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Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden. The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017. In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies. There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm. [ABSTRACT FROM AUTHOR]

Background:The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy. Methods:A prospectively planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirty-seven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years. Results:Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures. Conclusions:These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis.ClinicalTrials.gov:NCT00925002 [ABSTRACT FROM AUTHOR]

Hereditary (familial) amyloid polyneuropathy (FAP) is a systemic disease that includes a sensorimotor polyneuropathy related to transthyretin (TTR) mutations. So far, a scale designed to classify the severity of this disease has not yet been validated. This work proposes the implementation of an artificial neural network (ANN) in order to develop a severity scale for monitoring the disease progression in FAP patients. In order to achieve this goal, relevant symptoms and laboratory findings were collected from 98 Brazilian patients included in THAOS – the Transthyretin Amyloidosis Outcomes Survey. Ninety-three percent of them boreVal30Met, the most prevalent variant of TTR worldwide; 63 were symptomatic and 35 were asymptomatic. These data were numerically codified for the purpose of constructing a Self-Organizing Map (SOM), which maps data onto a grid of artificial neurons. Mapped data could be clustered by similarity into five groups, based on increasing FAP severity (from Groups 1 to 5). Most symptoms were virtually absent from patients who mapped to Group 1, which also includes the asymptomatic patients. Group 2 encompasses the patients bearing symptoms considered to be initial markers of FAP, such as first signs of walking disabilities and lack of sensitivity to temperature and pain. Interestingly, the patients with cardiac symptoms, which also carry cardiac-associated mutations of the TTR gene (such asVal112IleandAla19Asp), were concentrated in Group 3. Symptoms such as urinary and fecal incontinence and diarrhea characterized particularly Groups 4 and 5. Renal impairment was found almost exclusively in Group 5. Model validation was accomplished by considering the symptoms from a sample with 48 additional Brazilian patients. The severity scores proposed here not only identify the current stage of a patient’s disease but also offer to the physician an easy-to-read, 2D map that makes it possible to track disease progression. [ABSTRACT FROM AUTHOR]

Transthyretin hereditary amyloid polyneuropathy, also traditionally known as transthyretin familial amyloid polyneuropathy (ATTR-FAP), is a rare, relentless, fatal hereditary disorder. Tafamidis, an oral, non-NSAID, highly specific transthyretin stabilizer, demonstrated safety and efficacy in slowing neuropathy progression in early-stage ATTRV30M-FAP in a 1.5-year, randomized, double-blind, placebo-controlled trial, and 1-year open-label extension study, with a second long-term open-label extension study ongoing. Subgroup analysis of the effectiveness of tafamidis in the pivotal study and its open-label extensions revealed a relatively cohesive cohort of patients with mild neuropathy (i.e. Neuropathy Impairment Score for Lower Limbs [NIS-LL] ≤ 10) at the start of active treatment. Early treatment with tafamidis for up to 5.5 years (≥1 dose of tafamidis meglumine 20 mg once daily during the original trial or after switching from placebo in its extension) resulted in sustained delay in neurologic progression and long-term preservation of nutritional status in this cohort. Mean (95% CI) changes from baseline in NIS-LL and mBMI were 5.3 (1.6, 9.1) points and −7.8 (−44.3, 28.8) kg/m2× g/L at 5.5 years, respectively. No new safety issues or side effects were identified. These data represent the longest prospective evaluation of tafamidis to date, confirm a favorable safety profile, and underscore the long-term benefits of early intervention with tafamidis. Trial Registration:ClincalTrials.gov Identifier: NCT00409175, NCT00791492, and NCT00925002. [ABSTRACT FROM AUTHOR]

Familial amyloidotic polyneuropathy (FAP) is a dominantly inherited systemic amyloidosis caused by mutated transthyretin (TTR). Liver transplantation is currently the only available treatment that halts the progress of the disease. Cardiovascular complications are common in FAP, and cardiac arrhythmias are typical complications in FAP Val30Met. For patients with late onset FAP, as the Swedish patients, coronary heart disease has been found in several patients, and a QS complex is not an uncommon finding in FAP-patients ECG raising the suspicion of coronary heart disease. The aim of this study was to evaluate exercise ECG in FAP patients before transplantation with regard to mortality and morbidity. Thirty-eight FAP patients who underwent examination by exercise ECG, as part of the evaluation for liver transplantation were included in the study. Of these, 30 patients were transplanted, and the surviving patients were followed for at least 2 years. Exercise ECG was performed on bicycles with standard 12 leads. Non-parametric statistical analyses were used in all calculations. Six patients died 0-5.5 years after transplantation. They were older than the survivors (p < 0.01), but their duration of disease did not deviate from that of survivors (p = 0.8). They were also less able to increase their heart rates during exercise than the survivors (p < 0.05). For all transplanted patients, a significant relationship was found between patients' increase of heart rate, blood pressure and maximal workload, and the duration of disease and also for the PND-score, signifying that the outcome of exercise ECG predominantly was related to the patients autonomic and motor function, and not to their heart function. [ABSTRACT FROM AUTHOR]

For familial amyloidotic polyneuropathy (FAP) patients, several problems regarding reproduction are present. For males, erectile dysfunction and retrograde ejaculation are well known complications of the disease In addition, the risk of transferring a fatal disease to their offspring is a matter of concern for the patients. For transplanted fertile patients, the risk of side effects of immunosupression therapy causing congenital malformations must be addressed, and for female patients the additional risk of complications during pregnancy and delivery is a case of concern. After delivery, the problem of breast-feeding arises. In the Swedish population of transplanted patients, five successful pregnancies, of which male FAP recipients fathered three, are reported. All patients were on stable immunosuppressive therapy with cyclosporine or tacrolimus and prednisolone. From our experience, successful fatherhood and pregnancy is possible for liver transplanted FAP patients, as it has been reported for patients transplanted for other medical reasons. [ABSTRACT FROM AUTHOR]