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Background and objective We report 2 carriers of the TTRV30M mutation and its plasmatic biochemical marker with clinical symptoms compatible with hereditary TTR amyloidosis. Materials and methods Based on our previously reported casual finding of amyloid TTR in nasal mucosa (2008), we requested biopsy of this tissue to search for amyloid with Congo red staining and TTR immunohistochemical analysis. Results The histological diagnosis was achieved by retrospective analysis of surgical sinonasal biopsy in the first patient and prospective biopsy of inferior nasal concha in the second. Large interstitial deposits of ATTR were observed in both cases. Conclusions We suggest nasal mucosa as a suitable site for tissue biopsy in patients with suspected hereditary TTR amyloidosis.

We present two families, from Spain and Portugal, with familial amyloid polyneuropathy (FAP) associated with the mutation TTRSer50Arg. This mutation was first described in two Japanese patients from independent families and later in a French-Italian patient and a Vietnamese family. The two families presented here, are the first to be diagnosed with this mutation in the Iberian Peninsula. In the patients of both families, FAP was very aggressive as they rapidly developed multiple symptoms with progressive deterioration; we emphasize the presence of severe orthostatic hypotension in the Spanish proband which confined him to a wheelchair. This proband was the first patient with this mutation to have undergone liver transplantation and results were encouraging. The mutation was detected in four patients and one disease-free relative by DNA sequencing of exon 3 and induced mutation restriction analysis. The most outstanding feature was the single base transversion A to C in codon 50 (CGT instead of AGT), whereas in both Japanese patients and the French-Italian patient it was T to G (AGG instead of AGT). To our knowledge only six FAP mutations with more than one single nucleotide mutation for the same codon have been reported to date.

Until recently, liver transplantation (Ltx) was the only available treatment for hereditary transthyretin (TTR) amyloidosis; today, however, several pharmacotherapies are tested. Herein, we present survival data from the largest available database on transplanted hereditary TTR patients to serve as a base for comparison.Liver transplantation was evaluated in a 20-year retrospective analysis of the Familial Amyloidosis Polyneuropathy World Transplant Registry.From April 1990 until December 2010, data were accumulated from 77 liver transplant centers. The Registry contains 1940 patients, and 1379 are alive. Eighty-eight Ltx were performed in combination with a heart and/or kidney transplantation. Overall, 20-year survival after Ltx was 55.3%. Multivariate analysis revealed modified body mass index, early onset of disease (50 years of age), disease duration before Ltx, and TTR Val30Met versus non-TTR Val30Met mutations as independent significant survival factors. Early-onset patients had an expected mortality rate of 38% that of the late-onset group (P0.001). Furthermore, Val30Met patients had an expected mortality rate of 61% that of non-TTR Val30Met patients (P0.001). With each year of duration of disease before Ltx, expected mortality increased by 11% (P0.001). With each 100-unit increase in modified body mass index at Ltx, the expected mortality decreased to 89% of the expected mortality (P0.001). Cardiovascular death was markedly more common than that observed in patients undergoing Ltx for end-stage liver disease.Long-term survival after Ltx, especially for early-onset TTR Val30Met patients, is excellent. The risk of delaying Ltx by testing alternative treatments, especially in early-onset TTR Val30Met patients, requires consideration.

Fundamento El trasplante hepatico domino o secuencial (DTXH) es un tipo de injerto de donante vivo propuesto en 1993 y realizado por primera vez en 1995; posteriormente se han publicadomas de 45. El higado de un paciente con polineuropatia amiloidotica familiar (PAF) se implanta a un enfermo mayor de 60 anos afectado de un proceso hepatico generalmente neoplasico, porque el higado de esos donantes es normal desde el punto de vista anatomico y funcional, salvo la sintesis de la variante sistemica de la transtirretina (TTR), que solo podria originar la PAF en el receptor al cabo de un periodo mayor de 8 anos. Pacientes y metodo Se presentan los tres primeros casos de DTXH realizados en Espana. Los donantes eran pacientes con PAF con variante TTRMet30 procedentes del foco mallorquin. El primero de los receptores presentaba un gravisimo hiperinsulismo debido a metastasis hepaticas de insulinoma maligno; los otros dos tenian hepatocarcinoma implantado sobre higado cirrotico. Resultados En el postoperatorio de los receptores, la funcion del higado fue perfecta, y desaparecio inmediatamente el hiperinsulinismo en el primero; este fallecio a los 10 dias por sepsis, mientras que los otros siguen con funcion hepatica normal, sin recidiva neoplasica ni inicio de PAF. En los donantes, la evolucion fue normal, con perfecta funcion hepatica. Conclusiones Nuestros datos, coincidentes con los publicados, permiten concluir que el DTXH es un metodo valido para un determinado grupo de pacientes. Ademas, aumenta el contingente de donantes hepaticos y, por consiguiente, disminuyen las sobrecargadas listas de espera.

We report the case of a female patient with familial amyloid polyneuropathy (FAP) who demonstrated TTR amyloid deposition in the inferior nasal conchal vessels. To our knowledge this location has not been described previously in FAP; in addition, it was detected in a patient who had undergone successful liver transplantation (LTX) 4 years earlier. The amyloid deposition was found incidentally during examination of a right nasal obstruction caused by a nonspecific inflammatory polyp. Small focal deposits of amyloid TTR were observed on deep thick walled vessels, contrasting with the massive deposition reported in neoformed vessels in amyloidomas. This amyloid was clearly deposited between the onset of FAP and LTX and had probably decreased since the graft. If amyloid deposition is frequent in inferior nasal concha in FAP, this location could be a suitable biopsy site.

Between 1976 and 2003, we diagnosed 144 patients with familial amyloid polyneuropathy (FAP) in the Balearic Islands (Spain). Analysis of genetic epidemiological data from 102 confirmed patients showed 62% were men. Parental transmission was paternal in 38, maternal in 25, and unknown in 39. No family history of FAP was found in 32 patients. TTRVal30Met associated with haplotype I was present in the individuals studied. Mean age-at-onset was 45.7 years which lies between that of Sweden and those of Portugal, Japan and Brazil. Duration of FAP was of 9.7 years. Age-at-onset, age-at-death, duration and fertility were similar between sexes. Twenty-nine intergeneration familial pairs of patients were ascertained. Raw anticipation was positive in twenty-four pairs, zero in one, and negative in four. Differences greater than 9 years between age-at-onset of the first and second member were considered relevant; positive relevant anticipation was found in 76% of the whole pairs. The frequency of positive anticipation of parent-child pairs was not significantly different than those described in the Swedish and Portuguese series. Significant positive correlation in age-at-onset was confirmed in twenty-seven types of pairs supporting the hypothesis that a genetic factor may modulate age-at-onset. The Balearic focus of FAP is expanding and constitutes a public health problem.

The possibility of a patient with familial ATTR amyloidosis receiving a liver from an asymptomatic variant TTR carrier is remote [corrected].However, in 2008, it was reported that this unlikely event occurred in a patient in Portugal. We report our protocol for early diagnosis and management of this entity.

Two Spanish sibs with familial amyloidotic polyneuropathy (FAP) homozygous for the V30M-TTR gene, were diagnosed by DNA and protein analyses. Their clinical picture was very similar to the Majorcan FAP heterozygous patients except for the sensorimotor syndrome which was more aggressive. Noteworthy were clinical differences between the sibs concerning autonomic involvement, cranial neuropathy and kidney disturbances. These differences can be due to genetic and/or environmental factors.

The most frequent transthyretin (TTR) variant associated with hereditary amyloidosis is TTR Met 30, which has its major focus in Portugal, although it also occurs in many other countries. The distribution of the mutation and its occurrence in a CpG dinucleotide lead us to question the origin of the mutation and the possibility of its having originated in Portugal. In order to investigate these questions, we studied the distribution of haplotypes associated with the Met 30 mutation in families from different European countries. All the analysed Portuguese families presented the same haplotype associated with the Met 30 mutation (haplotype I). The same was found for the Swedish and Spanish families studied. However, a distinct haplotype (haplotype III) was found in three families, one Italian, one English and one Turkish. These results suggest that, although the Portuguese Met 30 carriers might have one founder, the mutation probably recurred in populations in Europe in a similar manner to that reported in Japan. In this study, we have also analysed the haplotypes associated with other TTR variants frequent in the Portuguese population.

Vitreous amyloidosis has been reported in patients with familial amyloidotic polyneuropathy (FAP) who are carriers of different mutant transthyretins (TTR). The mutant TTR constitutes the majority of the amyloid vitreous fibrils in heterozygous Val30Met patients. Due to the ocular synthesis of TTR, it is possible that the retina constitutes the source of vitreous amyloid fibrils, if so, orthotopic liver transplantation (OLT) performed to remove the mutant TTR from circulation might not be effective in treating/avoiding vitreous amyloid. We present vitreous amyloidosis in a FAP patient from Maiorca with ATTR Val30Met who underwent OLT at age 38. Progressive impairment of visual acuity (VA) appeared bilaterally 2 years after OLT due to vitreous opacities consistent with amyloid; successful bilateral vitrectomy was performed. Amyloid was demonstrated in the vitrectomy material by Congo red staining, immunohistochemistry and Western blotting analyses were positive with an antibody for human TTR. Mass spectrometry of TTR revealed the presence of the mutant in approximately 20% of the TTR. Future structural studies on vitreous material with different proportions of normal/versus mutant TTR might shed some light on TTR fibrillogenesis. These results show that vitreous deposition of TTR amyloidfibrils occurs after OLT, suggesting that ongoing intraocular synthesis of mutant TTR might contribute to this process. We also present the progression after OLT of vitreous amyloidosis previously diagnosed in three patients with TTR Val71Ala.

We analyzed data from 78 Majorcan patients with familial amyloidotic polyneuropathy (FAP): 57 confirmed and 21 non-confirmed. Diagnosis was established in the first group by histopathological study or detection of the biochemical marker in serum, and in the second was sup-ported by clinical information and family history.Eighteen confirmed patients were isolated cases and 39 had a family history of FAP. Age of onset was 46. 7 years; later in males; predominance of males (72%) and late on-set cases (65%). The TTR variant was Met 30 associated with haplotype I. Initial sensorimotor syndrome was present only in 55% of patients. Multiple progressive handicaps appeared. Duration averaged 10.5 years and was longer in males. Prevalence rate was 3.3 patients per 100,000 and asymptomatic carriers were 83. Twelve patients underwent liver transplantation.Since 1989, the number of FAP families, patients, prevalence, isolated cases and municipalities with affected families was increased. One founder hypothesis is supp...

We present a Spanish patient with familial amyloidotic polyneuropathy associated with the TTR Thr49Ile mutation previously described in a Japanese patient. This is the first report in a Caucasian patient and the second in the literature. Age of onset at 66 and the clinical picture were similar to the Japanese patient: sensorimotor polyneuropathy, digestive autonomic disturbances, cardiomyopathy and loss of weight. The mutation was diagnosed by DNA sequencing and induced mutation restriction analysis.

Common origin of the Val30Met mutation responsible for the amyloidogenic transthyretin type of familial amyloidotic polyneuropathy.