Transthyretin Glu54Leu - an unknown mutation within the Swedish population associated with amyloid cardiomyopathy and a unique fibril type.

For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.

A novel transthyretin Lys70Glu (p.Lys90Glu) mutation presenting with vitreous amyloidosis and carpal tunnel syndrome.

OBJECTIVE: We describe a novel TTR mutation with vitreous opacities and carpal tunnel syndrome. MATERIALS AND METHODS: A 78 year-old woman with vitreous opacities, her daughter with dry eye syndrome, and brother with carpal tunnel syndrome were tested for a mutation in the TTR gene. The vitreous opacities were removed and stained with Congo red and immunohistochemistry against wild type TTR. Skin and gut biopsies and specimens of soft tissue were examined histopathologically. Leukocyte DNA from the proband was analysed by direct sequencing of exons 1 to 4 of the TTR gene and DNA from her daughter and brother using segregation analysis. RESULTS: A point mutation c.268 A>C, in the TTR gene, leading to a missense mutation p.Lys90Glu was found in all subjects. The vitreous opacities were pearl string-like. Histopathology showed red to green birefringence in Congo red, typical to amyloid, and the specimens were immunoreactive with antibodies against TTR. CONCLUSION: We present a novel autosomally inherited Lys90Glu mutation in the TTR gene. This is the first reported FAP family with this mutation in Finland.

Frequency of the transthyretin Val30Met mutation in the northern Swedish population.

By genotyping a large number of samples from the Northern Sweden Health and Disease Study cohort, a carrier frequency could be determined for the Skellefteå and Lycksele populations. A previous study of the amyloidogenic transthyretin mutation TTRV30M in Northern Sweden's endemic area has shown a large variation in carrier frequency and penetrance of the trait within the area. However, the estimations have been based on a small sample size within the different regions in the area and therefore, the wide variation in TTRV30M carrier frequency observed between the Lycksele and Skellefteå populations are uncertain. Based on a total of 3460 samples, the estimated overall carrier frequency in the two regions was 1.82% with a carrier frequency in the Skellefteå and Lycksele population of 1.63% and 2.02%, respectively. Thus, the previously reported extremely high frequency in the Lycksele region compared to that of the Skellefteå region could not be substantiated. However, it does not change the previous finding of a surprisingly higher carrier frequency in the population from endemic area of Northern Sweden compared to that reported from endemic areas in Portugal.

A possible role for miRNA silencing in disease phenotype variation in Swedish transthyretin V30M carriers.

BACKGROUND: Familial amyloidosis with polyneuropathy (FAP) is an autosomal dominant disease caused by transthyretin (TTR) mutations, of which V30M (TTR c.148G > A, p.Val50Met, "Val30Met") is the most common. Swedish V30M carriers display later age at onset and lower penetrance compared to other populations. METHODS: In the study, 130 Swedish V30M carriers (32 early, 30 late onset and 68 asymptomatic carriers) and 50 controls, 23 French symptomatic V30M carriers and 29 controls and 18 Japanese symptomatic V30M carriers and 29 controls were included. We aimed to identify additional genetic factors in the TTR gene and its surrounding region that could have an impact on phenotype. RESULTS: We identified three SNPs (rs71383038, rs3794885 and rs62093482) with a significant difference in allele frequency between Swedish V30M carriers and controls. The two Swedish V30M homozygous patients present in the study also displayed homozygosity for the CA10 (rs71383038), A (rs3794885) and T (rs62093482) alleles in these SNPs. Hence, these alleles are present on the Swedish V30M haplotype. Of these, rs62093482 is located in the 3'UTR of TTR gene and thus more interesting since SNPs in the 3'UTR can affect gene expression levels by modifying microRNA (miRNA) targeting activity. miRNA target predictions revealed four potential miRNAs with predicted targets unique for the polymorphic allele. CONCLUSIONS: Our results are the first to show the presence of a 3'UTR polymorphism on the V30M haplotype in Swedish carriers, which can serve as a miRNA binding site potentially leading to down-regulated expression from the mutated TTR allele. This finding may be related to the low penetrance and high age at onset of the disease observed in the Swedish patient population.

Report of five rare or previously unknown amyloidogenic transthyretin mutations disclosed in Sweden.

The number of amyloidogenic transthyretin (TTR) mutations described in the literature is more than 100. However, for several mutations, the phenotype has been described in a few individuals only; thus, the knowledge of the clinical course and the outcome after therapeutical interventions such as liver transplantation is limited. We describe the phenotype associated with five rare amyloidogenic TTR mutations that lately were discovered in Sweden: ATTR Val30Leu, Ala45Ser, Leu55Gln, Gly57Arg and Tyr69His of which ATTR Gly57Arg is previously unknown. The symptoms at onset differed, but cardiomyopathy and peripheral neuropathy were observed in all except the ATTR Tyr69His mutation. Likewise, carpal tunnel syndrome was found or had been present in all cases except the case with the ATTR Val30Leu mutation. The phenotype of the ATTR Tyr69His mutation was characterised by oculo-meningeal symptoms with seizures and a steadily progressing dementia, symptoms rarely found in ATTR amyloidosis, but similar to those previously described for this mutation, where all cases appear to originate from one Swedish family. Two patients with the ATTR Leu55Gln and Ala45Ser mutations have been subjected to liver transplantation, but echocardiographic examination has revealed an increasing cardiomyopathy after transplantation in both cases, the ATTR Leu55Gln patient succumbed 2 years after transplantation from progressive disease.

Cardiomyopathy in Swedish patients with the Gly53Glu and His88Arg transthyretin variants.

We report two new amyloidogenic transthyretin (TTR) variants detected in the Swedish population. One variant was previously unknown, while the other has been described in a French family. In Swedish patients, both variants have caused late-onset cardiac amyloidosis characterised by heart failure. In both cases, the diagnosis was determined by the detection of amyloid deposits in skin and/or rectal biopsies and identification of TTR mutations by genetic analysis. The index case of the previously unknown mutation (ATTR His88Arg) was a 66-year-old Swedish man, who sought medical attention for increasing dyspnea. Echocardiographic examination disclosed a restrictive cardiomyopathy, and subsequent examinations disclosed TTR amyloidosis. The patient is alive with moderate symptoms one year after the onset of disease. The index case for the new Swedish mutation (ATTR Gly53Glu) is a woman who sought medical attention at the age of 57 because of increasing dyspnea. Echocardiographic examination disclosed a hypertrophic cardiomyopathy with diastolic impairment. The diagnosis of systemic amyloidosis was made by fat aspiration biopsy and histopathology. The patient developed severe intractable heart failure, with pulmonary effusion and ascites. She died four years after the onset of her disease of intractable heart and kidney failure. Post mortem examination of biopsy specimens and blood revealed TTR amyloid deposits and the ATTR Gly53Glu mutation was detected.

A Swedish family with the rare Phe33Leu transthyretin mutation.

Familial amyloidotic polyneuropathy (FAP) designates TTR mutations where the phenotype is dominated by a peripheral sensory-motor polyneuropathy. The most common mutation is ATTR Val30Met. FAP in association with ATTR Phe33Leu has been described previously in two American families, one of Polish-Lithuanian descent and the other of Polish-American. In this study, we report the phenotype of the ATTR Phe33Leu in a Swedish family. The proband is a 48 year-old patient from northern Sweden, whose father died with symptoms suggestive of FAP. Characteristic clinical features included polyneuropathy, carpal tunnel syndrome and asymptomatic, but echocardiographic examination diagnosed cardiomyopathy. The family history supports an early intervention with orthotopic liver transplantation in patients with FAP associated with the TTR Phe33Leu, and the patient was submitted for liver transplantation.