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Circulation. Genomic and Precision... Oct 2021The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly...
BACKGROUND
The p.Val142Ile variant, predominantly found among people of African descent, is the most common cause of variant transthyretin amyloidosis and carriers predominantly develop a cardiomyopathy (variant transthyretin amyloidosis cardiomyopathy) phenotype. Yet, there are conflicting data on the prevalence and outcomes of p.Val142Ile variant carriers.
METHODS
We performed a systematic review of the prevalence and outcomes of p.Val142Ile variant transthyretin amyloidosis cardiomyopathy among subjects of African descent. We found 62 relevant articles after searching the MEDLINE databases from 1980 to 2020 that reported data for ≈150 000 subjects.
RESULTS
The reported worldwide prevalence of the p.Val142Ile variant is 0.3% to 1.6% in the general population. Among people of African descent, the reported prevalence from all studies ranges from 1.1% to 9.8%, but for studies with >1000 subjects, it is 3% to 3.5%. The prevalence of the p.Val142Ile variant in a region is dependent on the reported percentage of subjects who are of African descent in that region. p.Val142Ile variant transthyretin amyloidosis cardiomyopathy typically presents in the seventh to eighth decade of life and the majority of cases reported were male, with 25% to 38% diagnosed with atrial fibrillation. It was associated with a longitudinally worse quality of life and a lower adjusted survival compared with other types of transthyretin amyloidosis cardiomyopathy.
CONCLUSIONS
The p.Val142Ile variant is the most common variant of the transthyretin gene with most carriers being of African descent. The true penetrance is unknown but the p.Val142Ile variant is associated with increased rates of incident heart failure and portends a lower overall survival. Increased awareness could lead to earlier diagnosis and improved heart failure outcomes among those of African descent, which is of increasing importance given the advent of novel therapeutics for this disease.
Topics: Amino Acid Substitution; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Humans; Male; Mutation, Missense; Prealbumin; Prevalence; Risk Factors; Sex Factors
PubMed: 34461737
DOI: 10.1161/CIRCGEN.121.003356 -
European Journal of Clinical... Dec 2021Transthyretin-related cardiac amyloidosis (TTR-CA) is thought to be particularly common in specific at-risk conditions, including aortic stenosis (AS), heart failure...
BACKGROUND
Transthyretin-related cardiac amyloidosis (TTR-CA) is thought to be particularly common in specific at-risk conditions, including aortic stenosis (AS), heart failure with preserved ejection fraction (HFpEF), carpal tunnel syndrome (CTS) and left ventricular hypertrophy or hypertrophic cardiomyopathy (LVH/HCM).
METHODS
We performed a systematic revision of the literature, including only prospective studies performing TTR-CA screening with bone scintigraphy in the above-mentioned conditions. Assessment of other forms of CA was also evaluated. For selected items, pooled estimates of proportions or means were obtained using a meta-analytic approach.
RESULTS
Nine studies (3 AS, 2 HFpEF, 2 CTS and 2 LVH/HCM) accounting for 1375 screened patients were included. One hundred fifty-six (11.3%) TTR-CA patients were identified (11.4% in AS, 14.8% in HFpEF, 2.6% in CTS and 12.9% in LVH/HCM). Exclusion of other forms of CA and use of genetic testing was overall puzzled. Age at TTR-CA recognition was significantly older than that of the overall screened population in AS (86 vs. 83 years, p = .04), LVH/HCM (75 vs. 63, p < .01) and CTS (82 vs. 71), but not in HFpEF (83 vs. 79, p = .35). In terms of comorbidities, hypertension, diabetes and atrial fibrillation were highly prevalent in TTR-CA-diagnosed patients, as well as in those with an implanted pacemaker.
CONCLUSIONS
Screening with bone scintigraphy found an 11-15% TTR-CA prevalence in patients with AS, HFpEF and LVH/HCM. AS and HFpEF patients were typically older than 80 years at TTR-CA diagnosis and frequently accompanied by comorbidities. Several studies showed limitations in the application of recommended TTR-CA diagnostic algorithm, which should be addressed in future prospective studies.
Topics: Amyloid Neuropathies, Familial; Amyloidosis; Aortic Valve Stenosis; Cardiomyopathies; Cardiomyopathy, Hypertrophic; Carpal Tunnel Syndrome; Heart Failure; Humans; Hypertrophy, Left Ventricular; Radionuclide Imaging; Stroke Volume
PubMed: 34390490
DOI: 10.1111/eci.13665 -
Heart Failure Reviews Mar 2022Transthyretin cardiac amyloidosis (ATTR-CM) is caused by the accumulation of misfolded transthyretin (TTR) protein in the myocardium. Diflunisal, an agent that... (Review)
Review
Transthyretin cardiac amyloidosis (ATTR-CM) is caused by the accumulation of misfolded transthyretin (TTR) protein in the myocardium. Diflunisal, an agent that stabilizes TTR, has been used as an off-label therapeutic for ATTR-CM. Given limited data surrounding the use of diflunisal, a systematic review of the literature is warranted. We searched the PubMed, MEDLINE, and Embase databases for studies that reported on the use of diflunisal therapy for patients with ATTR-CM. We included English language studies which assessed the effect of diflunisal in adult patients with ATTR-CM who received diflunisal as primary treatment and reported clinical outcomes with emphasis on studies that noted the safety and efficacy of diflunisal in cardiac manifestations of ATTR amyloidosis. We excluded studies which did not use diflunisal therapy or used diflunisal therapy for non-cardiac manifestations of TTR amyloidosis. We also excluded case reports, abstracts, oral presentations, and studies with fewer than 10 subjects. Our search yielded 316 records, and we included 6 studies reporting on 400 patients. Non-comparative single-arm small non-randomized trials for diflunisal comprised 4 of the included studies. The 2 studies that compared diflunisal versus no treatment found improvements in TTR concentration, left atrial volume index, cardiac troponin I, and global longitudinal strain. Overall, diflunisal use was associated with decreased mortality and number of orthotopic heart transplant in ATTR-CM patients. Although a smaller number of patients had to stop treatment due to gastrointestinal side effects and transient renal dysfunction, there were no severe reactions reported in the studies included in our review. This systematic review supports the use of diflunisal for ATTR-CM. Additional long-term analyses and randomized clinical trials are needed to confirm these results.
Topics: Adult; Amyloid Neuropathies, Familial; Diflunisal; Humans; Myocardium; Prealbumin
PubMed: 34272629
DOI: 10.1007/s10741-021-10143-4 -
Revista Da Associacao Medica Brasileira... Jan 2021To review the literature and to report a clinical case with initial suspicion of pure neural leprosy and final diagnosis of amyloid neuropathy.
OBJECTIVE
To review the literature and to report a clinical case with initial suspicion of pure neural leprosy and final diagnosis of amyloid neuropathy.
METHODS
The study was conducted in two stages. In stage one, a systematic literature review was carried out, with searches performed in the PubMed, Medline, and Lilacs databases, as well as in the leprosy sectoral library of the Virtual Health Library, using the following descriptors: neuritic leprosy, pure neural leprosy, primary neural leprosy, pure neuritic leprosy, amyloid polyneuropathy, amyloid neuropathies, and amyloid polyneuropathy. The search was carried out on May 28, 2020. Clinical trials, cohort studies, cross-sectional studies, clinical cases, and case studies published in Portuguese, English or Spanish between 2010 and 2020 were included. Stage two reports a case with initial suspicion of pure neural leprosy. Laboratory tests, electroneuromyography, ultrasound, and biopsy of the sural nerve were requested.
RESULTS
Twenty-three scientific texts were included. No publications were found that contained both topics together. The challenging diagnosis of pure neural leprosy and the possibility of using auxiliary resources in diagnosis were the most emphasized themes in the studies. In the clinical case, the patient's electroneuromyography showed sensitive and motor polyneuropathy of the lower limbs, which was predominantly sensory and axonal, symmetrical, of moderate intensity, and the mixed type (axonal-demyelinating). Ultrasonography of the sural nerve revealed changes in the contour of the deep fibular nerves; biopsy of the sural nerve showed an accumulation of amorphous eosinophilic material in the nerve path, and Congo red stain showed apple-green birefringence of the deposit under polarized light. The final diagnosis was amyloid neuropathy.
CONCLUSIONS
The final clinical diagnosis was amyloid neuropathy. The diagnosis of pure neural leprosy in endemic areas in Brasil is still a challenge for the health system.
Topics: Amyloid Neuropathies; Brazil; Cross-Sectional Studies; Humans; Leprosy; Leprosy, Tuberculoid
PubMed: 34161469
DOI: 10.1590/1806-9282.67.01.20200422 -
Amyloid : the International Journal of... Sep 2021Hereditary transthyretin (ATTRv) amyloidosis is a progressive multisystemic disease of adult-onset that arises from an inherited mutation in the transthyretin gene....
BACKGROUND
Hereditary transthyretin (ATTRv) amyloidosis is a progressive multisystemic disease of adult-onset that arises from an inherited mutation in the transthyretin gene. Currently available disease severity and progression evaluation tools only cover one single organ or system, impacting data collection uniformity and its use in clinical settings.
METHODS
The Jandhyala Method, including a systematic literature review and SMART interviews, was used to observe expert opinion from eight leaders in the treatment of ATTRv across Europe. The aim was to propose a multidisciplinary core dataset (CD) and disease severity scoring (DSS) tools.
RESULTS
The multidisciplinary team of experts identified 140 indicators that form part of the standard diagnostic and monitoring practice (SDMP) and should be collected as the ATTRv CD. Thirty-one (22%) of these indicators informed disease severity and comprised the ATTRv DSS, whilst 25 (18%) were deemed to monitor disease progression.
CONCLUSIONS
The resulting CD and DSS have different purposes. The ATTRv CD supports the collection of high-quality data for clinical research, whereas the ATTRv DSS can be rapidly conducted in a clinical setting and aid patient management.
Topics: Adult; Amyloid Neuropathies, Familial; Europe; Humans; Prealbumin; Severity of Illness Index
PubMed: 34042016
DOI: 10.1080/13506129.2021.1931099 -
European Journal of Neurology Jul 2021The coexistence of peripheral neuropathy (PN) and restless legs syndrome (RLS) or Willis-Ekbom disease is relatively frequent, but its prevalence has shown a high... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND AND PURPOSE
The coexistence of peripheral neuropathy (PN) and restless legs syndrome (RLS) or Willis-Ekbom disease is relatively frequent, but its prevalence has shown a high variability across studies. In addition, several reports have shown data suggesting the presence of PN in patients with idiopathic RLS.
METHODS
A search was undertaken using the PubMed, Embase and Web of Science Databases, from 1966 to 6 December 2020, crossing the search term 'restless legs syndrome' with 'neuropathy', 'polyneuropathy' (PNP) and 'peripheral neuropathy', and the references of interest for this topic were identified; a meta-analysis was performed, according to PRISMA guidelines, and a calculation of pooled prevalences, where appropriate, was made using standard methods.
RESULTS
Restless legs syndrome has been reported in 5.2%-53.7% of patients with PN (average 21.5%; 95% confidence interval 18.6%-24.5%), and PN has been reported in 0%-87.5% of patients with RLS (average 41.8%; 95% confidence interval 39.9%-43.6%), both being significantly more frequent than in controls. The heterogeneity across studies could be due to differences in the diagnostic criteria used for both RLS and PN. RLS is a frequent clinical complaint in patients with PN of different aetiologies, mainly diabetic PN, uraemic PNP, familial amyloid PNP, Charcot-Marie-Tooth disease and chronic dysimmune inflammatory PNP. Recent neurophysiological findings suggest the presence of small sensory fibre loss in patients diagnosed with idiopathic RLS, but it remains to be determined whether RLS associated with small sensory fibre loss and idiopathic RLS are different clinical entities.
CONCLUSIONS
Future studies including clinical and neurophysiological assessment and skin biopsy involving a large series of patients with PN and RLS are needed for a better understanding of the association between these two entities.
Topics: Amyloid Neuropathies, Familial; Charcot-Marie-Tooth Disease; Diabetic Neuropathies; Humans; Polyneuropathies; Restless Legs Syndrome
PubMed: 33772991
DOI: 10.1111/ene.14840 -
Heart Failure Reviews May 2022V122I genotype variant (pV142I) is the most common hereditary transthyretin amyloidosis (hATTR) in the USA, with 3-3.5% of African-Americans being the carriers of this...
V122I genotype variant (pV142I) is the most common hereditary transthyretin amyloidosis (hATTR) in the USA, with 3-3.5% of African-Americans being the carriers of this mutation. We aimed to compare baseline clinical features, cardiac parameters, and mortality in V122I-ATTR with the wild-type ATTR and other hATTR subtypes. We systematically searched PubMed/Medline and Google Scholar databases to identify relevant studies from inception to 10th September, 2020 reporting phenotypic, echocardiographic, and/or laboratory parameters in patients with hereditary and wild types of cardiac amyloidoses. A total of 2843 patients from 7 individual studies with 67-100% males and an overall follow-up duration of 51.6 ± 30.4 months were identified. The mean age of diagnosis among wild-type ATTR patients was 77 years, followed by 71.2 and 65 years in V122I and T60A group patients, respectively. V122I patients were mostly black, had a poor quality of life, and highest mortality risk compared with other subtypes. Merely, the presence of V122I mutation was identified as an independent predictor of mortality. V30M subtype correlated with the least severe cardiac disease and a median survival duration comparable with T60A subtype. V122I ATTR is an aggressive disease, prevalent in African-Americans, and is associated with a greater morbidity and mortality, which is partly attributed to its misdiagnosis and/or late diagnosis. Current advances in non-invasive studies to diagnose hATTR coupled with concurrent drug therapies have improved quality of life and provide a survival benefit to these patients.
Topics: Aged; Amyloid Neuropathies, Familial; Cardiomyopathies; Female; Genotype; Humans; Male; Prealbumin; Quality of Life
PubMed: 33768376
DOI: 10.1007/s10741-021-10098-6 -
BMC Neurology Feb 2021We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including... (Meta-Analysis)
Meta-Analysis
BACKGROUND
We aimed to compare neuropathic progression rate between hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and other peripheral neuropathies, including diabetic peripheral neuropathy (DPN) and Charcot-Marie-Tooth disease (CMT).
METHODS
Literature searches identified studies reporting neuropathic progression, measured by Neuropathy Impairment Score (NIS) or NIS-Lower Limbs (NIS-LL). Our study also included unpublished data from a clinical registry of patients who were diagnosed with different peripheral neuropathies and seen at the Oregon Health & Science University (OHSU) during 2016-2020. Meta-analysis and meta-regression models examined and compared annual progression rates, calculated from extracted data, between studies of ATTRv-PN and other peripheral neuropathies.
RESULTS
Data were synthesized from 15 studies in which NIS and/or NIS-LL total scores were assessed at least twice, with ≥12 weeks between assessments, among untreated patients with ATTRv-PN or other peripheral neuropathies. Meta-analysis models yielded that the annual progression rate in NIS total scores was significantly different from zero for studies in ATTRv-PN and CMT (11.77 and 1.41; both P < 0.001), but not DPN (- 1.96; P = 0.147). Meta-regression models showed significantly faster annual progression in studies in ATTRv-PN, which statistically exceeded that in other peripheral neuropathies by 12.45 points/year for NIS, and 6.96 for NIS-LL (both P < 0.001).
CONCLUSIONS
Peripheral nervous function deteriorates more rapidly in patients with ATTRv-PN than for other peripheral neuropathies. These findings may improve understanding of the natural history of neuropathy in ATTRv-PN, facilitate early diagnosis, and guide the development of assessment tools and therapies specifically targeting neuropathic progression in this debilitating disease.
Topics: Amyloid Neuropathies, Familial; Disease Progression; Female; Humans; Male; Middle Aged; Polyneuropathies; Registries
PubMed: 33579211
DOI: 10.1186/s12883-021-02094-y -
BMC Musculoskeletal Disorders Jan 2021Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid...
BACKGROUND
Transthyretin and immunoglobulin light-chain amyloidoses cause amyloid deposition throughout various organ systems. Recent evidence suggests that soft tissue amyloid deposits may lead to orthopedic conditions before cardiac manifestations occur. Pharmacologic treatments reduce further amyloid deposits in these patients. Thus, early diagnosis improves long term survival.
QUESTIONS/PURPOSES
The primary purpose of this systematic review was to characterize the association between amyloid deposition and musculoskeletal pathology in patients with common orthopedic conditions. A secondary purpose was to determine the relationship between amyloid positive biopsy in musculoskeletal tissue and the eventual diagnosis of systemic amyloidosis.
METHODS
We performed a systematic review using PRISMA guidelines. Inclusion criteria were level I-IV evidence articles that analyzed light-chain or transthyretin amyloid deposits in common orthopedic surgeries. Study methodological quality, risk of bias, and recommendation strength were assessed using MINORS, ROBINS-I, and SORT.
RESULTS
This systematic review included 24 studies for final analysis (3606 subjects). Amyloid deposition was reported in five musculoskeletal pathologies, including carpal tunnel syndrome (transverse carpal ligament and flexor tenosynovium), hip and knee osteoarthritis (synovium and articular cartilage), lumbar spinal stenosis (ligamentum flavum), and rotator cuff tears (tendon). A majority of studies reported a mean age greater than 70 for patients with TTR or AL positive amyloid.
CONCLUSIONS
This systematic review has shown the presence of amyloid deposition detected at the time of common orthopedic surgeries, especially in patients ≥70 years old. Subtyping of the amyloid has been shown to enable diagnosis of systemic light-chain or transthyretin amyloidosis prior to cardiac manifestations.
LEVEL OF EVIDENCE
Level IV.
Topics: Aged; Amyloid Neuropathies, Familial; Humans; Immunoglobulin Light-chain Amyloidosis; Orthopedic Procedures; Osteoarthritis, Hip; Osteoarthritis, Knee
PubMed: 33419417
DOI: 10.1186/s12891-020-03912-z -
Journal of Neurochemistry Mar 2021The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization...
The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.
Topics: Amyloid; Amyloidosis, Familial; Animals; Gene Knockdown Techniques; Humans; Prealbumin
PubMed: 33155274
DOI: 10.1111/jnc.15233