Primary Data on ATTR-Amyloidosis Prevalence Among Elderly Patients With Left Ventricular Hypertrophy in Russia.

AIM: To estimate the prevalence of amyloid cardiomyopathy (CM) caused by transthyretin amyloidosis (ATTR) and immunoglobulin light chain (AL) amyloidosis among patients aged >65 years with interventricular septal (IVS) hypertrophy of ≥14 mm. MATERIAL AND METHODS: From January through August 2023, 60 patients (mean age 7.2±7.3 years, 34 (56.67%) men) were enrolled. Patients meeting the inclusion criteria underwent an echocardiographic study with determining the myocardial longitudinal strain, myocardial scintigraphy with 99mTc-pyrfotech, myocardial single-photon emission computed tomography, measurement of N-terminal fragment of brain natriuretic peptide and troponin I, and the immunochemical study of serum and urine proteins with measurement of free light chains. In the presence of grades 2 and 3 radiopharmaceutical uptake according to scintigraphy, a molecular genetic study was performed for differential diagnosis of wild-type transthyretin amyloidosis (wtATTR) and hereditary/variant (hATTR) ATTR-CM. RESULTS: According to data of myocardial scintigraphy with 99mTc-pyrfotech, grade 3 uptake in the absence of monoclonal secretion was detected in 5 (8.3%) cases and grade 2 radiotracer uptake in the absence of monoclonal secretion was detected in 6 (10%) patients. Myeloma complicated by AL amyloidosis and primary AL amyloidosis were found in 5 (8.3%) patients. CONCLUSION: Among patients aged ≥65 years with IVS hypertrophy ≥14 mm, amyloid CM was detected in 20% of cases (12 patients), including 5 cases (8.3%) of AL amyloidosis and 7 cases (11.7%) of ATTR amyloidosis.

Atrial Fibrillation, Thromboembolic Risk, and Anticoagulation in Cardiac Amyloidosis: A Review.

Cardiac amyloidosis (CA) is caused by extracellular myocardial deposition of amyloid fibrils that are primary derived either from misfolding of transthyretin (ATTR) or light-chain (AL) proteins. CA is associated with atrial fibrillation, potentiated by electromechanical changes as a result of amyloid infiltration in the myocardium. CA also predisposes to thromboembolism and could potentially simultaneously elevate bleeding risk. In this review, we aim to explore and compare the prevalence and pathophysiological mechanisms of atrial fibrillation and thromboembolism in ATTR and AL, examine bleeding risk and factors that promote bleeding, and compare anticoagulation strategies in CA. Finally, we highlight knowledge gaps in the field of thromboembolism in CA to guide future research.

Prevalence of ATTR-CA and high-risk features to guide testing in patients referred for TAVR.

PURPOSE: Transthyretin cardiac amyloidosis (ATTR-CA) is thought to be prevalent in patients with severe aortic stenosis (AS) who are referred for transcatheter aortic valve replacement (TAVR). However, prior studies were published when TAVR was only offered to elderly, inoperable, and high-risk patients. The aim of this study was to reevaluate the prevalence of ATTR-CA in a contemporary TAVR population and identify high-risk features to guide referral for technetium-99 pyrophosphate scan (99mTc-PyP scan) screening. METHODS: Patients seen in a multidisciplinary TAVR clinic for severe AS 70 years and older were referred for a 99mTc-PyP scan to evaluate for ATTR-CA. The primary outcome was the percent with a positive scan. The discriminatory ability of high-risk features was assessed to develop a more judicious screening system. RESULTS: Over the study period, 380 patients underwent screening, and 20 patients (5.3%) had a positive scan, with 17 patients having confirmed ATTR-CA, 1 patient deferring confirmatory testing (combined 4.7%), 1 having light chain amyloidosis, and 1 negative on biopsy. Compared to other patient and echocardiographic measures, elevated NT-pro BNP (> 1000 ng/L) was the best discriminator on who should be referred for 99mTc-PyP scan screening, with a sensitivity of 90% and a negative predictive value of 99%. CONCLUSION: The prevalence of ATTR-CA may be lower in a contemporary TAVR population due to its expanded indication for low-risk patients. NT-pro BNP is a simple test that can improve screening yield and more judiciously guide screening for ATTR-CA in this at-risk population. Comparison of the original versus the proposed algorithm.

Cardiac amyloidosis in Latin America: Gaps and opportunities to increase awareness of the disease. Findings from the AMILO-LATAM research group.

BACKGROUND: Cardiac amyloidosis (CA) is an under-diagnosed disease presenting as a restrictive cardiomyopathy with high morbidity and mortality. Wild-type transthyretin amyloid cardiomyopathy (ATTR-CM) is mostly seen in elderly patients, with increasing prevalence as life expectancy is growing. New diagnostic imaging techniques and treatments allow for a better prognosis, but lack of clinical awareness delays timely diagnosis and appropriate management. Our purpose was to investigate the knowledge of clinicians regarding ATTR-CM and to assess the availability of imaging resources in the Latin-American region. METHODS AND RESULTS: Two online surveys were distributed among clinicians and nuclear medicine professionals, respectively: one asking about awareness of CA in different clinical scenarios, and the other about the availability of diagnostic resources and studies performed. 406 responses were received for the first survey and 82 for the second, representing 17 and 14 countries, respectively. A significant lack of awareness was identified among clinicians, although appropriate diagnostic resources are generally available. Survey data showed that very few patients are evaluated for ATTR-CM in most Latin-American countries. CONCLUSIONS: The surveys demonstrated the need for educational programs and other measures to increase clinical awareness and early detection of CA, so patients receive timely treatment and management of the disease.

Prevalence, incidence and clinical outcomes of epicardial coronary artery disease among transthyretin amyloidosis cardiomyopathy patients.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) patients are often older and may be at risk for obstructive epicardial coronary artery disease (oeCAD). While ATTR-CM may cause small vessel coronary disease, the prevalence and clinical significance of oeCAD is not well described. METHODS AND RESULTS: The prevalence and incidence of oeCAD and its association with all-cause mortality and hospitalization among 133 ATTR-CM patients with ≥ 1-year follow-up was evaluated. The mean age was 78 ± 9 years, 119 (89%) were male, 116 (87%) had wild-type and 17 (13%) had hereditary subtypes. Seventy-two (54%) patients underwent oeCAD investigations, with 30 (42%) receiving a positive diagnosis. Among patients with a positive oeCAD diagnosis, 23 (77%) were diagnosed prior to ATTR-CM diagnosis, 6 (20%) at the time of ATTR-CM diagnosis, and 1 (3%) after ATTR-CM diagnosis. Baseline characteristics between patients with and without oeCAD were similar. Among patients with oeCAD, only 2 (7%) required additional investigations, intervention or hospitalization after ATTR-CM diagnosis. After a median follow-up of 27 months there were 37 (28%) deaths in the study population, including 5 patients with oeCAD (17%). Fifty-six (42%) patients in the study population required hospitalization, including 10 patients with oeCAD (33%). There was no significant difference in the rates of death or hospitalization among ATTR-CM patients with and without oeCAD, and oeCAD was not significantly associated with either outcome by univariable regression analysis. CONCLUSIONS: While oeCAD is prevalent in ATTR-CM patients, this diagnosis is frequently known at time of ATTR-CM diagnosis and characteristics are similar to patients without oeCAD.

Glaucoma is probably not useful as a red flag for amyloidosis.

Purpose. Transthyretin is produced in the retina and approximately one quarter of patients with variant transthyretin amyloidosis (ATTRv) develop ocular involvement. Glaucoma is the most important ocular manifestation, leading to rapid loss of vision. The usefulness of glaucoma as a red flag for cardiac amyloidosis is unknown. Materials and Methods. On a national scale, we investigated the association between glaucoma and development of amyloidosis, compared to an age- and sex-matched population from the general population. Results. The study population included 365,496 subjects (1:1 ratio). Adjusted Cox-models showed no significant association between glaucoma and future diagnosis of amyloidosis (hazard ratio: 1.16 [0.80-1.70], p = .44). Conclusion. We conclude that while ocular involvement is a possible early manifestation of ATTRv, nationwide data suggest that glaucoma is probably not useful as a red flag for cardiac amyloidosis.

First description of Portuguese patients with cardiac amyloidosis and p.Val142Ile: more evidence of an "African variant" in Caucasians.

Objectives. Hereditary transthyretin amyloidosis caused by the (ATTRv) p. Val142Ile variant is a common cause of cardiac amyloidosis among Western African countries and Afro-Americans populations. However, in recent years, Caucasian patients have been identified in greater numbers, raising the question of whether this variant has been undeappreciated in this population. We now have new cases of cardiac amyloidosis caused by the p.Val142Ile from a center in northern Portugal. In addition, we reviewed and discussed the published data concerning p.Val142Ile in Caucasians. Design. Patients diagnosed with cardiac amyloidosis underwent genetic testing using TTR gene sequencing and their relatives were recommended for genetic counsellingand testing if a pathogenic TTR variant was found. In our center, we reviewed the clinical data of patients who had the p.Val142Ile variant. A review of published cases of p.Val142Ile in Caucasians was also performed, to which our data was compared. Results. We found three ATTRv patients with the p.Val142Ile variant (one homozygotic), all Caucasian males with a median age at diagnosis of 69 years old. All of them had heart failure and arrhythmias. During the follow-up period, two patients died. There were 47 unrelated unrelated Caucasian cases of ATTRv p.Val142Ile variant reported worldwide until May 2022. Conclusions. Our findings add to the mounting evidence that the global prevalence of p.Val142Ile is likely understated. This highlights the importance of the systematic screening of the TTR gene in amyloidosis and phenocopies, as well as larger epidemiologic studies to determine the true ATTRv p.Val142Ile prevalence in non-African communities.

Cardiac Amyloidosis: Overlooked, Underappreciated, and Treatable.

Cardiac amyloidosis (CA) is an infiltrative and restrictive cardiomyopathy that leads to heart failure, reduced quality of life, and death. The disease has two main subtypes, transthyretin cardiac amyloidosis (ATTR-CA) and immunoglobulin light chain cardiac amyloidosis (AL-CA), characterized by the nature of the infiltrating protein. ATTR-CA is further subdivided into wild-type (ATTRwt-CA) and variant (ATTRv-CA) based on the presence or absence of a mutation in the transthyretin gene. CA is significantly underdiagnosed and increasingly recognized as a cause of heart failure with preserved ejection fraction. Advances in diagnosis that employ nuclear scintigraphy to diagnose ATTR-CA without a biopsy and the emergence of effective treatments, including transthyretin stabilizers and silencers, have changed the landscape of this field and render early and accurate diagnosis critical. This review summarizes the epidemiology, pathophysiology, diagnosis, prognosis, and management of CA with an emphasis on the significance of recent developments and suggested future directions.

Electrical Dyssynchrony in Cardiac Amyloidosis: Prevalence, Predictors, Clinical Correlates, and Outcomes.

BACKGROUND: Conduction-system involvement in cardiac amyloidosis (CA) is common. The prevalence, clinical correlates and impact on outcome related to ventricular electrical dyssynchrony in CA remain insufficiently elucidated. METHODS: Data from a prospectively maintained registry of patients with CA diagnosed in the Cleveland Clinic's amyloidosis clinic was used to determine the frequency of electrical dyssynchrony (defined as a QRS > 130 msec). The relation with the clinical profile and clinical outcome was assessed. To determine the impact of hypertrophy on QRS prolongation, a QRS-matched cohort without CA was used for comparison of cardiac magnetic resonance imaging. RESULTS: A total of 1140 patients with CA (39% AL, 61% TTR) were evaluated, of whom 230 (20%) had electrical dyssynchrony. The type of conduction block was predominantly a right bundle branch block (BBB, 48%) followed by left BBB (35%) and intraventricular conduction delay (17%). Presence of transthyretin amyloidosis (ATTR-CA), older age, male gender, white race, and coronary artery disease were independently (P< 0.05 for all) associated with electrical dyssynchrony, and patients were more commonly prescribed a mineralocorticoid receptor antagonist. In ATTR-CA, specifically, every increase in ATTR-CA disease stage was associated with a 1.55-fold (1.23--1.95; P< 0.001) increased odds for electrical dyssynchrony. In a subset of patients with CA who underwent cardiac magnetic resonance imaging (n = 41), left ventricular mass index was unrelated to the QRS duration (r = 0.187; P = 0.283) in CA, in contrast to a non-CA QRS-matched cohort (r = 0.397; P< 0.001). Patients with electrical dyssynchrony were more symptomatic at initial presentation, as illustrated by a higher New York Heart Association class (P= 0.041). During a median follow-up of 462 days (IQR:138--996 days), a higher proportion of patients with electrical dyssynchrony died from all-cause death (P= 0.037) or developed a permanent pacing indication (3% vs 10.4%; P< 0.001) during follow-up. CONCLUSION: Electrical dyssynchrony is common in CA, especially in ATTR-CA, and is associated with worse functional status and clinical outcome. Given the high rate of permanent pacing indications at follow-up, additional studies are necessary to determine the best monitoring and pacing strategies in CA.

Epidemiology and clinical manifestations of cardiac amyloidosis.

Cardiac amyloidosis, once considered a rare disease, has garnered significant attention over the last few years due to three key reasons: first, increased recognition of this disease in conjunction with various common cardiac conditions such as heart failure with preserved ejection fraction and aortic stenosis; second, due to the advent of promising new therapies for light chain disease (AL), transthyretin (ATTR) cardiomyopathy, and amyloid neuropathy; finally, the advancements in cardiac imaging including echocardiography, magnetic resonance imaging, and nuclear cardiac scintigraphy aid in non-biopsy diagnosis of ATTR cardiac amyloidosis. The hereditary forms of ATTR have further come into importance with the availability of genetic testing and increased prevalence of certain mutations in African Americans. Recognition of non-cardiac clues to this disease has gained importance and reiterates that high clinical suspicion, detailed patient history, and examination with appropriate use of imaging are vital to confirm the diagnosis.

Established and candidate transthyretin amyloidosis variants identified in the Saudi population by data mining.

BACKGROUND: Familial transthyretin (TTR) amyloidosis (ATTR) is an autosomal dominant disease with significant phenotypic heterogeneity. Its prevalence in Saudi Arabia has not previously been investigated. An existing exome variant database of Saudi individuals, sequenced to globally investigate rare diseases in the population, was mined for TTR variants and filtered for missense mutations resulting in single amino acid changes. A total of 13,906 Saudi exomes from unrelated individuals were analyzed blindly. RESULTS: Three TTR variants known to be associated with ATTR amyloidosis were identified. Additionally, three novel TTR mutations were identified. Structural analysis of the three novel variants suggests that at least two could be amyloidogenic. The most common variant associated with amyloidosis was p.Val142Ile (allele frequency 0.001). Further investigation of these variants and their translation to clinical practice may help to diagnose, monitor, and manage patients with ATTR amyloidosis. CONCLUSION: Multiple TTR variants potentially associated with systemic ATTR amyloidosis were identified in the Saudi population. Early diagnosis and intervention, facilitated by familial genetic testing of patients with ATTR amyloidosis, may benefit in the management of this disease. Early diagnosis could be enhanced through inclusion of ATTR variants in existing population-based screening programs.

Association of Transthyretin Val122Ile Variant With Incident Heart Failure Among Black Individuals.

Importance: A genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis. Objective: To estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals. Design, Setting, and Participants: Retrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020. Exposures: TTR Val122Ile (rs76992529) genotype. Main Outcome and Measures: The primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors. Results: Among 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes. Conclusions and Relevance: Among a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.

Transthyretin amyloid cardiomyopathy in women: frequency, characteristics, and diagnostic challenges.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, life-threatening disease characterized by deposition of insoluble amyloid fibrils in the myocardium, resulting in cardiac structural and functional abnormalities and ultimately heart failure. Disease frequency is reportedly lower in women than men, but sex-related differences have not been well established. We conducted a systematic literature review (SLR), based on PRISMA-P guidelines and registered with PROSPERO, to assess whether the epidemiology and clinical presentation of ATTR-CM differ between women and men. MEDLINE, Embase, and Cochrane databases and selected conference proceedings were searched (August 16, 2019) to identify observational and clinical studies reporting sex-specific data for patients with wild-type or hereditary ATTR-CM. Of 193 publications satisfying final eligibility criteria, 69 studies were included in our pooled analysis. Among the 4669 patients with ATTR-CM analyzed, 791 (17%) were women, including 174 (9%), 366 (29%), and 251 (18%) in studies of wild-type, hereditary, and undefined ATTR-CM, respectively. Data available on disease characteristics were limited and very heterogeneous, but trends suggested some cardiac structural/functional differences, i.e., lower interventricular septal and posterior wall thickness and left ventricular (LV) end diastolic diameter, and higher LV ejection fractions, in women versus men across ATTR-CM subtypes. Because LV wall thickness > 12 mm is generally the suggested threshold for ATTR-CM diagnosis in both sexes, smaller cardiac anatomy in women with the disease may lead to underdiagnosis. Additional research and studies are needed to elucidate potential disparities between sexes in ATTR-CM frequency, clinical characteristics, and underlying biological mechanisms. This study was registered within the International Prospective Register of Systematic Reviews (PROSPERO) database of the University of York (CRD42019146995).

A Review of Novel Agents and Clinical Considerations in Patients With ATTR Cardiac Amyloidosis.

ABSTRACT: Transthyretin (ATTR) amyloidosis is a multisystem disease caused by organ deposition of amyloid fibrils derived from the misfolded transthyretin (TTR) protein. The purpose of this article is to provide an overview of current treatment regimens and summarize important considerations for each agent. A literature search was performed with the PubMed database for articles published through October 2020. Search criteria included therapies available on the market and investigational therapies used for ATTR amyloidosis treatment. Both prospective clinical trials and retrospective studies have been included in this review. Available therapies discussed in this review article are tafamidis, diflunisal, patisiran, and inotersen. Tafamidis is FDA approved for treatment of wild-type ATTR (ATTRwt) and hereditary ATTR (ATTRv) cardiomyopathy, and patisiran and inotersen are FDA approved for ATTRv polyneuropathy. Diflunisal does not have an FDA-labeled indication for amyloidosis but has been studied in ATTRv polyneuropathy and ATTRwt cardiomyopathy. Investigational therapies include a TTR stabilizer, AG10; 2 antifibril agents, PRX004 and doxycycline/tauroursodeoxycholic acid; and 2 gene silencers, vutrisiran and AKCEA-TTR-LRx; and clinical trials are ongoing. ATTR amyloidosis treatment selection is based on subtype and presence of cardiac or neurological manifestations. Additional considerations such as side effects, monitoring, and administration are outlined in this review.

Utility of Neuropathy Screening for Wild-Type Transthyretin Amyloidosis Patients.

BACKGROUND: Wild-type transthyretin amyloidosis (wtATTR) is an important cause of heart failure (HF); however, the prevalence and clinical significance of neurologic complications remains uncertain. METHODS: This analysis reports findings from a single-centre experience of routine neuropathy screening at the time of wtATTR diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls. RESULTS: Forty-one wtATTR patients were included, 39 (95%) males, mean age 78.4 ± 7.7 years, 22 (54%) New York Heart Association (NYHA) class III-IV HF, along with 15 age-matched controls (mean age 77.1 ± 4.2 years, 80% male). Twenty-one (51%) wtATTR patients were diagnosed with polyneuropathy, 15 (37%) with spinal stenosis, 36 (88%) with carpal tunnel syndrome (CTS) and 14 (34%) with ulnar neuropathy. Comparison diagnoses among controls were 1 (7%), 0, 1 (7%) and 3 (20%), respectively. Among patients with NYHA class III-IV HF, 16 (73%) had polyneuropathy compared with 5 (26%) with class I-II (p < 0.01), odds ratio of 7.5 (95% confidence interval 1.9-29.9). After neuropathy screening, 19 (46%) patients were offered neurologic therapy and/or additional diagnostic evaluation. This included CTS release surgery (16, 39%), neuropathic pain medication (3, 7%), nerve block (1, 2%), wrist splinting (2, 5%) and foot care (1, 2%). Spine imaging was performed for 3 (7%) patients, and deltoid muscle and sural nerve biopsy for 1 (2%) patient. CONCLUSIONS: Screening of wtATTR patients for neurologic complications resulted in a management change for nearly half. CTS, polyneuropathy and ulnar neuropathy were common. This approach warrants consideration as part of routine assessment for newly diagnosed wtATTR patients.

Electro-clinical presentation of hereditary transthyretin related amyloidosis when presenting as a polyneuropathy of unknown origin in northern France.

INTRODUCTION: Hereditary transthyretin related amyloidosis (h-ATTR) classically presents as a small fiber neuropathy with positive family history, but can also be revealed by various other types of peripheral neuropathy. OBJECTIVE: To describe the initial electro-clinical presentation of patients from in a single region (northern France) of h-ATTR when it presents as a polyneuropathy of unknown origin. METHOD: We reviewed the records of patients referred to two neuromuscular centers from northern France with a peripheral neuropathy of unknown origin who were subsequently diagnosed with h-ATTR. RESULTS: Among 26 h-ATTR patients (10 Val30Met, 16 Ser77Tyr), only 14 patients had a suspicious family history (53.8%). The electro-clinical presentation was mostly a large-fiber sensory motor polyneuropathy (92.3%), which could be symmetric or not, length-dependent or not, or associated with nerve entrapment or not. Demyelinating signs were observed in 17 patients (70.8%), among whom nine fulfilled the criteria for a definite diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (37.5%). CONCLUSION: h-ATTR may have a wide spectrum of clinical profiles, and should be considered in the screening of polyneuropathies of unknown origin.

Poor Yield of Routine Transthyretin Screening in Patients with Idiopathic Neuropathy.

BACKGROUND AND OBJECTIVES: Transthyretin familial amyloid polyneuropathy (TTR-FAP) is caused by a mutation in the transthyretin (TTR) gene. Although classically described as rapidly progressive and life-threatening, recent studies on TTR-FAP show significant genetic and phenotypic heterogeneity depending on geographic localization. In light of new therapeutic advances and their implication for patient management, the aim of our study was to determine the prevalence of TTR-FAP within patients with idiopathic neuropathy in a North American population. METHODS: We sequenced the TTR gene in a cohort of patients with idiopathic neuropathy. Genetic screening was performed in 110 patients from two neuromuscular clinics in Montreal, Canada. RESULTS: No variants of unknown significance or pathogenic mutations were detected in the TTR gene. CONCLUSION: Our study confirms that TTR-FAP is a rare entity in our patient population, and that diagnostic yield of screening all patients with idiopathic neuropathy is very low.

The frequency of central nervous system complications in the Cypriot cohort of ATTRV30M neuropathy transplanted patients.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTR) is a hereditary, sensorimotor and autonomic neuropathy caused by deposits of mutated transthyretin (TTR). The commonest TTR mutation is V30M (ATTRV30M) with patients usually living for about 10 years after disease onset. Liver transplantation (LT) until recently was considered the standard treatment. OBJECTIVE AND METHODS: This study aims to assess the frequency of CNS complications in post-LT patients from the Cypriot cohort. Epidemiological data were collected for all genetically confirmed ATTRV30M neuropathy patients diagnosed at CING since 1992, and CNS-associated symptoms were assessed and evaluated by two neurology specialists. RESULTS: Out of the 48 transplanted patients, 10 (20.8%) presented with a CNS complication. All patients had ocular involvement, mainly glaucoma (7/10). Eight presented with transient focal neurological episodes (TFNEs), with expressive dysphasia being reported by four of them. The mean time of TFNE-emergence was 16.6 years after the LT. Three died from cerebral hemorrhage. CONCLUSIONS: CNS complications in post-LT ATTRV30M patients are not rare and usually manifest themselves at a time that surpasses the mean time the patients would have survived without a LT. CNS involvement is associated with increased mortality, due to cerebral hemorrhage.

Upper limb onset of hereditary transthyretin amyloidosis is common in non-endemic areas.

BACKGROUND AND PURPOSE: The aim is to describe an uncommon phenotype of hereditary ATTR neuropathy with upper limb onset. METHODS: The French TTR Familial Amyloid Polyneuropathy database was used for a retrospective evaluation of 32 consecutive patients with upper limb onset of the neuropathy (study group) and they were compared to 31 Portuguese early-onset patients and 99 late-onset patients without upper limb onset. RESULTS: Initial upper limb symptoms were mostly sensory. Lower limb symptoms began 2.3 ± 3 years after upper limb symptoms. Twenty-four (75%) patients were initially misdiagnosed, with 15 different diagnoses. More patients in the study group had a Neuropathy Impairment Score upper limb/lower limb ratio > 1 compared to the late-onset patient group. The study group had significantly more pronounced axonal loss in the median and ulnar motor nerves and the ulnar sensory and sural nerves. On radial nerve biopsies (n = 11), epineurial vessels were abnormal in six cases, including amyloid deposits in vessel walls (3/11), with vessel occlusion in two cases. CONCLUSION: Upper limb onset of hereditary ATTR neuropathy is not rare in non-endemic areas. It is important to propose early TTR sequencing of patients with idiopathic upper limb neuropathies, as specific management and treatment are required.

Hereditary transthyretin-related amyloidosis.

Hereditary transthyretin(TTR)-related amyloidosis (ATTRm amyloidosis) is an endemic/non-endemic, autosomal-dominant, early- and late-onset, rare, progressive disorder, predominantly manifesting as length-dependent, small fiber dominant, axonal polyneuropathy and frequently associated with cardiac disorders and other multisystem diseases. ATTRm amyloidosis is due to variants in the TTR gene, with the substitution Val30Met as the most frequent mutation. TTR mutations lead to destabilization and dissociation of TTR tetramers into variant TTR monomers, and formation of amyloid fibrils, which are consecutively deposited extracellularly in various tissues, such as nerves, heart, brain, eyes, intestines, kidneys, or the skin. Neuropathy may not only include large nerve fibers but also small fibers, and not only sensory and motor fibers but also autonomic fibers. Types of TTR variants, age at onset, penetrance, and clinical presentation vary between geographical areas. Suggestive of a ATTRm amyloidosis are a sensorimotor polyneuropathy, positive family history, autonomic dysfunction, cardiomyopathy, carpal tunnel syndrome, unexplained weight loss, and resistance to immunotherapy. If only sensory A-delta or C fibers are affected, small fiber neuropathy ensues. Diagnostic tests for small fiber neuropathy include determination of intraepidermal nerve fiber density, laser-evoked potentials, heat- and cold-detection thresholds, and measurement of the electrochemical skin conductance. Therapy currently relies on liver transplantation and TTR-stabilizers (tafamidis, diflunisal).