Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey

Durmuş-Tekçe, Hacer; Matur, Zeliha; Atmaca, Murat Mert; Poda, Mehveş; Çakar, Arman; Ulaş, Ümit Hıdır; Oflazer-Serdaroğlu, P.; Deymeer, Feza; Parman, Yeşim

doi:10.1016/j.nmd.2016.04.013

Cited by 20 publications

(15 citation statements)

References 21 publications

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“…However, recent progress in diagnostic techniques has increased the number of newly diagnosed patients with non-Val30Met mutations [11]. Over 130 mutations have been reported so far [12], and certain types of non-Val30Met patients are more frequent than Val30Met patients in some countries [13,14,15].…”

Section: Introductionmentioning

confidence: 99%

Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Koike

Katsuno

2019

Biomedicines

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Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.

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Section: Introductionmentioning

confidence: 99%

Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Koike

Katsuno

2019

Biomedicines

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“…12 In a study of 206 genetically confirmed patients with ATTRm-related polyneuropathy from the United States, (Minnesota) mean age at onset was 63.3 years. 25 Interestingly, in two patients, ATTRm amyloidosis started with dysarthria and hemiparesis. 25 Interestingly, in two patients, ATTRm amyloidosis started with dysarthria and hemiparesis.…”

Section: Age and Manifestations At Onsetmentioning

confidence: 98%

“…25 Interestingly, in two patients, ATTRm amyloidosis started with dysarthria and hemiparesis. 25 Generally, age at onset depends on the genotype and the gender of the mutation carrier.…”

Section: Age and Manifestations At Onsetmentioning

confidence: 98%

“…24 In a Turkish study of 17 patients with ATTRm amyloidosis, mean age at onset was 40.4 years and the initial manifestation was feet paresthesias in 15 patients. 25 Generally, age at onset depends on the genotype and the gender of the mutation carrier. 25 Generally, age at onset depends on the genotype and the gender of the mutation carrier.…”

Section: Age and Manifestations At Onsetmentioning

confidence: 99%

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Hereditary transthyretin-related amyloidosis

et al. 2018

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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). K E Y W O R D Samyloid, neuropathy, small fiber, tafamidis, transplantation, transthyretin | 93 FINSTERER ET al. eyes, the gastrointestinal tract, the kidneys, and the skin. ATTRm amyloidosis is resistant to immunotherapy. Though ATTRm-related polyneuropathy or TTR-CA may occur without affection of another tissue, a variable combination of organ affection (multiorgan involvement) is the most frequent phenotype. This review aims at summarizing and discussing previous and recent findings concerning the clinical presentation, genetic background, pathogenesis, diagnosis, treatment, and outcome of ATTRm-related polyneuropathy. | ME THODSData for this review were identified by searches of MEDLINE for references of relevant articles. Search terms applied were "transthyretin," "gene," "TTR-FAP," or "mutation," combined with "neuropathy," "hereditary," "autonomic," "small fiber neuropathy," and "polyneuropathy." Results of the search were screened for potentially relevant studies by application of inclusion and exclusion criteria for the full texts of the relevant studies. Included were randomized controlled trials (RCTs), observational studies with controls, case series, and case reports. Only original articles about humans, and published between 1966 and 2018 were included. Reviews, editorials, and letters were not considered. Reference lists of retrieved studies were checked for reports of additional studies. Websites checked for additional, particularly geneti...

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“…Although Val30Met (p.Val50Met) is the most common mutation in ATTRm amyloidosis, over 130 other mutations have been reported to date (1). Recent studies have revealed that certain types of non-Val30Met patients are more frequent than Val30Met patients in some countries (2-4). The phenotypes associated with non-Val30Met ATTRm amyloidosis are highly diverse and primarily include neuropathy, cardiomyopathy, or oculoleptomeningeal involvement (5).…”

Section: Introductionmentioning

confidence: 99%

Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis

et al. 2018

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Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients. Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123) I-metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys). Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60° tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy. Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy.

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Genotypic and phenotypic presentation of transthyretin-related familial amyloid polyneuropathy (TTR-FAP) in Turkey

Cited by 20 publications

References 21 publications

Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Ultrastructure in Transthyretin Amyloidosis: From Pathophysiology to Therapeutic Insights

Hereditary transthyretin-related amyloidosis

Widespread Cardiac and Vasomotor Autonomic Dysfunction in Non-Val30Met Hereditary Transthyretin Amyloidosis

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