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Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis.

ABSTRACT: Genetic testing is the most reliable test for hereditary transthyretin related amyloidosis and should be performed in most cases of transthyretin amyloidosis (ATTR). ATTR is a rare but fatal disease with heterogeneous phenotypes; therefore, the diagnosis is sometimes delayed. With increasing attention and broader recognition on early manifestations of ATTR as well as emerging treatments, appropriate diagnostic studies, including the transthyretin (TTR) genetic test, to confirm the types and variants of ATTR are therefore fundamental to improve the prognosis. Genetic analyses with polymerase chain reaction (PCR) methods confirm the presence of TTR point mutations much more quickly and safer than conventional methods such as southern blot. Herein, we demonstrate genetic confirmation of the ATTR Ala97Ser mutation, the most common endemic mutation in Taiwan. The protocol comprises four main steps: collecting whole blood specimen, DNA extraction, genetic analysis of all four TTR exons with PCR, and DNA sequencing.

SUBMITTER: Hsu HC

PROVIDER: S-EPMC6101697 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis.

Hsu Hui-Ching HC Liao Ming-Feng MF Hsu Jung-Lung JL Lee Yun-Lin YL Ro Long-Sun LS

Journal of visualized experiments : JoVE 20180609 136

Genetic testing is the most reliable test for hereditary transthyretin related amyloidosis and should be performed in most cases of transthyretin amyloidosis (ATTR). ATTR is a rare but fatal disease with heterogeneous phenotypes; therefore, the diagnosis is sometimes delayed. With increasing attention and broader recognition on early manifestations of ATTR as well as emerging treatments, appropriate diagnostic studies, including the transthyretin (TTR) genetic test, to confirm the types and vari ...[more]

PMID: 29939164

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Project description:BACKGROUND:Hereditary Transthyretin Amyloidosis Polyneuropathy is a rare life-threatening neurologic disease that imposes considerable mortality and it is associated with progressive related disabilities. In this study, we aimed to assess the effect of the disease across health-related quality of life dimensions, in both carriers of the mutation and patients, to compare health-related quality of life with general population, as well as to explore health-related quality of life prognostic factors among patients, including disease progression and treatment. METHODS:This study was a multi-institutional, longitudinal, prospective, observational study of hereditary Transthyretin Amyloidosis Polyneuropathy Portuguese adult subjects (621 asymptomatic carriers and 733 symptomatic patients) enrolled in the Transthyretin Amyloidosis Outcomes Survey. Health-related quality of life was captured with the preference-based instrument EQ-5D-3?L. For general population the dataset included all subjects enrolled in a representative national study (n?=?1500). Different econometric models were specified; multivariate probit, generalized linear model and generalized estimating equations model; including demographic and clinical covariates. RESULTS:Hereditary Transthyretin Amyloidosis Polyneuropathy patients have their health status severely impaired in all quality of life dimensions and more anxiety/depression problems were found among asymptomatic carriers. No differences on utility were found between carriers and general population (p?=?0.209). Among patients, the utility value is estimated to be 0.51 (0.021), a decrement of 0.27 as compared with general population utility. Higher disease duration, advanced disease stage and not receiving treatment are associated with impaired health-related quality of life. No differences were found between genders (p?=?0.910) or between late (?50?years) and early-onset patients (p?=?0.254). The utility estimate ranged from 0.63 (0.009) in stage I to 0.01 (0.005) in stage IV. CONCLUSIONS:Hereditary Transthyretin Amyloidosis Polyneuropathy symptoms and progressive associated disabilities substantially decrease patient's health-related quality of life. Clinical strategies focused on health-related quality of life preservation such as close follow-up of asymptomatic carriers, prompt diagnosis and adequate, early treatment would benefit patient's long-term outcomes, slowing the progressive decline in health-related quality of life.

Project description:BackgroundHereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4-5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology.MethodA multicenter observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis"-TRAM study was performed in Germany, Austria, and Switzerland.ResultsA total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants (TTR-positive) were identified. Body Mass Index was lower in the TTR-positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR-positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR-positive patients.ConclusionsOur data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation.KEY MESSAGESMore than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational "Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis" TRAM study and screened for pathogenic TTR variants.The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant.Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

Dataset Information

Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis.

Publications

Genetic Analysis of Hereditary Transthyretin Ala97Ser Related Amyloidosis.

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