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Results for “Amyloid Neuropathies, Familial”

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PubMed1975

[Familial amyloid neuropathy of Corino Andrade. Ultrastructural study of the peripheral nerve in 2 patients].

The authors describe two typical cases of Portuguese amyloid neuropathy in immigrants. One of the patients had been ill for only a short time while the other's condition had been developing over more than ten years. The first patient's neuropathy was characterized by a perforating ulcer of the foot and loss of sensation. The neurological disorder as well as the effect on general health were much more serious in the second patient. Neuro-muscular biopsy was carried out on each of these patients and revealed excessive endoneural amyloid and very severe lesions of nerve parenchyma mainly secondary to Wallerian degeneration. The results were compared with the few existing ultrastructural studies on the peripheral nerve in amyloid neuropathies.

Adult↗

PubMed1978

[Familial amyloid neuropathy].

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Adult↗

PubMed1978

Electroneurophysiological studies in familial amyloid polyneuropathy--Portuguese type.

Electroneurophysiological studies were performed in 15 patients with familial amyloid neuropathy (ages 29 to 67 years) and in 16 symptom-free members of affected families (ages 9 to 64 years). These studies included needle EMG, motor conduction velocities of deep peroneal and median nerves, sensory conduction velocities, sensory potentials, and nerve potentials of the sural and medium nerves. Results support the view that familial amyloid neuropathy is a peripheral neuropathy with predominantly axonal damage, which affects first the distal segments of the sensory fibres and then the motor fibres. It is suggested that, in some respects, this condition is akin to the dying-back neuropathies. Results also show that it is possible to detect the disease before it becomes obvious clinically, and this has important implications for genetic counseling.

Adolescent↗

PubMed1978

[Amyloid neuropathy associated with a benign monoclonal gammopathy (lambda light chains)].

The authors report a case of non-familial amyloid neuropathy in which there was sensory-motor neuropathy of the 4 limbs, multiple lesions in the cranial nerves, and large subcutaneous amyloid deposits. Biopsy samples showed the presence of amyloid deposits in the interstitial tissues, the vessel walls in the muscle hypodermis, and in the bone marrow. A light monoclonal lambda chain was present in the serum. Immunofluorescent studies of the biopsy specimens showed the presence of elective fluorescence with an anti-lambda immunoserum in the amyloid substance.

Amyloidosis↗

PubMed2026

Bioepidemiology of cardiac amyloidosis.

BACKGROUND: Cardiac amyloidosis, primarily due to immunoglobulin light chain (AL) or transthyretin (ATTR) amyloid, is an increasingly recognized cause of heart failure. Modern diagnostic advances suggest that ATTR, particularly in older adults, may be more prevalent than historically reported. METHODS: All Olmsted County decedents aged ≥40 years from 1970 to 1976 were identified. Available ventricular myocardium from retained paraffin blocks was screened histologically for amyloid using sulfated Alcian blue staining; positive cases underwent grading and proteomic typing by laser microdissection coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Beyond prevalence estimation, this analysis characterizes amyloid type, deposition grade and distribution, associated comorbidities, and cause-of-death patterns, comparing amyloid-positive decedents with age- and sex-matched controls. RESULTS: Of 2,566 eligible deaths, 1,028 autopsy cases with evaluable myocardium formed the study cohort (mean age 70.5 years; 61.1% male; 97% White). Cardiac amyloid was present in 52 cases giving an overall prevalence of 5.1% (95% CI: 3.8-6.6, which rose from 0% under age 60 to 37.5% (95% CI: 21.1-56.3) in those ≥90 years (p < 0.001). While prevalence estimates were higher in men above age 80 compared to women, there was no evidence of an interaction of age and sex (p = 0.90). The quantity of amyloid was sufficient for typing in 38 cases: ATTR (84.2%), AL (7.9%), serum amyloid A (5.3%), and apolipoprotein A-IV (2.6%). Adjusted estimates assuming untyped mild cases were ATTR-type increased ATTR prevalence to 4.5% (95% CI: 3.3-5.9) overall. Comorbidity profiles were similar between amyloid-positive and negative groups, though syncope and leg weakness were more common in amyloid-positive decedents. CONCLUSIONS: In an unselected autopsy cohort, cardiac amyloid was common, particularly ATTR in older adults. Prevalence increased steeply after age 80. These findings suggest that ATTR amyloidosis is not rare and is likely underdiagnosed and has similar prevalence in women and men, despite the male predominance reported in the literature.

Humans↗

PubMed2025

Kidney Outcomes in Transthyretin Amyloid Cardiomyopathy.

IMPORTANCE: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive cardiomyopathy that commonly presents with concomitant chronic kidney disease. Chronic kidney dysfunction is associated with worse outcomes, but the prognostic value of changes in kidney function over time has yet to be defined. OBJECTIVE: To assess the prognostic importance of a decline in estimated glomerular filtration rate (eGFR) in a large cohort of patients with ATTR-CM. DESIGN, SETTING, AND PARTICIPANTS: This retrospective, observational, single-center cohort study evaluated patients diagnosed with ATTR-CM at the National Amyloidosis Centre (NAC) in the UK who underwent an eGFR baseline assessment and a follow-up assessment at 1 year between January 2000 and April 2024. Data analysis was performed in June 2024. MAIN OUTCOMES AND MEASURES: The primary outcome was the risk of all-cause mortality associated with decline in kidney function (defined as a decrease in eGFR >20%). RESULTS: Among 2001 patients, mean (SD) age was 75.5 (8.4) years, and 263 patients (13.1%) were female. The median (IQR) change in eGFR was -5 mlL/min/1.73 m2 (-12 to 1), and 481 patients (24.0%) experienced decline in kidney function. Patients who experienced decline in kidney function more often had the p.(V142I) genotype than patients with stable kidney function (99 [20.6%] vs 202 [13.3%]; P < .001) and had a more severe cardiac phenotype at baseline, as evidenced by higher median (IQR) concentrations of serum cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP]: 2949 pg/mL [1759-5182] vs 2309 pg/mL [1146-4290]; P < .001; troponin T: 0.060 ng/mL [0.042-0.086] vs 0.052 ng/mL [0.033-0.074]; P < .001), while baseline median (IQR) kidney function was similar between the 2 groups (eGFR: 63 mL/min/1.73 m2 [51-77] vs 61 mL/min/1.73 m2 [49-77]; P = .41). Decline in kidney function was associated with a 1.7-fold higher risk of mortality (hazard ratio [HR], 1.71; 95% CI, 1.43-2.04; P < .001), with a similar risk across the 3 genotypes (wild type: HR, 1.64; 95% CI, 1.31-2.04; p.(V142I): HR, 1.70; 95% CI, 1.21-2.39; non-p.(V142I): HR, 1.51; 95% CI, 0.87-2.61) (P for interaction = .93) and the 3 NAC disease stages (stage 1: HR, 1.69; 95% CI, 1.22-2.32; stage 2: HR, 1.69; 95% CI, 1.30-2.18; stage 3: HR, 1.61; 95% CI, 1.11-2.35) (P for interaction = .97). Decline in kidney function remained independently associated with mortality after adjusting for increases in NT-proBNP and outpatient diuretic intensification (HR, 1.48; 95% CI, 1.23-2.76; P < .001). CONCLUSIONS AND RELEVANCE: In this retrospective cohort study, decline in kidney function was frequent in patients with ATTR-CM and was consistently associated with an increased risk of mortality, even after adjusting for established markers of worsening ATTR-CM. eGFR decline represents an independent marker of ATTR-CM disease progression that could guide treatment optimization in clinical practice.

Humans↗

PubMed2025

Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration.

IMPORTANCE: Patients with transthyretin (ATTR) cardiac amyloid infiltration are increasingly diagnosed at earlier disease stages with no heart failure (HF) symptoms and a wide range of cardiac amyloid infiltration. OBJECTIVE: To characterize the clinical phenotype and natural history of asymptomatic patients with ATTR cardiac amyloid infiltration. DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data of all patients at 12 international centers for amyloidosis from January 1, 2008, through December 31, 2023. Inclusion criteria were asymptomatic ATTR cardiac amyloid infiltration, defined as an absence of HF history, HF signs and symptoms, diuretic therapy, and plasma cell dyscrasia with evidence of myocardial uptake on bone scintigraphy. If plasma cell dyscrasia was present, histologic confirmation of ATTR amyloid was required. EXPOSURE: Asymptomatic ATTR cardiac amyloid infiltration. MAIN OUTCOMES AND MEASURES: The primary outcomes were all-cause and cardiovascular (CV) mortality. The secondary outcomes were unplanned HF hospitalization, unplanned CV-related hospitalization, and a composite outcome of CV mortality and HF hospitalization. RESULTS: The study comprised 485 patients with asymptomatic ATTR cardiac amyloid infiltration (mean [SD] age, 74.9 [9.9] years, 85.8% male, 112 [23.1%] with hereditary ATTR amyloidosis), with 369 (76.1%) having grade 2 or 3 and 116 (23.9%) having grade 1 cardiac uptake at baseline. Patients with grade 2 or 3 uptake exhibited significantly more cardiac functional and structural abnormalities vs patients with grade 1 uptake. At 3 years, compared with grade 1 uptake, patients with grade 2 or 3 uptake had greater development of HF (54.3% [95% CI, 47.7%-61.3%] vs 23.1% [95% CI, 14.8%-35.1%]), greater outpatient diuretic initiation and N-terminal pro-B-type natriuretic peptide progression (35.0% [95% CI, 28.0%-43.2%] vs 12.4% [95% CI, 6.3%-23.7%]), and greater HF hospitalization (8.7% [95% CI, 5.9%-12.9%] vs 0%) and unplanned CV hospitalization (20.0% [95% CI, 15.7%-25.3%] vs 4.3% [95% CI, 1.6%-11.3%]). Over a median follow-up of 37 months (IQR, 20-64 months), the all-cause death rate was similar between patients with grade 1 vs 2 and 3 uptake; however, those with grade 2 or 3 compared with grade 1 uptake had a significantly higher risk of CV mortality (unadjusted hazard ratio, 5.30; 95% CI, 1.92-14.65). CONCLUSIONS AND RELEVANCE: This study shows that asymptomatic ATTR cardiac amyloid infiltration encompasses a wide spectrum of disease severity, with patients with grade 2 or 3 cardiac uptake experiencing an increased rate of CV events and CV mortality and patients with grade 1 uptake experiencing a lower CV event rate and predominantly non-CV mortality. These findings support the use of disease-modifying treatments in asymptomatic patients with grade 2 or 3 uptake and highlight the need of large-scale studies to assess their role in grade 1 uptake.

Humans↗

PubMed2026

Efficacy of Acoramidis in Wild-Type and Variant Transthyretin Amyloid Cardiomyopathy: Results From ATTRibute-CM and Its Open-Label Extension.

IMPORTANCE: Transthyretin amyloid cardiomyopathy (ATTR-CM), a progressive disease caused by misfolded transthyretin (TTR), occurs as wild-type (ATTRwt-CM) or variant (ATTRv-CM) forms. p.Val142Ile is the most common variant in the US, linked to rapid progression and increased mortality. Acoramidis achieves near-complete (≥90%) TTR stabilization and showed clinical benefit in the 30-month ATTRibute-CM trial and through month 42 in the ongoing open-label extension (OLE). OBJECTIVE: To evaluate the efficacy of acoramidis in ATTRwt-CM, ATTRv-CM, and variant subgroups (p.Val142Ile and non-p.Val142Ile). DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, phase 3, randomized placebo-controlled study took place from April 2019 to May 2023 with ongoing OLE (month 42). ATTRibute-CM enrolled 632 participants with ATTR-CM; 611 of 632 were included in the modified intention-to-treat (mITT) population. There were 380 participants who continued into the OLE. These data were analyzed from January 2025 to July 2025. INTERVENTIONS: Oral acoramidis, 712 mg, or placebo twice daily for 30 months, followed by 12 months of open-label treatment. MAIN OUTCOMES AND MEASURES: All-cause mortality (ACM), cardiovascular-related hospitalizations (CVH), serum TTR, 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire Overall Summary score, and N-terminal pro B-type natriuretic peptide in participants with ATTRwt-CM and ATTRv-CM. Post-hoc analyses were conducted in variant subgroups, including p.Val142Ile. RESULTS: Overall, 552 participants with wild-type ATTR-CM (mean [SD] age, 78 [6.3] years; 92.0% male and 8.0% female) and 59 participants with variant ATTR-CM (mean [SD] age, 73 [7.7] years; 77.3% male and 22.7% female) were randomized (mITT population), including 35 with p.Val142Ile. Consistent efficacy was observed in wild-type and variant subgroups for ACM/CVH through month 30 and ACM through month 42. At month 30, acoramidis reduced the risk of ACM/first CVH vs placebo by 31% in ATTRwt-CM (hazard ratio [HR], 0.69; 95% CI, 0.52-0.90; P = .007) and by 59% in ATTRv-CM (HR, 0.41; 95% CI, 0.21-0.81; P = .01). ACM was reduced through month 42 with HRs of 0.70 (95% CI, 0.50-0.98; P = .04) and 0.41 (95% CI, 0.19-0.93; P = .03) in the ATTRwt-CM and ATTRv-CM groups, respectively. Consistent treatment benefit was observed in participants with ATTRwt-CM and ATTRv-CM for secondary end points. Within variant subgroups (p.Val142Ile vs non-p.Val142Ile), consistent treatment benefits were observed for ACM/CVH through month 30 and ACM through month 42. CONCLUSIONS AND RELEVANCE: The beneficial effect of acoramidis was observed consistently in ATTRwt-CM and ATTRv-CM groups. These hypothesis-generating results indicate that further studies are warranted to better characterize the therapeutic benefit of acoramidis in variant subgroups. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03860935; NCT04988386.

Humans↗

PubMed2024

Evolving knowledge of red flag clinical features associated with TTR p.(Val142Ile) in a diverse electronic health-record-linked biobank.

PURPOSE: Previous studies have established red flags that raise clinical suspicion for the hereditary form of transthyretin amyloidosis (ATTRv). However, these have not been specifically evaluated for the most common associated variant, TTR p.(Val142Ile). METHODS: Using an ancestrally diverse electronic health-record-linked biobank with exome sequence data from 27,630 unrelated adults, we evaluated 9 ATTRv-related clinical features among TTR p.(Val142Ile)-positive and -negative individuals. RESULTS: Among 337 variant-positive individuals (median age 63, 60% female), 10 (3.0%) were diagnosed with amyloidosis. TTR p.(Val142Ile) was associated with increased odds of cardiomyopathy/heart failure (CM/HF), atrial fibrillation, polyneuropathy, carpal tunnel syndrome, and proteinuria, but only in individuals ≥60 years. These features were evident 1.7 to 7.7 years earlier in variant-positive vs -negative individuals (hazard ratio [HR] 1.37, P = 3.99 × 10-2; HR 1.78, P = 2.52 × 10-3; HR 1.78, P = 1.70 × 10-3; HR 1.81, P = 5.14 × 10-3; HR 1.60, P = 1.94 × 10-2, respectively). By age 50, the cumulative incidence of CM/HF was 3.5-fold higher, and by age 60, the incidences of CM/HF, polyneuropathy, and proteinuria were 2-fold higher in variant-positive individuals. CONCLUSION: This study clarifies red flags that are associated with TTR p.(Val142Ile) in an age-dependent manner. With modifying therapies being available, early diagnosis of ATTRv in variant-positive individuals through the recognition of key clinical features is paramount.

Humans↗

PubMed2026

Impact of Baseline Polyneuropathy Severity on Eplontersen Efficacy in the NEURO-TTRansform Clinical Trial.

BACKGROUND AND AIMS: In the NEURO-TTRansform clinical trial (NCT04136184), eplontersen improved neuropathy impairment and quality of life (QoL) through Week 66 versus the NEURO-TTR historical placebo in patients with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). This analysis assessed the impact of baseline ATTRv-PN severity on eplontersen response in patients from NEURO-TTRansform. METHODS: This post hoc analysis grouped patients into tertiles by baseline Neuropathy Impairment Score (NIS): T1 (least baseline impairment: 3.5 to < 27.5; n = 67), T2 (27.5 to < 55.0; n = 67), and T3 (55.0 to < 127.8; n = 66). Outcomes assessed were neuropathy impairment (modified NIS+7 [mNIS+7] and NIS, Neuropathy Symptom and Change, Polyneuropathy Disability), QoL (Norfolk QoL-Diabetic Neuropathy), physical functioning (36-Item Short-Form Health Survey Physical Component Summary), nutritional status (modified body mass index), and serum transthyretin levels; these were compared with NEURO-TTR historical placebo. Autonomic dysfunction (Composite Autonomic Symptom Score-31), disability (Rasch-built Overall Disability Scale), and walking speed (10-Meter Walk Test) were also assessed. Final assessments were carried out following 65/66 or 81/85 weeks of treatment. RESULTS: Mean mNIS+7 composite scores were maintained over 85 weeks with eplontersen (changes from baseline of -4.5 [T1], -1.3 [T2], and -2.6 [T3] points). Other disease parameter scores were similarly maintained or improved with eplontersen. Patients receiving placebo experienced disease worsening across outcomes. T1 mean disease scores were typically better than in T2 and T3. INTERPRETATION: Consistent, sustained benefits of eplontersen were observed regardless of baseline ATTRv-PN severity. These findings strengthen the importance of early treatment initiation for patients with ATTRv-PN across the disease spectrum.

Humans↗

PubMed1977

Generalized amyloid in a family of Swedish origin. A study of 426 family members in seven generations of a new kinship with neuropathy, nephropathy, and central nervous system involvement.

We report a new kinship with systemic amyloid presenting as peripheral neuropathy in the fourth and fifth decades of life. A progressive sensory and motor loss starting in the lower extremities occurs from this disease, and there is subsequent renal, cardiac, gastrointestinal, ocular, and cutaneous involvement. Histologic studies show that amyloid deposition is mainly in connective tissue structures; there is an unusual infiltration of the meninges and central nervous system. Review of records of 426 family members in seven generations showed that this disease is inherited as an autosomal dominant. The absence of immunoglobulin disorders in two affected family members studied in depth suggests that this is not the primary type of amyloid in which the deposits are composed of fragments of immunoglobulin light chains. Similarly the absence of elevated levels of protein SAA (the serum precursor of secondary amyloid) suggests that this is not a secondary form of amyloid.

Adult↗

PubMed1976

[Histopathological findings of the nerve and muscles in familial primary amyloidosis, with special reference to the mechanism of amyloid fibril production].

T. I., a male aged 38, had a hereditary primary amyloidosis over four generation in his family history. He had peripheral neuropathy with dissociated sensory disturbances in the lower limbs, impotence, gastrointerstial dysfunction and orthostatic hypotention. N. suralis and M. quadriceps femoralis taken from him were examined by light and electron microscopy. N. suralis contained a lot of amyloids reacting with congo-red in the nerve fibres. Amyloid fibrils were remarkably observed around the blood vessels. They were continuous with the basement membrane of the endotherial cells. A few deposites were observed around the Schwann cell and fibroblasts. In M. quadriceps femoralis, amyloid like fibrils were noted in the perivascular spaces. Especially, a great deal of amyloid fibrils were continuous with the basement membranes. From this finding, it might be speculated that the basement membrane may play an important role in the production of amyloid fibrils.

Adult↗

PubMed1975

Genetic factors in amyloidosis.

In the absence of biochemical distinctions, the nosography of the inherited amyloidoses must at present depend largely upon clinical subdivisions. In the broad classification adopted here, the disorders have for convenience been grouped according to the anatomical system that is predominantly affected. It is evident that the amyloid syndromes display considerable heterogeneity. However, they overlap. Thus in the Iowa type classified with the hereditary amyloid neuropathies (van Allen et al, 1969; Gimeno et al, 1974), renal involvement was frequent and was the usual cause of death. In the English (Zalin et al, 1974) and Scandinavian (Andersson, 1970) families with neuropathy as the predominant feature, cardiac involvement was a common finding. In certain of the conditions discussed, such as medullary carcinoma of the thyroid and Down's syndrome, amyloid deposition is merely an incidental aspect of the disorder. In those conditions in which generalized or localized amyloid deposition occupies a more central position in the clinical syndrome, an autosomal dominant inheritance has been established or suggested in the majority. An autosomal recessive inheritance has so far only been recognized in familial Mediterranean fever. In the family with hereditary amyloid heart diseases reported by Fredricksen et al (1962), the disorder was confined to a single sibship, raising the possibility of recessive inheritance. This could also be true in sporadic examples of primary amyloidosis. The dominantly inherited amyloidoses comprise a number of geographically widely scattered families with clinical pictures that do not show consistent differences between some families. The families that do not show consistent differences are not necessarily harbouring nutations at the same locus, or the same mutation at any particular locus. However, many of these dominantly inherited clinical syndromes are sufficiently different from each other and the clinical manifestations of each sufficiently consistent to indicate that separate main genes are likely to be involved...

Amyloidosis↗

PubMed1979

[Dimethyl sulfoxide (DMSO) in familial amyloid polyneuropathy--clinical symptoms and peripheral nerve conduction velocity].

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Adult↗

PubMed1977

Secondary glaucoma accompanied with primary familial amyloidosis.

22 patients were diagnosed as having primary familial amyloidosis by the histological examination of biopsy specimens, clinical course of the disease, and family history, having a focus in the Nagano Prefecture in Japan. All patients belonged to the Andrade type of the neuropathy form in the primary familial amyloidosis. 15 out of 22 patients underwent ophthalmological examination, and secondary glaucoma, due to primary familial amyloidosis, was found in 4 patients. The clinical characteristic features of the secondary glaucoma were described as follows: (1) having the systemic symptoms of primary familial amyloidosis; (2) belonging to relatively older age groups and having a longer duration of the course of the disease; (3) having vitreous opacities; (4) having the wide open angle with pigment deposition in the gonioscopical examination; (5) having white flocculent materials in the pupillary margin, and (6) having flaky substances on the surface of the lens. The ophthalmological symptoms mentioned in 4, 5, and 6 were very similar to those of glaucoma capsulare. The tissue specimens obtained at the time of antiglaucoma surgery were subjected to light and electron microscopy. Amyloid fibrils were found in the iris and trabeculum, and the pathogenesis of secondary glaucoma was speculated to be a deposition of amyloid fibrils in the trabecular meshwork.

Adult↗