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Background and aims Patients with transthyretin amyloid polyneuropathy (ATTR-PN) show decreased motor and sensory nerve amplitudes and conduction. Electrophysiological changes over time may be sensitive indicators of progression. This analysis from the Transthyretin Amyloidosis Outcomes Survey (THAOS) assessed longitudinal changes in nerve conduction as signals of neurologic disease progression in patients with hereditary ATTR (ATTRv) amyloidosis. Methods Patients with ATTRv in THAOS with recorded nerve conduction values were included (data cut-off: January 06, 2020); changes in nerve amplitude and velocity over time were assessed. Results Patients (n=1389) were 45.0% male; 80.4% were the Val30Met (p.Val50Met) genotype. Mean (SD) age at enrollment was 43.6 (14.5) years; duration of symptoms was 9.3 (6.4) years. Median (10th, 90th percentile) sural nerve amplitude and velocity was 18.0 (4.9, 35.0) μV and 50.7 (41.0, 57.9) m/s; peroneal conduction was 13.0 (4.4, 27.0) μV and 51.0 (41.7, 59.7) m/s, respectively. Median (10th, 90th percentile) percentage change from baseline in sural nerve amplitude was variable, but generally decreased over time from -7.4 (-43.2, 52.4) at year 1 to -14.4 (-76.9, 46.7) at year 8. Percent change from baseline in sural nerve velocity declined similarly: -0.1 (-14.5, 15.3) at year 1 and -6.4 (-21.3, 10.5) at year 8. The decline was more pronounced in patients with greater disability at baseline. Similar patterns were observed for the peroneal nerve. Interpretation These data show an association between nerve amplitudes and velocities and disease severity, suggesting progressive deterioration in nerve conduction may be an indicator of ATTRv amyloidosis disease progression.

Hereditary systemic amyloidosis aside from transthyretin-related familial amyloid polyneuropathy is quite uncommon in Japan. We herein report a sporadic case of hereditary apolipoprotein A-I (apoAI) amyloidosis. The patient was a 43-year-old Japanese man who exhibited marked hepatomegaly with spleno-testicular enlargement. While he was initially thought to have primary AL amyloidosis, a proteomics analysis revealed that the amyloid was composed of variant apoAI with an E34K variant. To date, only one patient with apoAI amyloidosis has been reported in Japan. However, our study suggests that more patients may be present in Japan, and the majority may have been diagnosed with other types of amyloidosis due to its clinical similarity.

Background Transthyretin familial amyloid polyneuropathy (ATTR-FAP) is a rare autosomal dominant inherited disease affecting multiple organ systems. ATTR-FAP patients’ experiences have rarely been documented. The aim of this study was to collect patient reported outcomes across different countries to assess unmet needs and challenges. An anonymous survey was conducted at the 2nd European meeting on ATTR amyloidosis in Berlin in September 2019. Survey questions captured information on demographics, clinical characteristics, diagnostic experience, quality of life, disability and ATTR-FAP management. Results A total of 38 ATTR-FAP patients from 15 different countries participated in the survey. ATTR-FAP had a substantial impact on patients’ day-to-day life, including difficulties in standing, walking, and participation in community activities. It also had negative effects on the mental health of patients. The survey highlighted several unmet needs and challenges from a patients’ perspective, including (i) a need for increased awareness and a standardized diagnostic pathway, (ii) a need for better treatment access and supportive care and (iii) a need for better information about research and clinical trials. Conclusions This global patient survey provides valuable findings to address ATTR-FAP patients’ needs and challenges in order to further the goal of patient-centered care.

Background: Transthyretin amyloidosis due to V30M mutation (ATTR-V30M) is the most frequent hereditary ATTR amyloidosis. Besides neurophysiological measures, there are no biomarkers to detect precl...

BACKGROUND: Familial amyloid polyneuropathies (FAPs) are a group of rare autosomal dominant transmitted disorders that can progressively lead to disability from neuropathy, autonomic failure and other system involvement. OBJECTIVE: The aim of this commentary is to discuss Cochrane evidence on the efficacy and safety of disease-modifying drugs (DMDs) for the treatment of FAPs from a rehabilitation perspective. METHODS: To summarize and discuss from a rehabilitation perspective the published Cochrane Review “Pharmacological treatment for familial amyloid polyneuropathy” by Magrinelli et al. RESULTS: This Cochrane review included 4 randomized controlled trials (RCTs) involving 655 adults with FAP. These four trials compared four different DMDs with placebo. The Cochrane Systematic Review reported that current evidence is limited. CONCLUSIONS: FAPs are a group of chronic disabling conditions in which a multidisciplinary approach, including an adequate rehabilitation programme along with a long-term effective pharmacological therapy, should always be envisaged.

Familial amyloid polyneuropathy is a disease that occurs in southwestern Bulgaria. It causes a severe disability. The clinical picture is accompanied by weight loss, a muscle weakness, a cardiomyopathy and damage to the peripheral nervous system. The onset of symptoms is at a relatively early age (45-50 years). Specialists from Alexandrovska Hospital monitor patients with this type of disease. Purpose: The aim of the study is to create a kinesitherapeutic algorithm for the study of patients with familial amyloid polyneuropathy. Methods: The review study was undertaken in the Neurology department at Multidisciplinary hospital for active treatment- Blagoevgrad, Bulgaria. The study was conducted for the period 2015-2017, during which 10 patients with FAP were examined. In our algorithm we have included manual-musculе testing (ММТ) of the upper and lower limbs, an centimeter testing to measure hypotonia and a discriminant test to detect sensory disturbances. Results: The study involved 6 women and 4 men. The average age of the studied contingent is 48.0 ± 12.7 years. In the study we found that there is a change in the study of manual muscle testing. One unit increase available. There are no statistically significant differences in the study of centimeter in the lower extremities and in the study of the senses as well. Severe muscular hypotension and distal hypoesthesia persist. Conclusion: Unfortunately, these patients often progress rapidly. They remain disabled. Kinesitherapy, with its methods, can improve the quality of life.

There have now been randomized controlled trials of four different therapeutics for hereditary amyloid polyneuropathy related to transthyretin (TTR) deposition and one for amyloidotic cardiomyopathy of both genetic and sporadic origin. It is likely that in the next few months those not already approved by either the US Food and Drug Administration (FDA) and/or the European Medicines Authority (EMA) will receive similar approvals for treatment for all or particular groups of patients. This is a far cry from circumstances less than 10 years ago when the only available therapy was gene replacement by liver transplant. The randomized controlled trials have shown that all the treatments (tafamidis, diflunisal, patisiran, and inotersen) are effective in the context of a clinical trial. However, we have very little idea of whether individual patients will respond in an equally positive way to all the drugs or whether there will be some who respond better to one or another or not respond at all, nor do we know whether combinations will be additive or synergistic. We lack validated markers of clinical response. While the small molecule TTR stabilizers increase serum TTR levels, the RNA-based drugs lower serum TTR. In the latter case, it is not clear that the reduction in serum TTR is related to the clinical response in a 1:1 fashion. Pharmaceutical companies have made substantial investments in the development of these agents and will clearly attempt to recoup those investments quickly. It is incumbent upon those of us who care for these patients to develop ways to assess the effects of therapy in the shortest possible time at the lowest possible cost. The better we are able to accomplish this the more likely it is that we will be able to treat the most patients in the most clinically efficient fashion regardless of their economic status. We now have the drugs we just have to figure out who should get them and when.

Transthyretin (TTR) is an essential transporter of a thyroid hormone and a holo-retinol binding protein, found abundantly in human plasma and cerebrospinal fluid. In addition, this protein is infamous for its amyloidogenic propensity, causing various amyloidoses in humans, such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. It has been known for over two decades that decreased stability of the native tetrameric conformation of TTR is the main cause of these diseases. Yet, mechanistic details on the amyloidogenic transformation of TTR were not clear until recent multidisciplinary investigations on various structural states of TTR. In this review, we discuss recent advancements in the structural understanding of TTR misfolding and amyloidosis processes. Special emphasis has been laid on the observations of novel structural features in various amyloidogenic species of TTR. In addition, proteolysis-induced fragmentation of TTR, a recently proposed mechanism facilitating TTR amyloidosis, has been discussed in light of its structural consequences and relevance to acknowledge the amyloidogenicity of TTR.

Background: Transthyretin amyloid polyneuropathy (ATTR-PN) is a fatal disease associated with substantial burden of illness. Three therapies are approved by the European Medicines Agency for the management of this rare disease. The aim of this study was to compare the total annual treatment specific cost per-patient associated with ATTR-PN in Spain.Methods: An Excel-based patient burden and cost estimator tool was developed to itemize direct and indirect costs related to treatment with inotersen, patisiran, and tafamidis in the context of ATTR-PN. The product labels and feedback from five Spanish ATTR-PN experts were used to inform resource use and cost inputs.Results: Marked differences in costs were observed between the three therapies. The need for patisiran- and inotersen-treated patients to visit hospitals for pre-treatment, administration, and monitoring was associated with increased patient burden and costs compared to those treated with tafamidis. Drug acquisition costs per-patient per-year were 291,076€ (inotersen), 427,250€ (patisiran) and 129,737€ (tafamidis) and accounted for the majority of total costs. Overall, the total annual per-patient costs were lowest for patients treated with tafamidis (137,954€), followed by inotersen (308,358€), and patisiran (458,771€).Conclusions: Treating patients with tafamidis leads to substantially lower costs and patient burden than with inotersen or patisiran.

Backgrounds: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is frequently misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) because of similar phenotypes in the two diseases. This study was intended to identify the role of nerve ultrasonography in evaluating TTR-FAP and CIDP.Methods: Eighteen patients with TTR-FAP, 13 patients with CIDP, and 14 healthy controls (HC) were enrolled in this study. Consecutive ultrasonography scanning was performed in six pairs of nerves of bilateral limbs with 30 sites. The cross-sectional areas (CSAs) and CSA variability data of different groups were calculated and compared.Results: Both TTR-FAP and CIDP showed larger CSAs at most sites of both upper and lower limbs than in HC groups. CIDP patients had larger CSAs than TTR-FAP patients at 8/15 of these sites, especially at U1-3, Sci2 sites (p < 0.01). However, the CSAs at above sites were not a credible index to differentiate TTR-FAP from CIDP with a low area under the curve (Interpretation: TTR-FAP patients had milder nerve enlargement with less variability in CSAs of median nerves than those with CIDP, suggesting that nerve ultrasound can be a potential useful auxiliary tool to help differentiate the two neuropathies.

Objectives: Val30Met in transthyretin (TTR) gene is causative for familial amyloid polyneuropathy (FAP). FAP shows a wide variation in age-at-onset (AO) between clusters, families, and among generations. We aim at identifying genetic modifiers of disease onset that may contribute to this variability in Portuguese patients by identifying other variants in TTR locus, beyond the TTR-FAP causing variant that could play a regulatory role in its expression level. Methods: We analysed DNA samples of 330 Val30Met carriers (299 patients, 31 aged-asymptomatic carriers aged >40 years) from 120 families currently under follow-up. A generalized estimating equation analysis (GEE) was used to take into account non-independency of AO between relatives. An intensive in silico analysis was performed in order to understand a possible regulation of gene expression. Results: We found 11 rare variants in the promoter, coding and intron/exon boundaries of the TTR gene associated with the onset of symptoms before and after age 40 years, namely 2 novel ones and a tandem CA-dinucleotide repeat. The seven Val30Met/Val30Met homozygous do not carry any of the variants identified in this study, including the common ones. In silico analysis disclosed significant alterations in the mechanism of splicing, transcription factors and miRNAs binding. Conclusions: Variants within the promoter region may modify disease expressivity and variants in the 3’UTR can impact the efficacy of novel therapeutic interventions. Importantly, the putative mechanisms of regulation of gene expression within the TTR gene deserve to be better explored, in order to be used in the future as potential therapeutical targets. We would like to thank FEDER funds, through the Programa Operacional Factores de Competitividade – COMPETE 2020 and by Nacional funds through the FCT – Fundação para a Ciência e a Tecnologia [COMPETE: POCI-01-0145-FEDER-007440]. This work was supported by grants of Fundação para a Ciência e Tecnologia, FCT [PTDC/SAU-GMG/100240/2008 and PEsT], co-funded by ERDF and COMPETE; and by Financiamento Plurianual de Unidades de Investigac¸~ao (FCT). MAF is recipient of a FCT fellowship [SFRH/BD/ 101352/2014]. The funders had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Transthyretin-associated familial amyloid polyneuropathy (TTR-FAP) is an unusual but life-threatening disease that is autosomal dominant inherited and involves the mutation of the transthyretin (TTR) gene. A total of 26 patients with TTR-FAP and different mutations, including the p.Glu 109Gln mutation (previously annotated p. Glu89Gln), were previously reported in Turkey. Herein, we reported two patients from the same family who had the same p.Glu 109Gln mutation but had different clinical phenotypes. The clinical picture mainly involved polyneuropathy in one patient and cardiac involvement in the other patient. This case report mentions that TTR-FAP can cause different clinical phenotypes, even due to the same mutation and even in the same family.

Background The diagnostic accuracy of histopathological detection of transthyretin amyloid (ATTR) by Congo red staining of abdominal fat samples has been questioned since low sensitivity has been reported, especially for patients with ATTR cardiomyopathy. However, the outcome of surgically obtained fat pad biopsies has not yet been evaluated. The aim was to evaluate the diagnostic accuracy of skin punch biopsies from abdominal fat in patients with suspected ATTR amyloidosis. Material and methods Data were evaluated from patients who had undergone abdominal fat pad biopsies using a skin punch due to suspected amyloidosis from 2006 to 2015. The biopsies had been analysed using Congo red staining to determine the presence of amyloid, and immunohistochemistry or Western blot to determine the type of amyloidosis. The final diagnosis was based on the clinical picture, biopsy results and DNA sequencing. Minimum follow-up after the initial biopsy was 3 years. Results Two hundred seventy-four patients (61% males) were identified, and in 132 (48%), a final diagnosis of amyloidosis had been settled. The majority (93%) had been diagnosed with hereditary transthyretin (ATTRv) amyloidosis, and therefore subsequent analyses were focused on these patients. Overall, our data showed a test specificity of 99% and a sensitivity of 91%. Ninety-eight (94%) of the patients had neuropathic symptoms at diagnosis, whereas 57 (55%) had signs of amyloid cardiomyopathy. Subgroup analyses showed that patients with merely neuropathic symptoms displayed the highest test sensitivity of 91%, whereas patients with pure cardiomyopathy displayed the lowest sensitivity of 83%. However, no significant differences in sensitivity were found between patients with or without cardiomyopathy or between the sexes. Conclusions Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspect ATTRv amyloidosis, including patients presenting with cardiomyopathy. In addition, the method enables typing not only of the precursor protein but also of the amyloid fibril type, which is related to the phenotype and to the outcome of the disease.

Background: Hereditary transthyretin amyloidosis (ATTR) is a multisystemic disease involving mainly the peripheral nervous system and the heart. Liver transplantation (LT) is the reference treatment for ATTR neuropathy and preoperative detection of high risk patients is crucial. We aimed to document the causes of death of ATTR patients after LT, their temporal trends, and to evaluate whether the available preoperative tools that predict the risk of death after LT for hereditary ATTR amyloidosis matched with these trends. Methods: A retrospective longitudinal cohort study was performed on 215 consecutive ATTR patients who underwent LT between January 1993 and January 2011. Each patient’s death cause and timing were classified. Results: Over a median follow up of 5.9 years, 84 patients died. The rate of death was higher in the first year following LT than thereafter (13.0 vs. 4.3 ± 1.8%/year; p = .004). Cardiac events ranked as the leading cause of death (C: 38%), followed by infections (I: 24%), graft complications (G: 17%), end stage amyloidosis, stroke and others (ASO: 7% each). Deaths due to graft complications and infections (GI) occurred earlier than those due to end stage amyloidosis and stroke. Death prediction was less accurate for GI-related mortality than for other causes, which blunted the accuracy of the early-term risk prediction scores. Conclusions In ATTR amyloidosis, cardiac events were the leading cause of death after liver transplantation. Close preoperative evaluation allowed for accurate mid-term prediction of mortality, but the high rate of graft complications and infections blunted the early-term risk prediction.

Objective To reappraise the value of electrochemical skin conductance (ESC) measurement by Sudoscan® to assess the distal involvement of small autonomic fibers in familial amyloid polyneuropathy (FAP) due to various transthyretin (TTR) mutations. Methods ESC was measured at both hands and feet in 126 patients with either Val30Met (n = 65) or non-Val30Met (n = 61) TTR mutation. This series included clinically asymptomatic (n = 21) and paucisymptomatic (n = 30) patients, as well as patients with moderate (n = 37) or advanced (n = 38) TTR-FAP. Results ESC measures did not differ between patients according to the type of TTR variant and were reduced in 24% of clinically asymptomatic patients, 40% of paucisymptomatic patients, 65% of patients with moderate TTR-FAP, and 92% of patients with advanced TTR-FAP. ESC measures were found to correlate with patients' clinical status, especially assessed by the Neuropathy Impairment Score and Karnofsky Performance Status. Conclusion ESC measures well correlate with the severity of TTR-FAP and could provide early marker of the disease. Significance ESC measures appear to be relevant to evaluate distal autonomic involvement in the context of amyloidosis.

Skin temperature regulation is dependent on the autonomic nervous system function, which may be impaired in patients with neuropathy. Literature reporting thermographic assessment of patients with ...

Introduction This study sought to estimate the global prevalence of transthyretin familial amyloid polyneuropathy (ATTR-FAP). Methods Prevalence estimates and information supporting prevalence calculations was extracted from records yielded by reference-database searches (2005-2016), conference proceedings, and nonpeer reviewed sources. Prevalence was calculated as prevalence rate multiplied by general population size, then extrapolated to countries without prevalence estimates but with reported cases. Results Searches returned 3,006 records; 1,001 were fully assessed and 10 retained, yielding prevalence for 10 "core" countries, then extrapolated to 32 additional countries. ATTR-FAP prevalence in core countries, extrapolated countries, and globally was 3,762 (range 3639-3884), 6424 (range, 1,887-34,584), and 10,186 (range, 5,526-38,468) persons, respectively. Discussion The mid global prevalence estimate (10,186) approximates the maximum commonly accepted estimate (5,000-10,000). The upper limit (38,468) implies potentially higher prevalence. These estimates should be interpreted carefully because contributing evidence was heterogeneous and carried an overall moderate risk of bias. This highlights the requirement for increasing rare-disease epidemiological assessment and clinician awareness. Muscle Nerve 57: 829-837, 2018.

The aim of this study was to determine whether patients with transthyretin-related hereditary amyloidosis (V30M), after transplantation or under tafamidis treatment, have normal gamete reproductive capacity. A retrospective analysis was carried out of all preimplantation genetic diagnosis (PGD) cycles performed in patients with the V30M mutation. The groups analysed were: total cases with V30M, female cases with V30M and male cases with V30M. Detailed demographic, stimulation, embryological, clinical and newborn outcomes were evaluated. Comparisons revealed that patients have a high likelihood of achieving a live birth per PGD treatment cycle (48%). This is the first large report on patients with the V30M mutation treated with PGD. The high rate of live birth obtained should represent a strong stimulus for patients to use PGD as it proved to be effective and safe. As a neurodegenerative disease that leads to death, it is of maximum importance that it could be eradicated using PGD in order to definitively avoid the transmission of the disease.

We report a 73-year-old man with Val142Ile transthyretin (TTR) amyloidosis and an atypical clinical presentation of upper-extremity-predominant neuropathy without significant autonomic or cardiac involvement. TTR familial amyloid polyneuropathy commonly presents as length-dependent sensorimotor polyneuropathy with marked and early autonomic involvement. Multiple pathogenic mutations in TTR gene have been identified, of which Val50Met is commonly associated with TTR familial amyloid polyneuropathy, and Val142Ile is commonly associated with familial amyloid cardiomyopathy. Our patient is from a nonendemic region, without family history for amyloidosis. Predominant upper-extremity neuropathy, without significant cardiac or autonomic involvement, distinguishes this case from previously reported Val142Ile-mutated TTR amyloidosis.

Introduction. To evaluate the quantification of corneal sub-basal whorl-like nerve plexus parameters as a sensitive and static marker in early diagnosis of small fiber neuropathy (SFN) and monitor disease progression in familial amyloid polyneuropathy (FAP) patients. Methods. Fifteen FAP patients and fifteen healthy controls underwent neurological evaluation (including clinical scales and electrophysiological tests) and corneal nerve observation. Corneal nerve fiber density (CNFD), Corneal nerve fiber branch density (CNBD), Corneal nerve fiber length (CNFL) were detected in the central cornea (conventional method) and the whorl-like inferocentral cornea (new method). The Langerhans cells (LC) density in each image was calculated. Results. Corneal parameters were significantly reduced with disease progression. Only inferior whorl length (IWL) was significantly reduced in preclinical patients (with normal SSR and CHEPs results) comparing with age matched controls. IWL, CNFL, CNBD and CNFD were significantly lower in early phase patients. LC density was significantly increased around the central whorl in early phase patients than in healthy controls (p = 0.009), and was lower in the progressive patients. Both IWL and CNFL correlated with severity of neuropathy. IWL was more significantly reduced with the progression of disease than CNFL. The area under the ROC curve to distinguish FAP with CNFL and IWL was 88.0% and 89.3%, respectively, exceeding other parameters. The coefficient of variation of the IWL value was significantly (P Conclusion. The observation of corneal sub-basal whorl-like nerve plexus can detect SFN in preclinical FAP patients earlier than traditional electrophysiological methods. IWL is the most sensitive and reliable parameters and it can best discriminate FAP patients from controls. The clustering of immature LCs at the whorl area might reflect the inflammatory response of small- fiber nerves at the very early stage.

Transthyretin-related familial amyloid polyneuropathy (TTR-FAP) is caused by gain-of-toxic-function of TTR, which dissociates from its native tetramer form to a monomer form and aggregates in several tissues and organs. Mutations in the TTR gene lead to this amyloidogenic transformation and cause autosomal dominant disease. TTR-FAP typically causes sensorimotor FAP accompanied by autonomic involvement, but considerable phenotypic diversity is noted between different mutation types. In the event of clinical suspicion, TTR gene sequencing and pathologic confirmation are the recommended paths to follow. Significant improvement has been achieved in treating the disease over the past 20 years, starting with liver transplantation, followed by tetramer stabilizers and TTR-lowering therapies. Although there are still some uncertainties in diagnosing and treating TTR-FAP, recent advances are promising, especially in the field of treatment