Search

Amyloidosis is a term referring to a group of various protein-misfolding diseases wherein normally soluble proteins form aggregates as insoluble amyloid fibrils. How, or whether, amyloid fibrils contribute to tissue damage in amyloidosis has been the topic of debate. In vitro studies have demonstrated the appearance of small globular oligomeric species during the incubation of amyloid beta peptide (Aβ). Nerve biopsy specimens from patients with systemic amyloidosis have suggested that globular structures similar to Aβ oligomers were generated from amorphous electron-dense materials and later developed into mature amyloid fibrils. Schwann cells adjacent to amyloid fibrils become atrophic and degenerative, suggesting that the direct tissue damage induced by amyloid fibrils plays an important role in systemic amyloidosis. In contrast, there is increasing evidence that oligomers, rather than amyloid fibrils, are responsible for cell death in neurodegenerative diseases, particularly Alzheimer's disease. Disease-modifying therapies based on the pathophysiology of amyloidosis have now become available. Aducanumab, a human monoclonal antibody against the aggregated form of Aβ, was recently approved for Alzheimer's disease, and other monoclonal antibodies, including gantenerumab, solanezumab, and lecanemab, could also be up for approval. As many other agents for amyloidosis will be developed in the future, studies to develop sensitive clinical scales for identifying improvement and markers that can act as surrogates for clinical scales should be conducted.

As familial amyloid polyneuropathy (FAP) is an adult-onset disease, a long period is expected between domino liver transplantation (DLT) and the occurrence of amyloidosis in recipients of a FAP liver. However, as time passes, and increased numbers of patients have undergone DLT, patients with symptoms suggesting amyloidosis have been reported. The authors describe, for the first time, pathological findings in an autopsy case of a recipient of a FAP liver. A male patient with primary sclerosing cholangitis received a liver graft from a FAP patient with the transthyretin (TTR) Tyr114Cys mutation when he was 30 years old. Although a recurrence of primary sclerosing cholangitis was detected at age 34, he had no symptoms indicating amyloidosis. He died from Burkitt's lymphoma at 38 years of age. TTR immunoreactive amyloid was found in various organs including the heart, lung, gastrointestinal tract, pancreas, spleen, reproductive system and skeletal muscles. In the nervous system, TTR immunoreactive amyloid deposition was obvious in the sympathetic ganglia and the median nerve within the carpal tunnel, while loss of neurons or nerve fibres was not apparent. This case allows for the characterisation of amyloid deposition during the asymptomatic stage of FAP. Widespread amyloid deposition may occur before tissue damage in this disease.

Hereditary transthyretin (ATTRv) amyloidosis is a rare and autosomal dominant disorder associated with mutations in the transthyretin gene. Patients present with diverse symptoms related to sensory, motor, and autonomic neuropathy, as well as gastrointestinal, ocular, cardiac, renal and orthopedic symptoms, resulting from the deposition of transthyretin amyloid fibrils in multiple organs. The progressive nature of ATTRv amyloidosis necessitates pre- and post-onset monitoring of the disease. This review article is primarily based on a collation of discussions from a medical advisory board meeting in August 2021. In this article, we summarize the best practices in amyloidosis centers in three major endemic countries for ATTRv amyloidosis (Japan, Brazil, and Portugal), where most patients carry the Val30Met mutation in the transthyretin gene and the patients' genetic background was proven to be the same. The discussions highlighted the similarities and differences in the management of asymptomatic gene mutation carriers among the three countries in terms of the use of noninvasive tests and tissue biopsies and timing of starting the investigations. In addition, this article discusses a set of practical tests and examinations for monitoring disease progression applicable to neurologists working in diverse medical settings and generalizable in non-endemic countries and areas. This set of assessments consists of periodic (every 6 to 12 months) evaluations of patients' nutritional status and autonomic, renal, cardiac, ophthalmologic, and neurological functions. Physical examinations and patient-reported outcome assessments should be also scheduled every 6 to 12 months. Programs for monitoring gene mutation carriers and robust referral networks can aid in appropriate patient management in pre- to post-onset stages. For pre- and post-symptom onset testing for ATTRv amyloidosis, various noninvasive techniques are available; however, their applicability differs depending on the medical setting in each country and region, and the optimal option should be selected in view of the clinical settings, medical environment, and available healthcare resources in each region. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. Methods: The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. Results: At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10–10) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10–7), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10–7), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10–15), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10–15) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. Conclusion: Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. Trial Registration Number: ClinicalTrials.gov: NCT03759379. [ABSTRACT FROM AUTHOR]

Objective: Hereditary transthyretin amyloidosis (ATTRv) encompasses different phenotypes among various genotypes. The analysis of the natural history and risk factors of faster progression in different genotypes would refine the treatment strategy. Methods: The clinical manifestations of ATTRv from A97S (p.A117S) of Taiwanese and late-onset V30M (p.V50M) of Japanese were compared. An autopsy study of A97S was performed. Results: There existed three unique features in the A97S cohort compared to the V30M cohort: (1) dysphagia, (2) carpal tunnel syndrome (CTS), and (3) onset age. First, dysphagia was common in A97S (53.4%) but not in V30M and served as a contributor to fast disease progression. All phases of swallowing were affected. In the autopsy pathology, there were extensive amyloid deposits in the viscera and nerves of the tongue, larynx, and esophagus. In A97S, 45 patients (43.3%) had a history of CTS before the onset of length-dependent symptoms by 3 years. The amyloid deposition was more prominent in the median nerve than that in the transverse carpal ligament. The onset age at different stages was younger in the A97S cohort than the V30M cohort by 4–5 years. Conclusion: These phenotypic characteristics together with autopsy pathology in A97S are distinct from V30M. Early dysphagia in A97S correlated with fast progression. In A97S, median neuropathy leading to CTS might be in a continuous spectrum of ATTRv course rather than an independent disease entity. Such observations may serve as a foundation to explore and analyze unique phenotypes among various genotypes. [ABSTRACT FROM AUTHOR]

Amyloidosis caused by systemic deposition of transthyretin (TTR) is called ATTR amyloidosis and mainly includes hereditary ATTR (ATTRv) amyloidosis and wild-type ATTR (ATTRwt) amyloidosis. Until recently, ATTRv amyloidosis had been considered a disease in the field of neurology because neuropathic symptoms predominated in patients described in early reports, whereas advances in diagnostic techniques and increased recognition of this disease revealed the presence of patients with cardiomyopathy as a predominant feature. In contrast, ATTRwt amyloidosis has been considered a disease in the field of cardiology. However, recent studies have suggested that some of the patients with ATTRwt amyloidosis present tenosynovial tissue complications, particularly carpal tunnel syndrome, as an initial manifestation of amyloidosis, necessitating an awareness of this disease among neurologists and orthopedists. Although histopathological confirmation of amyloid deposits has traditionally been considered mandatory for the diagnosis of ATTR amyloidosis, the development of noninvasive imaging techniques in the field of cardiology, such as echocardiography, magnetic resonance imaging, and nuclear imaging, enabled nonbiopsy diagnosis of this disease. The mechanisms underlying characteristic cardiac imaging findings have been deciphered by histopathological studies. Novel disease-modifying therapies for ATTR amyloidosis, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotides, were initially approved for ATTRv amyloidosis patients with polyneuropathy. However, the indications for the use of these disease-modifying therapies gradually widened to include ATTRv and ATTRwt amyloidosis patients with cardiomyopathy. Since the coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, occurred, the minimization of hospital visits and telemedicine have become increasingly important. As older age and cardiovascular disease are major factors associated with increased disease severity and mortality of COVID-19, many ATTR amyloidosis patients are at increased risk of disease aggravation when they are infected with SARS-CoV-2. From this viewpoint, close interspecialty communication to determine the optimal interval of evaluation is needed for the management of patients with ATTR amyloidosis. [ABSTRACT FROM AUTHOR]

ATTR amyloidosis is caused by systemic deposition of transthyretin (TTR) and comprises ATTRwt (wt for wild-type) amyloidosis, ATTRv (v for variant) amyloidosis, and acquired ATTR amyloidosis after domino liver transplantation. ATTRwt amyloidosis has classically been regarded as cardiomyopathy found in the elderly, whereas carpal tunnel syndrome has also become a major initial manifestation. The phenotypes of ATTRv amyloidosis are diverse and include neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation and age of onset. In addition to variant TTR, the deposition of wild-type TTR plays a significant role, even in patients with ATTRv amyloidosis. The formation of amyloid fibrils tends to occur in association with the basement membrane. The thickening or reduplication of the basement membrane surrounding endoneurial microvessels, which is similar to diabetic neuropathy, is observed in ATTRv amyloidosis, suggesting that common mechanisms, such as an accumulation of advanced glycation end products, may participate in the disease process. In addition to direct damage caused by amyloid fibrils, recent studies have suggested that the toxicity of nonfibrillar TTRs, such as TTR oligomers, participates in the process of tissue damage. Although liver transplantation has been performed for patients with ATTRv amyloidosis since 1990, late-onset patients were not eligible for this treatment. However, as the efficacy of orally administered tafamidis and diflunisal, which stabilize TTR tetramers, was suggested in the early 2010s, such late-onset patients have also become targets for disease-modifying therapies. Additionally, recent studies of small interfering RNA (patisiran) and antisense oligonucleotide (inotersen) therapies have demonstrated the efficacy of these gene-silencing agents. A strategy for monitoring patients that enables the choice of an appropriate treatment from comprehensive and long-term viewpoints should be established. As many patients with ATTR amyloidosis are aged and have heart failure, they are at increased risk of aggravation if they are infected by SARS-CoV2. The optimal interval of evaluation should also be considered, particularly in this COVID-19 era. [ABSTRACT FROM AUTHOR]

Background: Hereditary transthyretin‐mediated (hATTR) amyloidosis is a rapidly progressive and fatal disease. Patisiran is an RNA interference therapeutic that inhibits synthesis of disease‐causing mutant and wild‐type transthyretin (TTR) protein in hATTR amyloidosis. Aim: The efficacy and safety of patisiran were evaluated in the Phase 3 APOLLO study in patients with hATTR amyloidosis with polyneuropathy. Methods: In total, 225 patients from 19 countries, including Japan (n = 16), received patisiran 0.3 mg/kg intravenously or placebo once every 3 weeks for 18 months. Patisiran halted or improved outcomes of polyneuropathy (measured by modified Neuropathy Impairment Score +7 [mNIS+7]) and improved quality of life (QOL) (measured by Norfolk Quality of Life‐Diabetic Neuropathy questionnaire). Present analyses assess the efficacy, safety, pharmacokinetic exposure, and pharmacodynamic effect of patisiran in the Japanese sub‐population of APOLLO. Results: Consistent with the overall APOLLO population, patisiran significantly improved outcomes of polyneuropathy (mNIS+7) compared with placebo at 18 months in the APOLLO Japanese patients. Patisiran treatment also demonstrated benefit in QOL, motor strength, gait speed, nutritional status, and autonomic symptoms compared with placebo at 18 months in the Japanese sub‐population. Patisiran was generally well tolerated in Japanese patients, with most adverse events mild or moderate; safety profile was similar to the overall APOLLO population, and no deaths were observed. Patisiran pharmacokinetic exposures and TTR reduction were comparable to the overall population. Conclusions: Data in the Japanese sub‐population were consistent with those from the overall APOLLO population and indicate a notable health benefit for patisiran treatment in Japanese patients with hATTR amyloidosis with polyneuropathy. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin (ATTRv) amyloidosis, also known as familial amyloid polyneuropathy, is a disease caused by the systemic deposition of variant transthyretin (TTR). Although this disease was primarily indigenous to endemic foci in Portugal, Japan, and Sweden, its prevalence has increased throughout the world. The clinical phenotypes of ATTRv amyloidosis are diverse, including neuropathy, cardiomyopathy, and oculoleptomeningeal involvement as the predominant features, depending on the mutation type and age of onset. Val30Met, one of the most common TTR mutations, exhibits varying characteristic features in the early‐onset patients from conventional endemic foci and the late‐onset patients from non‐endemic areas. Autonomic dysfunctions and dissociated sensory loss are the characteristic features of the former, whereas motor dysfunctions and loss of all sensory modalities are conspicuous in the latter. Distortion and atrophy of the Schwann cells due to the formation of amyloid fibrils seem to cause predominant small‐fiber loss in the early‐onset patients, while other mechanisms, such as microangiopathy and the toxicity of TTR oligomers, may contribute to nerve fiber loss in the late‐onset patients. In addition to liver transplantation, novel and less invasive disease‐modifying therapies, such as TTR stabilizers, short interfering RNA, and antisense oligonucleotide, have been shown to be effective in ATTRv amyloidosis patients. Given their ability to ameliorate ATTRv amyloidosis, early diagnosis and treatment are required. Physicians should be aware of the diversity in ATTRv amyloidosis because this disease can be misdiagnosed with other diseases such as chronic inflammatory demyelinating polyneuropathy and immunoglobulin light‐chain amyloidosis. [ABSTRACT FROM AUTHOR]

Hereditary amyloidogenic transthyretin (ATTRv) amyloidosis with polyneuropathy (also known as familial amyloid polyneuropathy) is a condition with adult onset caused by mutation of transthyretin (TTR) and characterized by extracellular deposition of amyloid and destruction of the somatic and autonomic PNS, leading to loss of autonomy and death. This disease represents a model of the scientific and medical progress of the past 30 years. ATTRv amyloidosis is a worldwide disease with broad genetic and phenotypic heterogeneity that presents a diagnostic challenge for neurologists. The pathophysiology of the neuropathy is increasingly understood and includes instability and proteolysis of mutant TTR leading to deposition of amyloid with variable lengths of fibrils, microangiopathy and involvement of Schwann cells. Wild-type TTR is amyloidogenic in older individuals. The main symptoms are neuropathic, but the disease is systemic; neurologists should be aware of cardiac, eye and kidney involvement that justify a multidisciplinary approach to management. Infiltrative cardiomyopathy is usually latent but present in half of patients. Disease-modifying therapeutics that have been developed include liver transplantation and TTR stabilizers, both of which can slow progression of the disease and increase survival in the early stages. Most recently, gene-silencing drugs have been used to control disease in the more advanced stages and produce some degree of improvement. [ABSTRACT FROM AUTHOR]

Objective: A nationwide survey on systemic wild-type ATTR (ATTRwt) amyloidosis was conducted to elucidate the frequency, clinical picture and possible diagnostic issues of ATTRwt amyloidosis in Japan. Methods: A questionnaire was sent to 4629 clinical departments across Japan. A total of 2341 (50.6%) responses were returned completed for further analysis. Results: Fifty-one patients with ATTRwt amyloidosis (82% male) were identified between January 2012 and December 2014. The study subjects were identified in 11 departments at 10 institutes. The mean age of onset and diagnosis were 71.6 and 73.6 years, respectively. The main clinical findings were cardiac failure (76%), cardiac conduction defects/arrhythmia (59%), renal dysfunction (49%), carpal tunnel syndrome (45%) and spinal canal stenosis (22%). Conclusions: ATTRwt amyloidosis is diagnosed in a limited number of institutes in Japan and is therefore considered to be underdiagnosed. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP and is now prevalent in areas other than those seen within conventional endemic foci. We investigated 15 patients with FAP ATTR Val30Met without a family history of FAP who were referred for sural nerve biopsy. Initial symptoms included somatic neuropathy in all patients, while sensory dissociation and autonomic symptoms were apparent only in two and seven patients, respectively. Nonspecific neuropathic features and slight abnormalities in cerebrospinal fluid protein levels and in electrophysiological indices related to nerve conduction led clinicians to initially suspect chronic inflammatory demyelinating polyneuropathy (CIDP) in some patients. Small-fiber predominant loss was observed in a minority of patients. In terms of cardiac involvement, findings suggestive of subclinical cardiomyopathy due to amyloid deposition, such as cardiomegaly on chest X-ray, thickening of the interventricular septum, and granular sparkling echo on echocardiography, were seen alone or in combination in 11 of 14 examined patients. In conclusion, clinicians should consider the possibility of FAP ATTR Val30Met in patients presenting with neuropathy of undetermined etiology to avoid misdiagnosis. Detecting subclinical cardiac involvement may help to diagnose late-onset FAP ATTR Val30Met in those without a family history of the disease. [ABSTRACT FROM AUTHOR]

Highlights from the article: Late-onset hereditary (variant) transthyretin (ATTRv) amyloidosis, particularly Val30Met, cases unrelated to endemic foci showed different clinicopathological features compared with early-onset cases in endemic foci [[1]]. Clinical and pathological features in Ala97Gly and Val94Gly patients were similar to those in late-onset Val30Met patients.

Highlights from the article: Studies regarding hereditary (variant) transthyretin (ATTRv) amyloidosis have mainly focused on patients with Val30Met mutation [[1]]. We examined four patients with ATTRv amyloidosis with non-Val30Met mutation (Pro24Ser, Val71Ala, Thr60Ala and Tyr114Cys) [[7]]. Both cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, even in patients without orthostatic hypotension.

Although polyneuropathy in patients with immunoglobulin light chain (AL) amyloidosis has been considered to be attributable to axonal degeneration resulting from amyloid deposition, patients with nerve conduction parameters indicating demyelination that mimics chronic inflammatory demyelinating polyneuropathy (CIDP) have also been reported anecdotally. We evaluated the electrophysiological and pathological features of 8 consecutive patients with AL amyloidosis who were referred for sural nerve biopsy. Although findings of axonal neuropathy predominantly in the lower limbs were the cardinal feature, all patients showed one or more abnormalities of nerve conduction velocities or distal motor latencies. In particular, 2 of these patients fulfilled the definite electrophysiological for CIDP defined by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS). On electron microscopic examination of sural nerve biopsy specimens, Schwann cells apposed to amyloid fibrils became atrophic in all patients, suggesting that amyloid deposits directly affect neighboring tissues. Additionally, detachment of the neurilemma from the outermost compacted myelin lamella was seen where amyloid fibrils were absent in 4 patients. Electrophysiological findings suggestive of demyelination were more conspicuous in these patients compared with the other patients. The detachment of the neurilemma from the outermost compacted myelin lamella was particularly conspicuous in patients who fulfilled the definite EFNS/PNS electrophysiological criteria for CIDP. Abnormalities of myelinated fibers unrelated to amyloid deposition may frequently occur in AL amyloidosis. Disjunction between myelin and the neurilemma may induce nerve conduction abnormalities suggestive of demyelination. • Electrophysiological findings suggestive of demyelination have anecdotally been reported in patients with AL amyloidosis. • This study evaluates the pathological findings of sural nerve biopsy specimens from AL amyloidosis patients, focusing on lesions of myelinated fibers leading to aberrant nerve conduction. • In addition to the direct damage by amyloid fibrils to Schwann cells, a detachment of the neurilemma from the outermost compacted myelin lamella was seen where amyloid fibrils were absent. • Nerve conduction abnormalities suggestive of demyelination were more conspicuous in patients with the disjunction between myelin and the neurilemma than the other patients. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) Val30Met-associated familial amyloid polyneuropathy (FAP ATTR Val30Met) is the most common form of FAP. We compared the clinicopathological features and natural history of late-onset FAP ATTR Val30Met cases from nonendemic areas of Japan with early-onset cases from endemic foci. The characteristics of early-onset cases from endemic foci of Japan included the presence of sensory dissociation and marked autonomic dysfunction associated with a predominant loss of small-diameter myelinated and unmyelinated nerve fibers. These characteristics were not common in the lateonset cases from non-endemic areas. The distribution and characteristics of amyloid deposits in late-onset cases were similar to those of senile systemic amyloidosis with wild-type TTR deposition. The causal mechanism of differences between the early- and late-onset forms of FAP with the same mutation in the TTR gene has not yet been determined. [ABSTRACT FROM AUTHOR]

Highlights from the article: Hereditary (variant) transthyretin (ATTRv) amyloidosis is the most common hereditary amyloidosis, prevalent even in areas other than conventional endemic foci [[1]]. Mature fibrils tended to be long in early-onset Val30Met patients, whereas amyloid fibrils were generally short in late-onset Val30Met patients. These findings suggested that protofibrillar amyloid precursors were present in the endoneurium before the formation of amyloid fibrils in patients with hereditary ATTRv amyloidosis.

Highlights from the article: Hereditary ATTR (ATTRm) amyloidosis with Val30Met mutation is the most common form of hereditary amyloidosis. We examined patients with late-onset (>50 years of age) ATTRm amyloidosis with Val30Met mutation from non-endemic areas of Japan who were referred to Nagoya University Graduate School of Medicine [[5]]. Although only a half of the patients manifested orthostatic hypotension during the head-up tilt test, CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated a higher prevalence of cardiac sympathetic and parasympathetic dysfunction.

Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program. [ABSTRACT FROM AUTHOR]

Hereditary transthyretin (ATTRv) amyloidosis is an adult-onset, systemic disorder caused by mutations in the transthyretin (TTR) gene. As ATTRv amyloidosis is inherited in an autosomal dominant manner, family members of the patients are at risk of developing the disease. With an objective of discussing recommendations on monitoring of family members for early diagnosis of ATTRv amyloidosis, we held a medical advisory board meeting in Tokyo, Japan, in October 2017. Our recommendations are summarized as follows: periodic follow-up genetic counseling should be offered to asymptomatic gene mutation carriers; follow-up assessments should be started when the carriers are still asymptomatic to test for amyloidosis onset, irrespective of TTR genotype and age at onset in the particular family. We suggest annual routine assessments and in-depth assessments every 3–5 years, with the frequency of these increased as required. Periodical monitoring of asymptomatic gene mutation carriers is crucial for attending physicians to detect early signs or symptoms of the disease and start disease-modifying therapy (DMT). The monitoring strategy for asymptomatic TTR gene mutation carriers should progress toward rapid diagnosis and early intervention with DMT. This approach may be more appropriate for countries with more resources. • Hereditary transthyretin (ATTRv) amyloidosis is an autosomal dominant disorder. • Families of patients with ATTRv amyloidosis are at risk of developing the disease. • We discussed recommendations on monitoring of early signs of ATTRv amyloidosis. • Periodic follow-up genetic counseling and routine assessments are recommended. • Annual and in-depth (every 3–5 years) assessment will help detect the disease early. [ABSTRACT FROM AUTHOR]

Abstract: Background: Age and sex differences are closely related to the onset of senile systemic amyloidosis (SSA) caused by wild-type (WT) transthyretin (TTR). However, the effects of these differences on the amyloid formation mechanism in familial amyloid polyneuropathy (FAP) caused by variant TTR, have remained unclear. To elucidate age and sex differences in FAP, we investigated biochemical characteristics of amyloid deposits in different tissue sites of FAP by proteomic analysis. Methods: We used shotgun liquid chromatography/tandem mass spectrometry to analyze the proportions of variant and WT TTR in amyloid deposits in different tissues, such as cardiac, kidney, peripheral nerves, and gastrointestinal tissues, from 23 autopsied FAP cases. Results and conclusions: The analysis revealed a highly significant correlation between the proportion of WT TTR and age at autopsy in cardiac tissues, whereas the analysis indicated no correlation in kidney, peripheral nerves, and gastrointestinal tissues. In addition, we demonstrated age-related significantly increased WT TTR deposits, but not variant TTR deposits, in cardiac tissues of male patients. Taken together, these data suggest that both age and sex differences affect cardiac amyloid formation, mainly derived from WT TTR, in FAP. [Copyright &y& Elsevier]