type of hereditary gelsolin amyloidosis (AGel amyloidosis) is an autosomal dominant disorder. Until recently, there has only been little knowledge of fatal complications of the disease and its possible impact on the patients' life span. Methods: We identified 272 deceased patients based on patient interviews and genealogical data. After collecting their death certificates we recorded the patients' underlying and immediate causes of death (CoD) and life span and compared them to the general Finnish population. We then calculated proportional mortality ratios (PMR), standardised for age and sex, for the CoDs. Results: The underlying CoD in 20% of the patients was AGel amyloidosis (PMR=114.2; 95% CI 85.6-149.4). The frequency of fatal cancers (10%) was significantly diminished (PMR=0.47; 95% CI 0.31-0.69). Renal complications were overrepresented as the immediate CoD in female patients (PMR=2.82 95% CI 1.13-5.81). The mean life span for male patients was 73.9 years (95% CI 72.0-75.6) and 78.0 years for female patients (95% CI 76.4-79.5) compared to 72.1 and 80.1 years for the general population. Conclusions: Our results suggest that the disease increases the risk for fatal renal complications, but does not substantially shorten the life span, possibly due to the significantly lower frequency of fatal cancers

GELS_FIN_GAR_ILLUMINA.zip

Genotyping of Finnish gelsolin amyloidosis families using an Illumina CoreExome SNP array. Included are full genotypes from all markers inside founder haplotype area overlapping the disease variant site plus a flanking megabase on both sides. Data is in plink format, applicable for haplotype analysis