Search Results (12)

Introduction. Hereditary transthyretin amyloidosis (hATTR) is a rare disorder with a largely variable worldwide prevalence, and it is caused by autosomal dominant mutations in the transthyretin (TTR) gene, leading to cardiological, neurological, or mixed phenotypes. Apart from the Glu89Gln, Phe64Leu, and Thr49Ala variants, recently, other mutations of TTR gene have been reported in Sicily (His90Asn, Val122Ile, Ser77Phe, Val20Ala). With this paper, we describe a novel mutation in the TTR gene, the Glu61Ala variant, which had been previously reported in only one case with a cardiac phenotype, and the clinical findings surrounding it. Materials and Methods. One individual affected by chronic idiopathic polyneuropathy and a major red flag for hATTR underwent genetic testing to look for mutations in the TTR gene. Then, his relatives were subjected to the same test. We assessed the anamnestic profile and conducted general and neurological examination, blood tests, nerve conduction studies (NCS), electrocardiogram, and Sudoscan for each patient. Written informed consent was acquired for every patient. Results. Among 7 patients screened, 5 patients carried the Glu61Ala variant (71%). The mean age was 64.6 ± 10.2 years, whereas the mean age at onset was 59.4 ± 7.9 years. In our study, three patients (60%) showed a mixed phenotype, whereas two of them (40%) showed a neurological phenotype. Discussion. The Glu61Ala variant was reported only in one case with a cardiological phenotype, but our patients showed both neurological and cardiological involvement. Further studies are needed to improve knowledge of this genetic variant. Full article

Background and Objectives: Amyloidosis is a disorder characterized by the abnormal folding of proteins, forming insoluble fibrils that accumulate in tissues and organs. This accumulation disrupts normal tissue architecture and organ function, often with serious consequences, including death if left untreated. Light-chain amyloidosis (AL) and hereditary transthyretin-type amyloidosis (hATTR) are two of the most common types. In amyloidosis, peripheral nervous system involvement is a significant diagnostic feature, particularly when it manifests as polyneuropathy, carpal tunnel syndrome (CTS), and dysautonomia. These neurological symptoms often point to the involvement of amyloid deposits in the peripheral and autonomic nervous systems, which can help identify and differentiate between the various types of amyloidosis. Materials and Methods: This retrospective study focused on the evolution of electrophysiological parameters in two groups: AL (n = 22) and hATTR-Glu54Gln patients (n = 14), with mixed axonal polyneuropathy. Patients were followed for two consecutive years to assess disease progression. The PND scale (polyneuropathy disability) was also used to assess motor impairment for each patient. Results: In our study AL amyloidosis patients presented with mixed, axonal polyneuropathy associated with CTS in 63.6% of cases and cardiomyopathy (45.5%). Serial EMGs (electromyography) showed decreased motor amplitudes of the common peroneal and tibial nerves and sensory amplitude of the superficial peroneal nerve, with mostly preserved conduction velocities. The patients maintained stage I PND throughout the monitoring period. The entire hATTR group displayed mixed, axonal polyneuropathy and cardiomyopathy; 85.7% of them had CTS, and 42.9% had orthostatic hypotension. EMG data showed decreased motor amplitudes of the tibial and common peroneal nerves, decreased sensory amplitudes of the superficial peroneal nerve, and mildly reduced conduction velocities, with significant progression at 12 and 24 months. The patients displayed additional reduced muscle strength, some reaching stage 3A and 3B-PND at the end of the study. Conclusions: The amyloidotic polyneuropathy found in the groups was similar in its axonal, sensory-motor, and length-dependent characteristics, but the study showed significant differences in its progression, with more abrupt changes in the hATTR-Glu54Gln group. The amyloidosis AL patients remained in stage 1 PND, while the hATTR-Glu54Gln patients progressed to stage 3 PND at 24 months. Full article

Background: Hereditary transthyretin-related amyloidosis is a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene (hATTR amyloidosis). Objective: The current study describes the demographic, clinical, and genetic characteristics of patients with suspected hATTR amyloidosis. Methods: This study is part of the “Hereditary transthyretin-related amyloidosis and longitudinal monitoring of TTR-positive patients” (TRAMmoniTTR) study. This study included 3167 participants, along with their clinical details. Principal component (PC) analysis was used to analyze their clinical symptomatology. Next-generation sequencing of the TTR gene was performed and genotype–phenotype relationships were investigated. We compared the demographic and clinical characteristics using the principal components (PCs) and also compared participants with and without the TTR pathogenic variants. Results: We identified five main clinical phenotypes out of 22 single symptoms that explained 49% of the variation. The first two PCs referred to polyneuropathy and cardiomyopathy. We found significant differences between gender and PC-polyneuropathy and PC-cardiomyopathy, with male over-representation in the higher quantiles of PC-polyneuropathy and male under-representation in the lowest quantiles of PC-cardiomyopathy. We identified 92 participants with hATTR (3%), exhibiting 17 unique heterozygous TTR variants. The p.Val50Met variant was the most frequent. Furthermore, 503 participants (20%) were identified with ATTR and no relevant TTR variants (ATTRwt). We detected significant differences between the ATTRwt and hATTR groups, with male gender predominance in only the ATTRwt group and a positive family history of polyneuropathy and/or cardiomyopathy among the hATTR participants. Conclusions: The current clinical and genetic characterization of this cohort serves as a foundation for further longitudinal monitoring and assessment. Full article

Hereditary transthyretin amyloidosis (hATTR) with polyneuropathy (formerly known as Familial Amyloid Polyneuropathy (FAP)) is an endemic amyloidosis involving the harmful aggregation of proteins, most commonly transthyretin (TTR) but sometimes also apolipoprotein A-1 or gelsolin. hATTR appears to be transmitted as an autosomal dominant trait. Over 100 point mutations have been identified, with the Val30Met substitution being the most common. Yet, the mechanism of pathogenesis and the overall origin of hATTR remain unclear. Here, we argue that hATTR could be related to harmful metal exposure. hATTR incidence is unevenly distributed globally, and the three largest defined clusters exist in Japan, Portugal, and Sweden. All three disease regions are also ancient mining districts with associated metal contamination of the local environment. There are two main mechanisms for how harmful metals, after uptake into tissues and body fluids, could induce hATTR. First, the metals could directly influence the expression, function, and/or aggregation of the proteins involved in hATTR pathology. Such metal–protein interactions might constitute molecular targets for anti-hATTR drug design. Second, metal exposure could induce hATTR -associated genetic mutations, which may have happened several generations ago. These two mechanisms can occur in parallel. In conclusion, the possibility that hATTR could be related to metal exposure in geochemically defined regions deserves further attention. Full article

Hereditary transthyretin amyloidosis (hATTR) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensory-motor nerves, heart, autonomic function, and other organs. There are over 130 mutations known in the TTR gene. The His90Asn mutation has been previously reported in several reports, but its pathogenetic role is still debated. We report two sporadic cases of adult women with a heterozygous His90Asn mutation in TTR gene and neurological involvement extensively investigated. A typical Congo red-positive pathologic deposition of amyloid fibrils in the salivary glands was documented in one subject. Patients were successfully treated with patisiran with a good clinical outcome. These data support a pathogenetic role of His90Asn mutation in hATTR, and suggest early treatment in symptomatic carriers of His90Asn mutation. Full article

Point mutations of the transthyretin (TTR) gene are related with hereditary amyloidosis (hATTR). The number of people affected by this rare disease is only partially estimated. The real impact of somatic mosaicism and other genetic factors on expressivity, complexity, progression, and transmission of the disease should be better investigated. The relevance of this rare disease is increasing and many efforts have been made to improve the time to diagnosis and to estimate the real number of cases in endemic and non-endemic areas. In this context, somatic mosaicism should be better investigated to explain the complexity of the heterogeneity of the hATTR clinical features, to better estimate the number of new cases, and to focus on early and personalized gene therapy. Gene therapy can potentially improve the living conditions of affected individuals and is one of the central goals in research on amyloidosis related to the TTR gene, with the advantage of overcoming liver transplantation as the sole treatment for hATTR disease. Full article

Hereditary transthyretin amyloidosis (hATTR) is a rare disease caused by a point mutation in the transthyretin (TTR) gene and inherited in an autosomal dominant fashion. TTR is a plasma protein that functions as a carrier for thyroxine (T4) and retinol (vitamin A). Ophthalmological manifestations are due to both the hepatic and ocular production of mutated TTR. In this case series, we report the ocular manifestations of hATTR in eighteen eyes of nine consecutive patients. Corneal nerve abnormalities as well as morphological and functional changes in the retina were investigated. The study was a single-center, retrospective, observational, clinical case series. In all patients, corneal confocal microscopy (CCM), multimodal imaging of the retina, including fundus photography and Optical Coherence Tomography (OCT), as well as rod and cone electroretinography (ERG) were performed. Eight patients had active disease and one was an unaffected carrier. In all study eyes, corneal nerve plexa examined with CCM were poorly represented or absent. Mixed rod-cone and cone ERG b-wave amplitudes were reduced, and photopic b-wave responses were significantly delayed. Photopic Negative Response (PhNR) amplitude was significantly reduced, while PhNR latency was significantly augmented. In 13/18 eyes, vitreous opacities and abnormalities of vitreo-retinal interface were found. The current results highlight the presence of corneal nerve damage. Functional retinal abnormalities, detected by ERG, can be found even in the presence of minimal or absent structural retinal damage. These findings support the use of CCM and ERGs to detect early biomarkers for primary hATTR. Full article

Hereditary amyloidosis associated with mutations in the transthyretin gene (hATTR) is a progressive devastating disease, with a fatal outcome occurring within 10years after onset. In recent years, TTR gene silencing therapy appeared as a promising therapeutic strategy, showing evidence that disease progression can be slowed and perhaps reversed. We report here 18 subjects affected by hATTR amyloidosis treated with patisiran, a small interfering RNA acting as TTR silencer, and evaluated with a PND score, the NIS and NIS-LL scale, and a Norfolk QOL-DN questionnaire at baseline and then every 6 months. A global clinical stabilizationwas observed for the majority of the patients, with mild-moderate improvements in some cases, even in advanced disease stage (PND score > 2). Analysis of NIS, NIS-LL and Norfolk QOL-DN results, and PND score variation suggest the possible presence of a 6-month latency period prior to benefit of treatment. Full article

The TTR V142I variant associated with hereditary transthyretin amyloidosis (hATTR) is present in up to 4% of African American (AA) and 1% of Hispanic/Latinx (HL) individuals and increases risk for heart failure. Delayed and missed diagnoses could potentiate health disparities in these populations. We evaluated whether population-based genomic screening could effectively identify individuals at risk for hATTR and prompt initiation of risk management. We identified participants of the BioMe Biobank in New York City who received TTR V142I results through a pilot genomic screening program. We performed a retrospective medical record review to evaluate for the presence hATTR-related systemic features, uptake of recommended follow-up, and short-term outcomes. Thirty-two AA (N = 17) and HL (N = 15) individuals received a TTR V142I result (median age 57, 81% female). None had a previous diagnosis of hATTR. Eighteen (56%) had hATTR-related systemic features, including 4 (13%) with heart failure, 10 (31%) with carpal tunnel syndrome, and 10 (31%) with spinal stenosis. Eighteen (56%) pursued follow-up with a cardiologist within 8 months. One person received a diagnosis of hATTR. Thus, we found that the majority of V142I-positive individuals had hATTR-related systemic features at the time of result disclosure, including well-described red flags. Genomic screening can help identify hATTR risk and guide management early on, avoiding potential delays in diagnosis and treatment. Full article

Pathological evidence of amyloid on nerve biopsy has been the gold standard for diagnosis in hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) for a long time. In this article, we reviewed the pathological findings of a large series of sural nerve biopsies from a cohort of hATTR-PN patients, collected by different Italian referral centers. Patients and Methods: We reviewed clinical and pathological data from hATTR-PN patients, diagnosed and followed in five Italian referral centers for peripheral neuropathies. Diagnosis was formulated after a positive genetic test for transthyretin (TTR) mutations. Sural nerve biopsy was performed according to standard protocols. Results: Sixty-nine sural nerve biopsies from hATTR-PN patients were examined. Congo red positive deposits were found in 73% of cases. Only the Phe64Leu mutation failed to show amyloid deposits in a high percentage of biopsies (54%), as already described. Unusual pathological findings, such as myelin abnormalities or inflammatory infiltrates, were detected in occasional cases. Conclusions: Even if no longer indicated to confirm hATTR-PN clinical suspicion, nerve biopsy remains, in expert hands, a rapid and inexpensive tool to detect amyloid deposition. In Italy, clinicians should be aware that a negative biopsy does not exclude hATTR-PN, particularly for Phe64Leu, one of the most frequent mutations in this country. Full article

Background: Hereditary transthyretin amyloidosis (hATTR) is an autosomal dominantly inherited disorder caused by an accumulation of amyloid fibrils in tissues due to mutations in the transthyretin (TTR) gene. The prevalence of hATTR is still unclear and likely underestimated in many countries. In order to apply new therapies in a targeted manner, early diagnosis and knowledge of phenotype-genotype correlations are mandatory. This study aimed to assess the prevalence and phenotypic spectrum of hATTR in Austria. Methods: Within the period of 2014–2019, patients with ATTR-associated cardiomyopathy and/or unexplained progressive polyneuropathies were screened for mutations in the TTR gene. Results: We identified 43 cases from 22 families carrying 10 different TTR missense mutations and confirmed two mutational hot spots at c.323A>G (p.His108Arg) and c.337G>C (p.Val113Leu). Two further patients with late onset ATTR carried TTR variants of unknown significance. The majority of patients initially presented with heart failure symptoms that were subsequently accompanied by progressive polyneuropathy in most cases. A total of 55% had a history of carpal tunnel syndrome before the onset of other organ manifestations. Conclusions: Our study underlined the relevance of hATTR in the pathogenesis of amyloid-driven cardiomyopathy and axonal polyneuropathy and indicated considerable genetic heterogeneity of this disease in the Austrian population. The estimated prevalence of hATTR in Austria based on this study is 1:200,000 but a potentially higher number of unknown cases must be taken into account. With respect to new therapeutic approaches, we strongly propose genetic testing of the TTR gene in an extended cohort of patients with unexplained heart failure and progressive polyneuropathy. Full article

Tegsedi (Inotersen) is a chemically modified antisense oligonucleotide that inhibits the hepatic production of transthyretin (TTR). Several single-point mutations in TTR destabilize its structure, leading to the aggregation and accumulation of amyloid deposits in the nervous system, heart, kidneys and eyes. In July 2018, Tegsedi was approved by the European Commission for use in adults with stage one and two polyneuropathies. Later on, in October 2018, the FDA and Health Canada also approved its use for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) in adults in the U.S. and Canada. Tegsedi was developed by Ionis Pharmaceuticals, the company that holds the global marketing license, together with its subsidiary Akcea Therapeutics. Full article