Evaluation of the 2021 ESC recommendations for family screening in hereditary transthyretin cardiac amyloidosis.

AIMS: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement. METHODS AND RESULTS: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%. CONCLUSIONS: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common.

Cardiovascular autonomic failure in hereditary transthyretin amyloidosis and TTR carriers is an early and progressive disease marker.

BACKGROUND: The cardiomyopathic and neuropathic phenotype of hereditary transthyretin amyloidosis are well recognized. Cardiovascular autonomic dysfunction is less systematically and objectively assessed. METHODS: Autonomic and clinical features, quantitative cardiovascular autonomic function, and potential autonomic prognostic markers of disease progression were recorded in a cohort of individuals with hereditary transthyretin amyloidosis and in asymptomatic carriers of TTR variants at disease onset (T0) and at the time of the first quantitative autonomic assessment (T1). The severity of peripheral neuropathy and its progression was stratified with the polyneuropathy disability score. RESULTS: A total of 124 individuals were included (111 with a confirmed diagnosis of hereditary transthyretin amyloidosis, and 13 asymptomatic carriers of TTR variants). Symptoms of autonomic dysfunction were reported by 27% individuals at T0. Disease duration was 4.5 ± 4.0 years [mean ± standard deviation (SD)] at autonomic testing (T1). Symptoms of autonomic dysfunction were reported by 78% individuals at T1. Cardiovascular autonomic failure was detected by functional testing in 75% individuals and in 64% of TTR carriers. Progression rate from polyneuropathy disability stages I/II to III/IV seemed to be shorter for individuals with autonomic symptoms at onset [2.33 ± 0.56 versus 4.00 ± 0.69 years (mean ± SD)]. CONCLUSIONS: Cardiovascular autonomic dysfunction occurs early and frequently in individuals with hereditary transthyretin amyloidosis within 4.5 years from disease onset. Cardiovascular autonomic failure can be subclinical in individuals and asymptomatic carriers, and only detected with autonomic function testing, which should be considered a potential biomarker for early diagnosis and disease progression.

Genetic counselling for at-risk family members with hereditary transthyretin amyloidosis: data from a single-centre study.

BACKGROUND: Hereditary transthyretin-related amyloidosis is an autosomal dominant disorder. Recently, disease-modifying therapies (DMTs) have been developed. For at-risk individuals, genetic analysis aids in the early administration of medical care; however, few studies have evaluated the current status of genetic counselling and management of presymptomatic carriers of amyloidogenic variants. METHODS: We retrospectively evaluated the medical records of 202 consecutive participants. RESULTS: A total of 103 clients who received genetic counselling for predictive testing were at-risk, and 83 underwent predictive testing. Genetic testing results were positive in 33 patients, 11 of whom had confirmed amyloid deposition and were administered DMTs. For presymptomatic V30M (p.V50M) carriers, 32.0 ± 2.4 years (median ± standard error) was the age when amyloid deposition was first identified (95% confidence interval 27.4-36.6). Serum transthyretin (TTR) levels decreased serially with an estimated slope of -1.2 mg/dL/year. CONCLUSIONS: Our study suggests the clinical utility of management using a combination of predictive testing and monitoring methods. Psychosocial support should be considered with collaboration between geneticists/genetic counsellors and psychologists. For a more optimised protocol for monitoring and designing future interventional trials in presymptomatic carriers, prospective cohort studies are necessary to clarify the natural history, particularly in the early stages of the disease.

Serum neurofilament light chain levels correlate with small fiber related parameters in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN).

BACKGROUND: Recent evidence suggests that both serum neurofilament light chain (sNfL) levels and small fiber related diagnostic variables may be valuable disease biomarkers of hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). Our study aimed to explore the relations between sNfL and small fiber related skin biopsy and quantitative sensory testing (QST) parameters in a cohort of ATTRv-PN patients and pre-symptomatic carriers. METHODS: We retrospectively analyzed data from 13 ATTRv patients and 21 pre-symptomatic carriers who underwent sNfL dosage, skin biopsy, and QST, and analyzed correlations between sNFL, intraepidermal nerve fiber density (IENFD), and cold (CDT) and warm detection thresholds (WDT). RESULTS: Both sNfL and small fiber related parameters significantly differed between carriers and patients (sNfL: p < 0.0001; IENFD: p = 0.0008; CDT, WDT: < 0.0001). sNFL levels were normal in all carriers, altered in 85% of patients, negatively correlated with distal IENFD (r = -0.47, p = 0.005), and significantly correlated with CDT (r = -0.68; p < 0.0001) and WDT (r = 0.57; p < 0.0001). CONCLUSIONS: Our study showed that sNfL reliably discriminates symptomatic ATTRv-PN patients from pre-symptomatic carriers, and found significant relations between sNfL, skin biopsy, and QST small fiber related parameters, suggesting that sNfL might be a valuable biomarker of peripheral nerve involvement in ATTRv-PN and a supportive criterion for symptomatic disease transition.

Heterogeneity in families with ATTRV30M amyloidosis: a historical and longitudinal Portuguese case study impact for genetic counselling.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is an inherited disease, where the study of family history holds importance. This study evaluates the changes of age-of-onset (AOO) and other age-related clinical factors within and among families affected by ATTRv amyloidosis. METHODS: We analysed information from 934 trees, focusing on family, parents, probands and siblings relationships. We focused on 1494 female and 1712 male symptomatic ATTRV30M patients. Results are presented alongside a comparison of current with historical records. Clinical and genealogical indicators identify major changes. RESULTS: Overall, analysis of familial data shows the existence of families with both early and late patients (1/6). It identifies long familial follow-up times since patient families tend to be diagnosed over several years. Finally, results show a large difference between parent-child and proband-patient relationships (20-30 years). CONCLUSIONS: This study reveals that there has been a shift in patient profile, with a recent increase in male elderly cases, especially regarding probands. It shows that symptomatic patients exhibit less variability towards siblings, when compared to other family members, namely the transmitting ancestors' age of onset. This can influence genetic counselling guidelines.

Hereditary Transthyretin Amyloidosis and the Impact of Classic and New Treatments on Kidney Function: A Review.

Hereditary transthyretin amyloidosis (ATTRv) is a rare, progressive, and life-threatening disease caused by misfolded transthyretin (TTR) proteins that aggregate as abnormal amyloid fibrils and accumulate throughout the body. The kidney is one of the main organs affected in amyloid light chain (AL) amyloidosis and ATTRv amyloidosis. The most common clinical presentation is proteinuria, which consists mainly of albumin; this is the first step in the natural history of ATTRv nephropathy. Not all TTR mutations are equal in terms of ATTRv kidney involvement. Kidney involvement in ATTRv itself is difficult to define, given the numerous associated confounding factors. There are several treatments available to treat ATTRv, including orthotopic liver transplant (OLT), which is the classic treatment for ATTRv. However, we should be careful regarding the use of calcineurin inhibitors in the setting of OLT because these can be nephrotoxic. New treatments for amyloidosis may have an impact on kidney function, including drugs that target specific pathways involved in the disease. Tafamidis and diflunisal, which are TTR stabilizers, patisiran (RNA interference agent), and inotersen (antisense oligonucleotide inhibitor) have been shown to reduce TTR amyloid. Tafamidis and patisiran are medications that have reduced the progression of kidney disease in amyloidosis, but inotersen and diflunisal may damage kidney function.

Gait abnormalities in older adults with transthyretin cardiac amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR cardiac amyloidosis) is caused by variant (ATTRv) or wild type (ATTRwt) transthyretin. While gait abnormalities have been studied in younger patients with ATTRv amyloidosis, research on gait in older adults with ATTR cardiac amyloidosis is lacking. Given ATTR cardiac amyloidosis' association with neuropathy and orthopedic manifestations, we explore the gait in this population. METHODS: Twenty-eight older male ATTR cardiac amyloidosis patients and 11 healthy older male controls walked overground with and without a dual cognitive task. Gait parameters: stride width, length, velocity and stance time percentage were measured using an instrumented mat. ATTR amyloidosis patients were further categorized based on clinical and functional assessments. RESULTS: We found significant gait differences between ATTR cardiac amyloidosis patients and healthy controls; patients had more variable, slower, narrower and shorter strides, with their feet spending more time in contact with the ground as opposed to in swing. However, the observed gait differences did not correlate with clinical and functional measures of ATTR cardiac amyloidosis severity. CONCLUSIONS: Our results suggest that gait analysis could be a complementary tool for characterizing ATTR cardiac amyloidosis patients and may inform clinical care as it relates to falls, management of anticoagulation, and functional independence.

Longitudinal analysis of serum neurofilament light chain levels as marker for neuronal damage in hereditary transthyretin amyloidosis.

OBJECTIVE: To evaluate serum neurofilament light chain (sNfL) as biomarker of disease onset, progression and treatment effect in hereditary transthyretin (ATTRv) amyloidosis patients and TTR variant (TTRv) carriers. METHODS: sNfL levels were assessed longitudinally in persistently asymptomatic TTRv carriers (N = 12), persistently asymptomatic ATTRv amyloidosis patients (defined as asymptomatic patients but with amyloid detectable in subcutaneous abdominal fat tissue) (N = 8), in TTRv carriers who developed polyneuropathy (N = 7) and in ATTRv amyloidosis patients with polyneuropathy on treatment (TTR-stabiliser (N = 20) or TTR-silencer (N = 18)). Polyneuropathy was confirmed by nerve conduction studies or quantitative sensory testing. sNfL was analysed using a single-molecule array assay. RESULTS: sNfL increased over 2 years in persistently asymptomatic ATTRv amyloidosis patients, but did not change in persistently asymptomatic TTRv carriers. In all TTRv carriers who developed polyneuropathy, sNfL increased from 8.4 to 49.8 pg/mL before the onset of symptoms and before polyneuropathy could be confirmed neurophysiologically. In symptomatic ATTRv amyloidosis patients on a TTR-stabiliser, sNfL remained stable over 2 years. In patients on a TTR-silencer, sNfL decreased after 1 year of treatment. CONCLUSION: sNfL is a biomarker of early neuronal damage in ATTRv amyloidosis already before the onset of polyneuropathy. Current data support the use of sNfL in screening asymptomatic TTRv carriers and in monitoring of disease progression and treatment effect.

Impact of Baseline Neuropathy Severity on Vutrisiran Treatment Response in the Phase 3 HELIOS-A Study.

INTRODUCTION: Hereditary transthyretin (ATTRv, v for variant) amyloidosis is a rare, progressive, fatal disease with multisystem manifestations, caused by pathogenic variants in the transthyretin (TTR) gene. Vutrisiran, an RNA interference therapeutic that results in rapid TTR knockdown, improved neuropathy and quality of life (QOL) versus external placebo in patients with ATTRv amyloidosis with polyneuropathy in the phase 3 HELIOS-A study (NCT03759379). This post hoc analysis evaluates the impact of baseline neuropathy severity on response to vutrisiran treatment. METHODS: Patients were randomized (3:1) to vutrisiran (n = 122; 25 mg subcutaneous injection once every 3 months) or patisiran (n = 42; 0.3 mg/kg intravenous infusion once every 3 weeks), which served as a reference group. In this post hoc analysis, patients were grouped into quartiles of increasing baseline Neuropathy Impairment Score (NIS): Quartile (Q)1 ≥ 5.0 to ≤ 20.5; Q2 > 20.5 to ≤ 44.1; Q3 > 44.1 to ≤ 73.1; Q4 > 73.1 to ≤ 127.0. Mean change from baseline to Month 18 was summarized by quartile for a range of efficacy endpoints. RESULTS: Across all baseline NIS quartiles, vutrisiran demonstrated benefit versus external placebo in measures of neuropathy severity (modified NIS + 7), QOL (Norfolk Quality of Life-Diabetic Neuropathy), disability (Rasch-built Overall Disability Scale), gait speed (10-m walk test), and nutritional status (modified body mass index). Overall, patients in lower versus higher NIS quartiles (less severe neuropathy) at baseline maintained better scores at Month 18. The external placebo group progressively worsened in all measures at Month 18. CONCLUSIONS: Vutrisiran demonstrated benefit in neurologic function and other key efficacy measures versus external placebo across all four baseline neuropathy severity quartiles. Patients initiating vutrisiran earlier in their disease course retained the highest neurologic function level after 18 months, highlighting the importance of early diagnosis and treatment. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT03759379.

Axonal excitability as an early biomarker of nerve involvement in hereditary transthyretin amyloidosis.

OBJECTIVES: The treatment of hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) has been revolutionised by genetic therapies, with dramatic improvements in patient outcomes. Whilst the optimal timing of treatment initiation remains unknown, early treatment is desirable. Consequently, the aim of the study was to develop biomarkers of early nerve dysfunction in ATTRv-PN. METHODS: Ulnar motor and sensory axonal excitability studies were prospectively undertaken on 22 patients with pathogenic hereditary transthyretin amyloid (ATTRv) gene variants, 12 with large fibre neuropathy (LF+) and 10 without (LF-), with results compared to age- and sex-matched healthy controls. RESULTS: In motor axons we identified a continuum of change from healthy controls, to LF- and LF+ ATTRv with progressive reduction in hyperpolarising threshold electrotonus (TEh40(10-20 ms): p = 0.04, TEh40(20-40 ms): p = 0.01 and TEh40(90-10 ms): p = 0.01), suggestive of membrane depolarisation. In sensory axons lower levels of subexcitability were observed on single (SubEx) and double pulse (SubEx2) recovery cycle testing in LF+ (SubEx: p = 0.015, SubEx2: p = 0.015, RC(2-1): p = 0.04) suggesting reduced nodal slow potassium conductance, which promotes sensory hyperexcitability, paraesthesia and pain. There were no differences in sensory or motor excitability parameters when comparing different ATTRv variants. CONCLUSIONS: These progressive changes seen across the disease spectrum in ATTRv-PN suggest that axonal excitability has utility to identify early and progressive nerve dysfunction in ATTRv, regardless of genotype. SIGNIFICANCE: Axonal excitability is a promising early biomarker of nerve dysfunction in ATTRv-PN.

Serum neurofilament light chain in hereditary transthyretin amyloidosis: validation in real-life practice.

BACKGROUND: Neurofilament light chain (NfL) has emerged as a sensitive biomarker in hereditary transthyretin amyloid polyneuropathy (ATTRv-PN). We hypothesise that NfL can identify conversion of gene carriers to symptomatic disease, and guide treatment approaches. METHODS: Serum NfL concentration was measured longitudinally (2015-2022) in 59 presymptomatic and symptomatic ATTR variant carriers. Correlations between NfL and demographics, biochemistry and staging scores were performed as well as longitudinal changes pre- and post-treatment, and in asymptomatic and symptomatic cohorts. Receiver-operating analyses were performed to determine cut-off values. RESULTS: NfL levels correlated with examination scores (CMTNS, NIS and MRC; all p < .01) and increased with disease severity (PND and FAP; all p < .05). NfL was higher in symptomatic and sensorimotor converters, than asymptomatic or sensory converters irrespective of time (all p < .001). Symptomatic or sensorimotor converters were discriminated from asymptomatic patients by NfL concentrations >64.5 pg/ml (sensitivity= 91.9%, specificity = 88.5%), whereas asymptomatic patients could only be discriminated from sensory or sensorimotor converters or symptomatic individuals by a NfL concentration >88.9 pg/ml (sensitivity = 62.9%, specificity = 96.2%) However, an NfL increment of 17% over 6 months could discriminate asymptomatic from sensory or sensorimotor converters (sensitivity = 88.9%, specificity = 80.0%). NfL reduced with treatment by 36%/year and correlated with TTR suppression (r = 0.64, p = .008). CONCLUSIONS: This data validates the use of serum NfL to identify conversion to symptomatic disease in ATTRv-PN. NfL levels can guide assessment of disease progression and response to therapies.

High-Sensitivity Cardiac Troponin T to Exclude Cardiac Involvement in TTR Variant Carriers and ATTRv Amyloidosis Patients.

(1) Background: Individuals carrying a pathogenic transthyretin gene variant (TTRv) are at high risk for developing hereditary transthyretin (ATTRv) amyloidosis and are routinely screened for the development of cardiomyopathy (ATTRv-CM). This study aims to evaluate whether the cardiac biomarkers N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) can be used to rule out ATTRv-CM. (2) Methods: In this retrospective case-control study, data from 46 ATTRv-CM patients and 101 TTRv carriers and ATTRv amyloidosis patients without cardiomyopathy were included. Binary logistic regression models were used to assess the ability of NT-proBNP and hs-cTnT to predict the diagnosis of ATTRv-CM. An optimal cutoff for the relevant biomarker(s) was determined based on a sensitivity of ≥99% and the highest possible percentage of additional tests avoided (%ATA) in the index dataset. (3) Results: Hs-cTnT demonstrated the highest predictive capabilities for ATTRv-CM. The addition of NT-proBNP did not improve the predictive model. A hs-cTnT cutoff of <6 ng/L resulted in a 97% sensitivity and a negative predictive value of 95% with a %ATA of 30% in the validation dataset. (4) Conclusion: In conclusion, hs-cTnT is a useful biomarker for excluding cardiac involvement in TTRv carriers and ATTRv amyloidosis patients and it has the potential to prevent unnecessary diagnostic procedures.

Performance of 99mTc-PYP scintigraphy in the diagnosis of hereditary transthyretin cardiac amyloidosis.

OBJECTIVE: Most reported research has primarily investigated wild-type transthyretin cardiac amyloidosis (ATTRwt-CA). However, the application of bone scintigraphy for hereditary transthyretin cardiac amyloidosis (ATTRv-CA) has not been systematically investigated. Therefore, in this study, we aimed to evaluate the diagnostic value of 99mTc-PYP scintigraphy in ATTRv-CA. METHODS: Fifty-four patients were enrolled in a highly suspected cardiac amyloidosis cohort. Transthyretin (TTR) gene characteristics were summarized in the ATTRv-CA group. In 99mTc-PYP scintigraphy, the diagnostic efficiency of the visual score (VGS) and heart-to-contralateral chest (H/CL) ratio were evaluated. Furthermore, the interobserver consistency among the diagnosticians was investigated. RESULTS: Twenty-eight patients were diagnosed with ATTRv-CA with eight genotypes. The Ala97Ser genotype accounts for 46% (n = 13) with a mean age of disease onset, definite diagnosis, and interval of 61.6 ± 1.9, 66.5 ± 1.3, and 4.0 (3.0, 6.2) years, respectively. Their VGS is Grade 3, and their H/CL ratio is higher than that of the non-Ala97Ser group, but no statistical significance exists (mean H/CL: 1.95 ± 0.06 vs. 1.87 ± 0.02, p = 0.844). Additionally, ATTRv-CA patients showed VGS ≥ 2, and mean H/CL ratio of 2.09 ± 0.06. The sensitivity and specificity of VGS were 100% and 65%, respectively. And the interobserver consistency analysis of VGS showed the intraclass correlation coefficient is 0.522. The best cutoff value of H/CL ratio was 1.51 (AUC = 0.996), and the diagnostic consistency of H/CL (bias: 0.018) was high. CONCLUSIONS: Ala97Ser is the most common genotype in ATTRv-CA in our cohort, with characteristics of later onset and rapid progression, but delayed diagnosis and extensive 99mTc-PYP uptake. Overall, ATTRv-CA patients showed moderate-to-extensive myocardial 99mTc-PYP uptake. Additionally, VGS carries subjectivity, low specialty and interobserver consistency. But H/CL exhibit high diagnostic efficacy and interobserver consistency. The H/CL ratio is more useful than VGS.

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

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.

Diagnosis and treatment of hereditary transthyretin amyloidosis with polyneuropathy in the United States: Recommendations from a panel of experts.

Hereditary transthyretin (ATTRv; v for variant) amyloidosis is a rare, multisystem, progressive, and fatal disease in which polyneuropathy is a cardinal manifestation. Due to a lack of United States (US)-specific guidance on ATTRv amyloidosis with polyneuropathy, a panel of US-based expert clinicians convened to address identification, monitoring, and treatment of this disease. ATTRv amyloidosis with polyneuropathy should be suspected in unexplained progressive neuropathy, especially if associated with systemic symptoms or family history. The diagnosis is confirmed through genetic testing, biopsy, or cardiac technetium-based scintigraphy. Treatment should be initiated as soon as possible after diagnosis, with gene-silencing therapeutics recommended as a first-line option. Consensus is lacking on what represents "disease progression" during treatment; however, the aggressive natural history of this disease should be considered when evaluating the effectiveness of any therapy.

Treatment response and neurofilament light chain levels with long-term patisiran in hereditary transthyretin-mediated amyloidosis with polyneuropathy: 24-month results of an open-label extension study.

BACKGROUND: Longitudinal changes in neurofilament light chain (NfL) levels were evaluated alongside prespecified clinical assessments 24 months into the patisiran Global open-label extension (OLE) study in patients with ATTRv amyloidosis with polyneuropathy. METHODS: All patients enrolled in the Global OLE, from phase III APOLLO and phase II OLE parent studies, received patisiran. Assessments included measures of polyneuropathy (modified Neuropathy Impairment Score+7 (mNIS+7)), quality of life (QOL; Norfolk QOL-Diabetic Neuropathy questionnaire (Norfolk QOL-DN)), and plasma NfL. RESULTS: Patients receiving patisiran in the parent study (APOLLO-patisiran, n = 137; phase II OLE-patisiran, n = 25) demonstrated sustained improvements in mNIS+7 (mean change from parent study baseline (95% confidence interval): APOLLO-patisiran -4.8 (-8.9, -0.6); phase II OLE-patisiran -5.8 (-10.5, -1.2)) and Norfolk QOL-DN (APOLLO-patisiran -2.4 (-7.2, 2.3)), and maintained reduced NfL levels at Global OLE 24 months. After initiating patisiran in the Global OLE, APOLLO-placebo patients (n = 49) demonstrated stabilized mNIS+7, improved Norfolk QOL-DN, and significantly reduced NfL levels. Patisiran continued to demonstrate an acceptable safety profile. Earlier patisiran initiation was associated with a lower exposure-adjusted mortality rate. CONCLUSIONS: Long-term patisiran treatment led to sustained improvements in neuropathy and QOL, with NfL demonstrating potential as a biomarker for disease progression and treatment response in ATTRv amyloidosis with polyneuropathy.

Cardiac [99mTc]Tc-hydroxydiphosphonate uptake on bone scintigraphy in patients with hereditary transthyretin amyloidosis: an early follow-up marker?

PURPOSE: There is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments. METHODS: In this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated. RESULTS: Median heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15-34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer. CONCLUSION: A change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.

Early detection of nerve involvement in presymptomatic TTR mutation carriers: exploring potential markers of disease onset.

BACKGROUND: Hereditary transthyretin (ATTRv) amyloidosis is a heterogeneous, progressive, multisystemic disease with a life-threatening course if left untreated. Given the current availability of effective therapies, close follow-up of presymptomatic TTR mutation carriers is essential to recognize disease onset at the earliest sign. In addition to routine techniques, in recent years several novel tools have been proposed, although a consensus on their use has not been reached yet. In this paper, we aimed to evaluate possible markers of neuropathic disease onset intended to discriminate clinically asymptomatic carriers from early symptomatic patients, thus allowing timely treatment initiation. METHODS: Thirty-eight presymptomatic carriers were enrolled. Clinical and electrophysiological findings at first evaluation and follow-up were collected. All carriers underwent an extensive clinical and instrumental evaluation according to the standard clinical practice. One or more non-routine investigations, whose use in this field is not yet validated (henceforth "unconventional"), were additionally assessed in a subgroup of individuals. RESULTS: Based on the exclusive use of routine investigations, it was possible to define disease onset in 4/38 carriers during the follow-up. Employing additionally one or more "unconventional" tests, abnormal findings, indicative of a possible "conversion" to symptomatic disease, were detected in further 12 cases. More than half of our study cohort showed findings suggestive of small nerve fiber (SF) involvement at either invasive or non-invasive tests. CONCLUSIONS: A close, multidisciplinary monitoring of presymptomatic TTR mutation carriers is fundamental, and diagnostic workup should include both routine and "unconventional" tests. Assessment of SF involvement is important also in non-endemic countries.

Serum neurofilament light chain: a promising early diagnostic biomarker for hereditary transthyretin amyloidosis?

BACKGROUND AND PURPOSE: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening disease caused by mutations in the gene encoding transthyretin (TTR). The recent therapeutic advances have underlined the importance of easily accessible, objective biomarkers of both disease onset and progression. Preliminary evidence suggests a potential role in this respect for neurofilament light chain (NfL). In this study, the aim was to determine serum NfL (sNfL) levels in a late-onset ATTRv population and evaluate whether it might represent a reliable biomarker of disease onset (i.e., 'conversion' from the asymptomatic status to symptomatic disease in TTR mutation carriers). METHODS: In all, 111 individuals harbouring a pathogenic TTR variant (61 symptomatic ATTRv patients and 50 presymptomatic carriers) were consecutively enrolled. Fifty healthy volunteers were included as the control group. Ella™ apparatus was used to assess sNfL levels. RESULTS: Serum NfL levels were increased in ATTRv patients compared to both presymptomatic carriers and healthy controls, whilst not differing between carriers and healthy controls. An sNfL cut-off of 37.10 pg/mL could discriminate between asymptomatic and symptomatic individuals with high diagnostic accuracy (area under the curve 0.958; p < 0.001), sensitivity (81.4%) and specificity (100%). CONCLUSIONS: Serum NfL seems to be a promising biomarker of peripheral nerve involvement in ATTRv amyloidosis and might become a reliable, objective measure to detect the transition from the presymptomatic stage to the onset of symptomatic disease. Further longitudinal studies are needed to confirm such a role and determine whether it could equally represent a biomarker of disease progression and response to therapy.

Hereditary transthyretin amyloidosis: a comprehensive review with a focus on peripheral neuropathy.

Amyloidoses represent a group of diseases characterized by the pathological accumulation in the extracellular area of insoluble misfolded protein material called "amyloid". The damage to the tissue organization and the direct toxicity of the amyloidogenic substrates induce progressive dysfunctions in the organs involved. They are usually multisystem diseases involving several vital organs, such as the peripheral nerves, heart, kidneys, gastrointestinal tract, liver, skin, and eyes. Transthyretin amyloidosis (ATTR) is related to abnormalities of transthyretin (TTR), a protein that acts as a transporter of thyroxine and retinol and is produced predominantly in the liver. ATTR is classified as hereditary (ATTRv) and wild type (ATTRwt). ATTRv is a severe systemic disease of adults caused by mutations in the TTR gene and transmitted in an autosomal dominant manner with incomplete penetrance. Some pathogenic variants in TTR are preferentially associated with a neurological phenotype (progressive peripheral sensorimotor polyneuropathy); others are more frequently associated with restrictive heart failure. However, many mutations express a mixed phenotype with neurological and cardiological involvement. ATTRv is now a treatable disease. A timely and definite diagnosis is essential in view of the availability of effective therapies that have revolutionized the management of affected patients. The purpose of this review is to familiarize the clinician with the disease and with the correct diagnostic pathways in order to obtain an early diagnosis and, consequently, the possibility of an adequate treatment.