The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosi...

Background: Systemic wild-type ATTR (ATTRwt) amyloidosis is a prevalent aging-related disorder. However, a limited number of systemic ATTRwt amyloidosis patients have been diagnosed antemortem, and therefore, the prevalence of ATTRwt is underestimated. Here, we investigated clinical findings of a series of systemic ATTRwt amyloidosis patients with antemortem diagnosis. Methods: Thirty-one consecutive patients diagnosed with systemic ATTRwt amyloidosis at Shinshu University Hospital were included in this study. Systemic ATTRwt amyloidosis was diagnosed based on proven ATTR amyloid deposition in biopsy specimens and confirmation of wild-type TTR genotype. Results: The systemic ATTRwt amyloidosis patients consisted of 24 men and seven women, and mean age of onset was 69.8 ± 9.0 years. The most common initial symptom was carpal tunnel syndrome (CTS, 17 patients), followed by heart failure symptoms (14 patients). The mean age at diagnosis was 74.5 ± 8.3 years and the duration of illness from onset to diagnosis was 5.4 ± 4.4 years. Cardiogenic embolism and renal dysfunction are also frequently seen during the course of the disease. Conclusions: CTS is the most common initial symptom of systemic ATTRwt amyloidosis. Our results suggest the possibility of systemic ATTRwt amyloidosis diagnosis at an early stage by carefully examining patients with CTS.

Carpal tunnel syndrome is the most common type of entrapment neuropathy. However, the cause of carpal tunnel syndrome remains unclear in most cases. Senile systemic amyloidosis, induced by wild-type transthyretin deposition, is a prevalent aging-related disorder and often accompanied by carpal tunnel syndrome. In this study, we measured the frequency of unrecognized wild-type transthyretin deposition in patients with idiopathic carpal tunnel syndrome. One hundred twenty-three patients with carpal tunnel syndrome, including 100 idiopathic patients, treated by carpal tunnel release surgery were analyzed. Tenosynovial tissues obtained at surgery were analyzed by Congo red and immunohistochemical staining. If staining for transthyretin was positive, the entire transthyretin gene was analyzed by direct DNA sequencing. We also analyzed tenosynovial tissues from 32 autopsy cases as controls. Thirty-four patients (34.0%) with idiopathic carpal tunnel syndrome showed amyloid deposition in the tenosynovial tissue, and all amyloid showed specific immunolabeling with antitransthyretin antibody. Direct DNA sequencing of the entire transthyretin gene did not reveal any mutations, indicating that all amyloid deposits were derived form wild-type transthyretin. Statistical analysis using logistic regression showed that the prevalence of transthyretin deposition in the idiopathic carpal tunnel syndrome group was significantly higher than that in controls (odds ratio, 15.8; 95% confidence interval, 3.3-5.7), and age and male sex were independent risk factors for transthyretin amyloid deposition. Our results demonstrate that wild-type transthyretin deposition is a common cause of carpal tunnel syndrome in elderly men. It is likely that many patients develop carpal tunnel syndrome as an initial symptom of senile systemic amyloidosis.

Hereditary ATTR (ATTRm) amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) is an autosomal-dominant, adult-onset, rare systemic disorder predominantly characterized by irreversible, progressive, and persistent peripheral nerve damage. TTR gene mutations (e.g. replacement of valine with methionine at position 30 [Val30Met (p.Val50Met)]) lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, which form amyloid fibrils that deposit in peripheral nerves and various organs, giving rise to peripheral and autonomic neuropathy and several non-disease specific symptoms. Phenotypic and genetic variability and non–disease-specific symptoms often delay diagnosis and lead to misdiagnosis. Red-flag symptom clusters simplify diagnosis globally. However, in Japan, types of TTR variants, age of onset, penetrance, and clinical symptoms of Val30Met are more varied than in other countries. Hence, development of a Japan-specific red-flag symptom cluster is warranted. Presence of progressive peripheral sensory-motor polyneuropathy and ≥1 red-flag sign/symptom (e.g. family history, autonomic dysfunction, cardiac involvement, carpal tunnel syndrome, gastrointestinal disturbances, unexplained weight loss, and immunotherapy resistance) suggests ATTR-FAP. Outside of Japan, pharmacotherapeutic options are first-line therapy. However, because of positive outcomes (better life expectancy and higher survival rates) with living donor transplant in Japan, liver transplantation remains first-line treatment, necessitating a Japan-specific treatment algorithm. Herein, we present a consolidated review of the ATTR-FAP Val30Met landscape in Japan and summarize findings from a medical advisory board meeting held in Tokyo on 18th August 2016, at which a Japan-specific ATTR-FAP red-flag symptom cluster and treatment algorithm was developed. Beside liver transplantation, a TTR-stabilizing agent (e.g. tafamidis) is a treatment option. Early diagnosis and timely treatment using the Japan-specific red-flag symptom cluster and treatment algorithm might help guide clinicians regarding apt and judicious use of available treatment modalities.

Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T4) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.

Objective: To investigate the prevalence and clinical features of posttransplant CNS symptoms in patients with hereditary ATTR amyloidosis and their Pittsburgh compound B (PiB)–PET imaging correlates. Methods: We monitored prevalence and type of CNS symptoms in 53 consecutive posttransplant patients with hereditary ATTR amyloidosis. ¹¹C-PiB-PET was performed in 15 patients with various disease durations. We also analyzed pathologic and biochemical characteristics of ATTR amyloid deposition in the brain of a posttransplant patient. Results: Transient focal neurologic episodes (TFNEs) attributed to ATTR-type cerebral amyloid angiopathy (CAA) were found in 11.3% of posttransplant hereditary ATTR amyloidosis patients. TFNE occurred on average 16.8 years after onset of the disease. Patients with longer duration of illness (≥10 years) showed increased ¹¹C-PiB retention in the brain. The ¹¹C-PiB accumulation pattern in hereditary ATTR amyloidosis was unique and different from those in Alzheimer disease or Aβ-type CAA. In the autopsy case, ATTR amyloid deposition was mainly localized to leptomeningeal vessels and leptomeninges of the brain. Amyloid fibrils in the brain were almost completely composed of variant transthyretin (TTR). Conclusions: TFNE due to ATTR-type CAA occurred frequently in posttransplant patients with long disease durations. ¹¹C-PiB-PET is a useful diagnostic tool for ATTR-type CAA. ATTR amyloid deposition in the CNS, as measured by PiB-PET, was detected approximately 10 years before onset of TFNE.