The Transthyretin Gene Mutation Research Articles

Transthyretin amyloidosis. Fundamentals of pathogenesis, diagnosis, treatment, prognosis

Among the 42 human amyloidoses described to date the so-called systemic transthyretin amyloidosis, which comprises hereditary forms (more than 140 variants in accordance with the number of identified mutations in the transthyretin gene) and a sporadic form without structural changes in the gene and the protein, is of particular interest. This review summarizes modern understandings of pathogenesis of transthyretin amyloidosis. The symptoms of different forms of transthyretin amyloidosis, issues of early diagnosis, differential diagnosis (including within the group of amyloidoses), advanced therapy and prognosis are considered. Special attention is given to the non-mutant form of transthyretin amyloidosis, the so-called senile amyloidosis, which significantly complicates the course of underlying pathologies in the age group older than 70 years and is still poorly diagnosed. A quite high occurrence of non-mutant form of transthyretin amyloidosis makes it to be considered as a socially significant disease.

A description of variant transthyretin amyloidosis (ATTRv) stage 1 patients and asymptomatic carriers in Spain: the EMPATIa study

BackgroundVariant transthyretin amyloidosis (ATTRv) is a rare multisystemic disorder caused by mutations in the transthyretin (TTR) gene. The aim of the present work was to describe the clinical profile of asymptomatic carriers (AC) and Coutinho stage 1 ATTRv patients in Spain.MethodsNational, multicentre, cross-sectional study that included 86 AC and 19 patients diagnosed in the previous 12 months to enrolment. Clinical and demographical data, TTR gene mutations, red flags anamnesis, neurological and cardiological assessments were collected.ResultsThe mean age of patients was 56.8 years at onset and 58.6 years at diagnosis; 53% of patients and 51% of AC were from non-endemic areas. Val50Met was the most frequent mutation in both groups. Neuropathy impairment score data (mean 17.7 ± 20.5) and small-fibre function in lower limbs assessed with SUDOSCAN revealed that patients were diagnosed at early stages of neurological impairment. Peripheral polyneuropathy (84.2%), autonomic neuropathy (73.7%), cardiac (63.2%) and gastrointestinal (47.4%) alterations were the most common symptoms in patients. Autonomic neuropathy, gastrointestinal impairment, carpal tunnel syndrome, cardiac and ocular alterations were potentially related to ATTRv in the AC group.ConclusionsThe EMPATIa study provides a detailed description of AC and Coutinho stage 1 ATTRv patients across Spain, confirming the multisystemic clinical profile of the disease. This study reveals a diagnosis delay around 1.8 years, highlighting the importance of a profound disease awareness to reach a diagnose in earlier stages of neurological impairment.

Long-term treatment of hereditary transthyretin amyloidosis with patisiran: multicentre, real-world experience in Italy.

Hereditary transthyretin (ATTRv, v for variant) amyloidosis with polyneuropathy is a rare disease caused by mutations in the transthyretin gene. In ATTRv amyloidosis, multisystem extracellular deposits of amyloid cause tissue and organ dysfunction. Patisiran is a small interfering RNA molecule drug that reduces circulating levels of mutant and wild-type TTR proteins. Prior to its regulatory approval, patisiran was available in Italy through a compassionate use programme (CUP). The aim of this study was to analyse the long-term outcomes of patients who entered into the CUP. This was a multicentre, observational, retrospective study of patients with ATTRv amyloidosis treated with patisiran. The analysis included change from baseline to 12, 24, 36 and 48 months in familial amyloid polyneuropathy (FAP) stage, polyneuropathy disability (PND) class, neuropathy impairment score (NIS), modified body mass index (mBMI), Compound Autonomic Dysfunction Test (CADT), Karnofsky Performance Status (KPS) scale and Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) questionnaire. Safety data were also analysed. Forty patients from 11 Italian centres were enrolled: 23 in FAP 1 (6 in PND 1 and 17 in PND 2) and 17 in FAP 2 (8 in PND 3a and 9 in PND 3b) stage. In this population, the mean NIS at baseline was 71.4 (± 27.8); mBMI, 917.1 (± 207) kg/m2; KPS, 67.1 (± 14.0); Norfolk QoL-DN, 62.2 (± 25.2); and CADT, 13.2 (± 3.3). Statistical analysis showed few significant differences from baseline denoting disease stability. No new safety signals emerged. Patisiran largely stabilised disease in patients with ATTRv amyloidosis.

Real-life experience with inotersen at CEPARM, Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro.

Hereditary transthyretin amyloidosis (ATTRv) is an inherited, progressive, and fatal disease still largely underdiagnosed. Mutations in the transthyretin (TTR) gene cause the TTR protein to destabilize, misfold, aggregate, and deposit in body tissues, which makes ATTRv a disease with heterogeneous clinical phenotype. To describe the long-term efficacy and safety of inotersen therapy in patients with ATTRv peripheral neuropathy (ATTRv-PN). Patients who completed the NEURO-TTR pivotal study and the NEURO-TTR OLE open-label extension study migrated to the present study and were followed-up for at least 18 more months to an average of 67 months and up to 76 months since day 1 of the inotersen therapy (D1-first dose of inotersen). Disease progression was evaluated by standard measures. Ten ATTRv-PN patients with Val30Met mutation were included. The mean disease duration on D1 was of 3 years, and the mean age of the patients was of 46.8 years. During an additional 18-month follow up, neurological function, based on the Neuropathy Impairment Score and the Polyneuropathy Disability Score, functionality aspects (Karnofsky Performance Status), and nutritional and cardiac aspects were maintained. No new safety signs have been noted. The treatment with inotersen was effective and well tolerated for the average of 67 months and up to 76 months. Our results are consistent with those of larger phase-III trials.

A clinical case of transthyretin amyloidosis with manifestations of seronegative arthritis

A clinical case of transthyretin amyloidosis with manifestations of seronegative arthritis

Non-Cardiac Amyloidosis Findings Are Not Increased in African American Carriers of TTR V142I with Heart Failure and/or Arrhythmia.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive systemic disease involving the extracellular deposition of misfolded transthyretin protein. The hereditary subtype is caused by mutations in the transthyretin (TTR) gene. An estimated 2-3% of individuals of African American (AA) ancestry carry the p.Val142Ile (V142I, also referred to as V122I) TTR pathogenic variant. The non-specific clinical nature of ATTR-CM makes it challenging to diagnose clinically, and the high allele frequency of TTR V142I suggests that many patients with hereditary ATTR-CM may not have been tested. An analysis of electronic health record data from over 13,000 AA patients with a diagnostic code for heart disease or arrhythmia who also had additional amyloid-related findings were not diagnosed with amyloidosis at higher rates than those with heart failure or arrhythmia who did not have additional amyloid-related clinical diagnoses. Similarly, after genotyping 666 AA patients with heart failure or arrhythmia, TTR V142I carriers appeared to be clinically indistinguishable based on amyloid-related non-cardiac diagnoses from those who did not carry the allele. No additional TTR gene sequence variants were found in the TTR wildtype V142V patients with heart failure or arrhythmia who had additional amyloid-related diagnoses. Genetic testing for ATTR-CM may be important for timely diagnosis.

Vutrisiran: a new drug in the treatment landscape of hereditary transthyretin amyloid polyneuropathy

ABSTRACT Introduction Hereditary transthyretin (ATTRv) amyloidosis is a progressive, fatal disorder caused by mutations in the transthyretin (TTR) gene leading to deposition of the misfolded protein in amyloid fibrils. The main phenotypes are peripheral neuropathy (PN) and cardiomyopathy (CM). Areas covered Gene silencing therapy, by dramatically reducing liver production of TTR, has transformed ATTRv-PN patient care in the last decade. In this drug discovery case history, the authors discuss the treatment history of ATTRv-PN and focus on the latest siRNA therapy: vutrisiran. Vutrisiran is chemically enhanced and N-acetylgalactosamin-conjugated, allowing increased stability and specific liver delivery. HELIOS-A, a phase III, multicenter randomized study, tested vutrisiran in ATTRv-PN and showed significant improvement in neuropathy impairment, disability, quality of life (QoL), gait speed, and nutritional status. Tolerance was acceptable, no safety signals were raised. Expert opinion Vutrisiran offers a new treatment option for patients with ATTRv-PN. Vutrisian’s easier delivery and administration route, at a quarterly frequency, as well as the absence of premedication, are major improvements to reduce patients’ disease burden and improve their QoL. Its place in the therapeutic strategy is to be determined, considering affordability.

Characterization and natural history of phenotypes in hereditary transthyretin amyloidosis

Abstract Background Hereditary systemic amyloidosis (ATTRv), caused by mutations in the transthyretin (TTR) gene, is a rare systemic disease with autosomal dominant transmission, incomplete penetrance, and variable expressivity. Purpose The purpose of this study was to describe the population of individuals with pathogenic mutations for TTR, comparing the genotype and clinical-instrumental characteristics of patients based on phenotype. Subsequently, the disease course was investigated in terms of the onset of new clinical manifestations, survival, and hospitalizations for heart failure. Methods Clinical and instrumental data from 325 consecutive patients carrying a pathogenic mutation of the TTR gene (asymptomatic carriers, n=106; cardiac phenotype, n=49; neurological phenotype, n=49; mixed phenotype, n=121) were analyzed at Our Center between 1979 and August 2022. Results A total of 23 different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most represented. Dominant mutations were found in patients with cardiac and neurological phenotypes, respectively Ile68Leu and Val30Met, while patients with mixed phenotype had marked genotypic variability. Patients with cardiac amyloidosis (CA) were predominantly male and had a more advanced NYHA functional class at presentation, while subjects with neurological involvement showed greater motor disabilities. There was also a significant difference in the age of disease diagnosis between the three groups: cardiac phenotype 73.2 years (IQR 66.5 – 78.1), mixed phenotype 58.4 years (IQR 47- 66.3), neurological phenotype 44 years (IQR 33.5 – 62.9). At the end of a median follow-up of 51 months (IQR 24 – 90 months), data from 290 subjects were analyzed, of whom 111 (38.3%) died and 123 (42.4%) had a major clinical event, including death or hospitalization for heart failure. Subjects without signs of disease had a prognosis similar to that of the healthy population, while patients with CA, with or without neurological manifestations, had a worse overall and event-free survival compared to those with isolated neurological phenotype. On multivariate analysis, age at diagnosis, NYHA functional class, and an mPND score ³ 2 were independently associated with adverse clinical events. Conclusions This study confirms the important clinical heterogeneity of patients with ATTRv, where three main phenotypes can be identified, characterized by specific clinical, demographic, and instrumental features. Although in some cases it is possible to identify a genotype-phenotype correlation, the extreme variability of clinical presentation is evident even among patients sharing the same mutation. In the study cohort, patients with CA had a worse prognosis. However, this finding should be interpreted with caution because it is influenced by disease-modifying therapy, which was performed unevenly among the three phenotypes.Univariate and multivariateKaplan-Meier curves

Practical Guidance for the Use of Patisiran in the Management of Polyneuropathy in Hereditary Transthyretin-Mediated Amyloidosis.

Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited genetic disorder that affects 5000-10,000 people worldwide. It is caused by mutations in the transthyretin (TTR) gene and results in amyloid deposition in a variety of organs due to abnormal accumulation of TTR protein fibrils. Although this is a multisystem disorder, the heart and peripheral nerves are the preferentially affected organs. Over 150 TTR gene mutations have been associated with this disease and the clinical phenotype can vary significantly. Severe forms of the disorder can be fatal. Fortunately, the oligonucleotide-based therapy era has resulted in the development of several novel treatment options. Patisiran is a small interfering RNA (siRNA) encapsulated in a lipid nanoparticle that targets both mutant and wild-type TTR and results in significant reductions of the TTR protein in the serum and in tissue deposits. Patisiran has been approved for treatment of adults with polyneuropathy due to hereditary TTR-mediated amyloidosis in both the United States (US) and European Union (EU). In this review, we will discuss the development of patisiran, the clinical trials that lead to treatment approval, and provide guideline parameters for use in clinical practice. .

Peripheral neuropathy secondary to a ‘domino’ liver transplant: a case report

BackgroundPeripheral neuropathy caused by amyloidosis is one of the well-recognised sequelae of mutations in the transthyretin gene (TTR).Case presentationWe describe a case of peripheral neuropathy in a White British 74 year old man with wild-type TTR, 8 years following receipt of a ‘domino’ liver transplant (from a donor with a TTR mutation). The clinical phenotype and neurophysiology, coupled with presence of ATTR amyloid deposits on fat biopsy, established the diagnosis of ATTR amyloid neuropathy, as a consequence of receipt of a variant-TTR secreting liver. A nerve biopsy was not clinically appropriate for this patient. Such cases are rare since recipients of such livers are typically restricted to people whose natural lifespan is unlikely to stretch into the anticipated symptomatic period of ATTR amyloidosis. However, novel “gene silencing” therapeutics are now available which can dramatically alter the course of this disorder, by reducing the proportion of abnormal proteins.ConclusionsThis represents a rare but predictable iatrogenic side effect, and doctors should be aware of this eventuality occurring in a shorter time span than previously anticipated.

P208 PREVALENCE OF TRANSTHYRETIN CARDIAC AMYLOIDOSIS IN PATIENTS HOSPITALIZED FOR HEART FAILURE

Abstract Background Bone scintigraphy with labeled diphosphonates allows for the non–invasive diagnosis of transthyretin cardiac amyloidosis, in case of high cardiac uptake of the radiotracer and concomitant absence of serum monoclonal component (Gillmore algorithm). Objective The aim of this study was to establish the prevalence of transthyretin cardiac amyloidosis in a population of patients hospitalized for heart failure. Methods In this prospective observational study, patients hospitalized for heart failure at the Cardiology Unit of Castelsangiovanni Hospital were evaluated in the period from 1 January 2021 to 31 July 2022. Twenty–five of them, who presented with echocardiographic moderate to severe left ventricular hypertrophy (i.e. maximum end–diastolic thickness of the interventricular septum ≥ 15 mm), were included in the study. All patients underwent anamnesis, physical examination, 12–lead electrocardiogram and transthoracic echocardiogram. Patients were divided into 2 groups according to the presence or absence of the following clinical, electrocardiographic and echocardiographic diagnostic red flags: history of carpal tunnel syndrome and/or rupture of the long head of the brachial biceps, low voltage QRS, granular sparkling of the ventricular myocardium, apical sparing pattern of the global longitudinal strain. Results Fifteen patients with heart failure, left ventricular hypertrophy and at least one diagnostic red flag were screened for cardiac amyloidosis by: a) search for a serum monoclonal component; b) bone scintigraphy with labeled diphosphonates. In thirteen patients, an high cardiac uptake of the radiotracer was found on bone scintigraphy. One patient with high cardiac uptake also presented a serum monoclonal component and was referred for tissue biopsy. In the remaining twelve patients (85% of the cases studied) a non–invasive diagnosis of transthyretin cardiac amyloidosis was made. In six patients affected by transthyretin cardiac amyloidosis, a salivary genetic test was also performed to search for mutations in the transthyretin gene, which resulted negative in all cases examined. Conclusions In this study of patients hospitalized for decompensated heart failure, rigorous application of Gillmore‘s algorithm in suspected cases led to non–invasive diagnosis of cardiac transthyretin amyloidosis in 85% of cases, without wasting healthcare resources.

A retrospective survey of patients with hereditary transthyretin-mediated (hATTR) amyloidosis treated with patisiran in real-world clinical practice in Belgium

IntroductionHereditary transthyretin-mediated (hATTR) amyloidosis, a genetic disease caused by mutations in the transthyretin gene, leads to progressive sensory and autonomic neuropathy and/or cardiomyopathy and is associated with renal and ophthalmologic manifestations and a poor prognosis.MethodsThis is a retrospective study based on data collected from the medical records of patients with hATTR amyloidosis treated with patisiran between 01 July 2018 and 01 February 2021. Six Belgian neuromuscular reference centers participated, covering all patisiran-treated hATTR amyloidosis patients at the study time. This study was conducted to collect data requested in the context of the reimbursement of patisiran in Belgium.ResultsThirty-one patients were diagnosed with hATTR amyloidosis with polyneuropathy, Coutinho stage 1 or 2, and eligible for active treatment during the data collection period. Of the hATTR amyloidosis patients treated with patisiran (n = 12), seven and five had polyneuropathy stages 1 and 2, respectively. Six patients had cardiac symptoms (New York Heart Association class 2 or above). Follow-up information was available for nine patients. Following patisiran treatment, eight patients showed stable or improved assessments for most neurological or cardiological parameters. Only one patient presented with worsening statuses at the end of the data collection period.ConclusionsThe patients with hATTR amyloidosis in Belgium have similar baseline demographics and disease characteristics to those studied in the patisiran APOLLO study and show a similar therapeutic response in the real-world, altering the expected disease progression in most patients.

Updated Evaluation of the Safety, Efficacy and Tolerability of Tafamidis in the Treatment of Hereditary Transthyretin Amyloid Polyneuropathy.

Hereditary amyloid transthyretin (ATTRv) amyloidosis is a devastating hereditary multisystemic disease affecting predominantly the peripheral and autonomic nervous systems and the heart. ATTRv is caused by mutations in the transthyretin (TTR) gene, leading to extracellular deposition of amyloid fibrils in multiple organs including the peripheral nervous system. If untreated, it is associated with a fatal outcome 10-12 years after disease onset. Different treatments are available for patients with ATTRv polyneuropathy. Tafamidis 20 mg is approved in Europe since 2011 for early stages of ATTRv polyneuropathy (stage I - able to walk without support) and it is recommended as first-line therapy in these patients. Tafamidis is a TTR stabilizer that selectively binds to TTR and kinetically stabilizes both wild-type native TTR and mutant TTR. Consequently, it has the potential to prevent the amyloidogenic cascade initiated by TTR tetramer dissociation into its monomers and subsequent misfolding and aggregation. Tafamidis is an oral drug, taken once per day, with proved efficacy, safety and tolerability in ATTRv-PN patients as demonstrated in different clinical trials and open-label extension studies as well in clinical practice setting with around 10 years of experience. Tafamidis treatment started in the earliest stages of the disease is associated with better neurological outcomes. A multidisciplinary approach in referral centres is also fundamental for monitoring patients to assess individual response to treatment.

Identification of a novel transthyretin mutation D39Y in a cardiac amyloidosis patient and its biochemical characterizations.

Hereditary transthyretin cardiac amyloidosis (hATTR-CA) is a rare autosomal dominantly inherited disease caused by mutations in the transthyretin (TTR) gene. TTR mutations often cause the instability of transthyretin, production of misfolded proteins, and ultimately excessive deposition of insoluble amyloid fibrils in the myocardium, thereby leading to cardiac dysfunction. Herein, we report a novel transthyretin D39Y mutation in a Chinese family. We characterized the kinetic and thermodynamic stabilities of D39Y mutant TTR, revealing that TTR D39Y mutant was less stable than WT TTR and more stable than amyloidogenic mutation TTR L55P. Meanwhile, the only FDA approved drug Tafamidis showed satisfactory inhibitory effect toward ATTR amyloid formation and strong binding affinity in test tube revealed by isothermal titration calorimetry. Finally, we measured the well-folded tetrameric TTR concentration in patient's and his descents' blood serum using a previously reported UPLC-based assay. Notably, the tetramer concentrations gradually increased from symptomatic D39Y gene carrier father, to asymptomatic D39Y gene carrier daughter, and further to wild type daughter, suggesting the decrease in functional tetrameric TTR concentration may serve as an indicator for disease age of onset in D39Y gene carriers. The study described a Chinese family with hATTR-CA due to the TTR variant D39Y with its destabilizing effect in both kinetic and thermodynamic stabilities.

P.Val142lle/p.Val122lle (C.424G>A) Transthyretin Mutation Presenting Exclusively As Small Fiber Neuropathy

Familial amyloid polyneuropathy is a rare autosomal dominant disorder caused by mutations in the transthyretin gene, TTR. More than 100 mutations in the TTR gene are known. p.Val30Met was identified first as a cause of FAP and is the most common mutation worldwide. p.Val30Met is associated with peripheral neuropathy while p.Val142lle (C.424G>A) (also known as p.Val122lle) is associated with cardiac amyloidosis [1, 2, 3] . In this context, we report a patient harboring p.Val142lle mutation with exclusive small fiber neuropathy and absence of any cardiac involvement representing genotypic-phenotypic heterogenicity.

A natural history analysis of asymptomatic TTR gene carriers as they develop symptomatic transthyretin amyloidosis in the Transthyretin Amyloidosis Outcomes Survey (THAOS)

Background Hereditary transthyretin amyloidosis (ATTRv amyloidosis) results from pathogenic mutations in the transthyretin (TTR) gene. This analysis aimed to better understand ATTRv amyloidosis development in asymptomatic TTR gene carriers. Methods The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with transthyretin amyloidosis, including both inherited and wild-type disease, and asymptomatic TTR gene carriers. Asymptomatic TTR gene carriers were assessed longitudinally to identify those who developed ATTRv amyloidosis after enrolment in THAOS (data cut-off: 1 August 2021). Results Of 740 asymptomatic TTR gene carriers, 268 (36.2%) (Val30Met, 212/613 [34.6%]; non-Val30Met, 48/111 [43.2%]) developed ATTRv amyloidosis within a median 2.2 years after enrolment. The most common first symptoms were sensory (49.5%) and autonomic (37.3%) neuropathy in Val30Met patients, and sensory neuropathy (45.8%) and cardiac disorder (22.9%) in non-Val30Met patients. Most patients first presented with a predominantly neurologic phenotype (Val30Met, 77.8%; non-Val30Met, 70.8%). Conclusions More than one-third of asymptomatic TTR gene carriers in THAOS developed ATTRv amyloidosis within a median 2 years of enrolment. Val30Met versus non-Val30Met patients had a lower transition rate. Given the importance of early treatment, these findings underscore the need for identification and careful monitoring of at-risk TTR gene carriers to enable prompt treatment. Trial registration ClinicalTrials.gov: NCT00628745.

Gene therapy options for hereditary transthyretin-related amyloidosis

Hereditary transthyretin-related amyloidosis (ATTRv) is arare autosomal dominant disease and is fatal if left untreated. It is caused by mutations in the transthyretin gene. All known mutations induce misfolding of the tetrameric transthyretin molecule and protein deposits in multiple organs. In peripheral nerves this result in sensorimotor and autonomic polyneuropathy and in cardiac muscle it causes cardiomyopathy. Untreated ATTRv is characterized by an irreversible and progressive course and death 7-11years after symptom onset. Treatment options consist of TTR stabilizing drugs, such as tafamidis and active agents that selectively interfere at the mRNA level, the so-called gene silencers patisiran and inotersen. All forms of treatment aim to prevent amyloid tissue deposition in tissues and organ dysfunction. Patisiran works by RNA interference on endogenous mechanisms of gene expression. It results in the cleavage of TTR-mRNA using the cytoplasmatic RNA-induced silencing complex. Inotersen, an antisense oligonucleotide, degrades TTR-mRNA via activation of nuclear RNaseH. Both mechanisms result in asignificant reduction of TTR protein serum levels. The efficacy could be demonstrated by slowing or improving neuropathy progression in the phase III study APOLLO (patisiran) or the NEURO-TTR study (inotersen). Furthermore, the use of both agents led to an improvement in the quality of life in patients with ATTRv. Both forms of treatment are approved in Germany since August 2018 for polyneuropathy stages1 and2 according to Coutinho. The choice of treatment should be carried out individually considering drug formulation, contraindications and the necessary safety monitoring controls.

Sex-related Differences In Cardiac Involvement In Wild-type Transthyretin Amyloidosis

<h3>Introduction</h3> Transthyretin amyloidosis (ATTR amyloidosis) is a rare but life-threatening disease that may arise from mutations in the transthyretin (<i>TTR</i>) gene (ATTRv amyloidosis) or from nonmutated, wild-type TTR (ATTRwt amyloidosis). Evidence suggests that female sex may be protective against cardiac involvement in ATTRv amyloidosis, but sex differences in cardiac involvement in ATTRwt amyloidosis have not been assessed. <h3>Hypothesis</h3> Cardiac involvement in patients with ATTRwt amyloidosis differs by sex. <h3>Methods</h3> The Transthyretin Amyloidosis Outcomes Survey (THAOS) is a global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with <i>TTR</i> mutations (NCT00628745). Data from THAOS (data cutoff: January 4, 2021) were analyzed to evaluate sex-based differences in cardiac symptoms in patients with ATTRwt amyloidosis. <h3>Results</h3> There were 1272 patients (females, n=76; males, n=1196) with ATTRwt amyloidosis enrolled in THAOS. Median age at enrollment (80.7 vs 77.6 years; <i>P</i><0.05) and symptom onset (75.5 vs 73.0 years; <i>P</i><0.05) were higher in females vs males, whereas median time from symptom onset to diagnosis was similar between the groups (1.09 vs 1.55 years). Females had a significantly higher mean left ventricular (LV) ejection fraction (53% vs 48%; <i>P</i><0.05). The lower mean LV wall thickness (16 vs 17 mm) and mean LV mass index (161 vs 189 g/m²) observed in females vs males were not statistically significant. LV wall thickness (mm) divided by height (m) was similar in females vs males (9.8 vs 9.6). Sex was not found to be a predictor of mean LV wall thickness divided by height in a linear regression analysis. <h3>Conclusions</h3> Females with ATTRwt amyloidosis were older and had a higher mean LV ejection fraction compared with males. Although there were signs of sex-related differences in cardiac involvement, the relatively low number of females in this analysis may have limited the ability to draw firmer conclusions.

Real-life experience with inotersen in hereditary transthyretin amyloidosis with late-onset phenotype: Data from an early-access program in Italy.

Background and purposeHereditary transthyretin (TTR) amyloidosis (ATTRv) is a dominantly inherited, adult‐onset, progressive, and fatal disease caused by mutations in the transthyretin gene. Therapeutic agents approved for this disease include the TTR stabilizer tafamidis and the gene‐silencing drugs patisiran and inotersen. Inotersen is an antisense oligonucleotide that suppresses the hepatic production of transthyretin. After European Medical Agency approval in 2018, an early‐access program was opened in Italy, and in this article, we present the long‐term outcome of a cohort of Italian ATTRv patients who received inotersen within this program.MethodsThis is a multicenter, observational, retrospective study of patients affected by ATTRv that started inotersen during the early‐access program. The primary end point was safety. Secondary end points included change from baseline in familial amyloid polyneuropathy (FAP) stage, Polyneuropathy Disability, Neuropathy Impairment Scale, Compound Autonomic Dysfunction Test, Norfolk Quality of Life–Diabetic Neuropathy, troponin, N‐terminal pro–brain natriuretic peptide, interventricular septum thickness, and body mass index.ResultsIn total, 23 patients were enrolled. No patient permanently discontinued the treatment because of thrombocytopenia, and no cases of severe thrombocytopenia were observed. Five patients discontinued the treatment permanently because of voluntary withdrawal (two patients), renal failure after infective pyelonephritis, not related to inotersen, drug‐related hypotension, and amyloid‐negative crescentic glomerulonephritis. In seven patients, dosing frequency was reduced to every 2 weeks due to recurrent thrombocytopenia. Considering the FAP stage, only two patients worsened, whereas the other 21 patients remained stable until the last follow‐up available.ConclusionsThe long‐term safety profile of inotersen is favorable. Neurologic disease severity at baseline is the main factor associated with progression.

Ophthalmological manifestations of hereditary transthyretin amyloidosis.

Transthyretin familial amyloidosis is the most common form of inherited systemic amyloidosis worldwide. The condition develops secondary to more than 100 different point mutations in the transthyretin gene (18q12.1). The mutations lead to abnormal amyloid deposits, mainly in the heart and peripheral nerves. Leptomeningeal and mainly ocular involvement is common. Although there are several different types of treatment available, ocular involvement, which occurs also in liver transplant recipients, remains a major challenge, progressing even in liver transplant recipients. Patients with ocular involvement require efficient ophthalmological follow-up to prevent vision loss. In this review, different forms of ocular involvement characterizing the subtypes of transthyretin mutations were described, and the effects of different treatments were summarized. Further research is necessary to fully elucidate these issues.