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For the first time, we report of a Swedish family of five individuals with a TTR Glu54Leu (p. Glu74Leu) mutation in the transthyretin gene. This mutation has been previously described a few times in the literature, but no phenotypic or clinical description has been done before. The most common mutation in the Swedish population is TTRVal30Met and is mostly found in the Northern part of Sweden. Interestingly, the TTRGlu54Leu mutation was found in the same endemic area. The main phenotype of the TTR Glu54Leu patients is severe cardiomyopathy, which resulted in heart transplantation for the index person. As previously seen for ATTR amyloidosis patients with mainly cardiomyopathy, the amyloid fibrils consisted of a mixture of full-length and fragmented TTR species. However, western blot analyses detected a previously unrecognized band, indicating that these patients may have a third, so far unrecognized, fibril composition type that is distinct from the usual type A band pattern.
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Neuropatias Amiloides Familiares/genética , Cardiomiopatias/genética , Pré-Albumina/genética , Substituição de Aminoácidos , Amiloide/química , Amiloide/genética , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Cardiomiopatias/complicações , Cardiomiopatias/diagnóstico , Humanos , Mutação , Linhagem , Fenótipo , SuéciaRESUMO
BACKGROUND: Hereditary transthyretin amyloid (ATTR) amyloidosis is a rare but fatal autosomal dominant condition that is present all over the world. A liver transplantation has been shown to halt the progress of the disease in selected patients and is currently considered to be the standard treatment. Gastrointestinal manifestations are common in hereditary ATTR amyloidosis and are important for the patients' morbidity and mortality. The aim of this study was to evaluate the long-term outcome of gastric emptying, gastrointestinal symptoms and nutritional status after liver transplantation for the disease. METHODS: Swedish patients with hereditary ATTR amyloidosis transplanted between 1990 and 2012 were included. A standardized method for measuring gastric emptying with a Tc(99m)-labelled meal followed by scintigraphy was utilized. Validated questionnaires were used to assess gastrointestinal symptoms and the modified body mass index (mBMI), in which BMI is multiplied by s-albumin, was used to evaluate nutritional status. Non-parametrical statistical tests were used. RESULTS: Gastric emptying rates and nutritional statuses were evaluated approximately eight months before and two and five years after liver transplantation, whereas gastrointestinal symptoms were assessed in median nine months before and two and nine years after transplantation. No significant change was found in gastric emptying (median half-time 137 vs. 132 vs. 125 min, p = 0.52) or nutritional status (median mBMI 975 vs. 991 vs. 973, p = 0.75) after transplantation. Gastrointestinal symptom scores, however, had increased significantly over time (median score 7 vs. 10 vs. 13, p < 0.01). CONCLUSIONS: Gastric emptying and nutritional status were maintained after liver transplantation for hereditary ATTR amyloidosis, although gastrointestinal symptom scores had increased over time.
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Neuropatias Amiloides Familiares/fisiopatologia , Neuropatias Amiloides Familiares/cirurgia , Esvaziamento Gástrico , Transplante de Fígado , Adulto , Idade de Início , Idoso , Neuropatias Amiloides Familiares/complicações , Índice de Massa Corporal , Constipação Intestinal/etiologia , Diarreia/etiologia , Feminino , Humanos , Masculino , Desnutrição/etiologia , Pessoa de Meia-Idade , Náusea/etiologia , Estado Nutricional , Período Pós-Operatório , Albumina Sérica/análise , Inquéritos e Questionários , Fatores de Tempo , Vômito/etiologia , Adulto JovemRESUMO
INTRODUCTION: In hereditary transthyretin amyloidosis (ATTRv), two different fibrillar forms causing the amyloid deposition, have been identified, displaying substantially cardiac or neuropathic symptoms. Neuropathic symptoms are more frequent in early-onset patients, whereas late-onset patients, besides cardiac symptoms, seem to develop carpal tunnel syndrome, more often. With ultrasonography (US) of peripheral nerves, it is possible to distinguish structural changes, and enlarged cross-sectional area (CSA). The main purpose of this study was, for the first time, to elucidate US of peripheral nerves in Swedish ATTRv patients at an early stage of the disease, and to evaluate possible early enlarged CSA. MATERIAL AND METHODS: This prospective study included first visit data of 13 patients, aged 30-88 years, of which 11 with late-onset age. All had a positive V30M mutation. Eight men and six women (aged 28-74 years) served as controls. RESULTS: Significantly enlarged CSA was seen in ATTRv patients for the tibial nerve at the ankle (p = .001), the sural nerve (p < .001), the peroneal nerve at the popliteal fossa (p = .003), and the ulnar nerve at the middle upper arm (p = .007). CONCLUSION: US of peripheral nerves could be a valuable tool in disease evaluation and could facilitate monitoring of disease progression.
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Neuropatias Amiloides Familiares , Feminino , Humanos , Masculino , Neuropatias Amiloides Familiares/diagnóstico por imagem , Neuropatias Amiloides Familiares/genética , Nervos Periféricos/diagnóstico por imagem , Estudos Prospectivos , Suécia/epidemiologia , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: In hereditary transthyretin amyloidosis (ATTRv), early manifestation and age at onset (AO) may vary strikingly. We assessed the disease'risk (penetrance), AO and initial features in ATTRv families to gain insights on the early disease presentation. METHODS: Genealogical information, AO and first disease manifestations were collected in ATTRv families, from Sweden, Italy (Sicily), Spain (Mallorca), France, Turkey, Brazil. Penetrance was computed using a non-parametric survival method. RESULTS: We analysed 258 TTRV30M kindreds and 84 carrying six other variants (TTRT49A, F64L, S77Y, S77F, E89Q, I107V). In ATTRV30M families, the earliest disease risk was found at age 20 years in the Portuguese and Mallorcan families and at age 30-35 years, in the French and Swedish groups. The risks were higher in men and in carriers of maternal descent. In families carrying TTR-nonV30M variants, the earliest disease risk ranged from 30 y-o in TTRT49A to 55 y-o in TTRI107V families. Peripheral neuropathy symptoms were the most frequent initial manifestations. Among patients carrying TTRnonV30M variants, about 25% had an initial cardiac phenotype, one third a mixed phenotype. CONCLUSION: Our work provided solid data on the risks and early features of ATTRv in a spectrum of families to enhance an early diagnosis and treatment.
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Neuropatias Amiloides Familiares , Humanos , Masculino , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Brasil , Diagnóstico Precoce , Etnicidade , Pré-Albumina/genéticaRESUMO
INTRODUCTION: Epidemiological data on hereditary transthyretin (ATTRv) amyloidosis from the northernmost region of Sweden (Norrbotten) are sparse. METHODS: We reviewed the medical records of all incident cases of ATTRv amyloidosis in Norrbotten between 2006 and 2018. Official population and mortality statistics were used to estimate incidence rates and standardised mortality ratios (SMRs). RESULTS: Ninety-three patients were diagnosed with ATTRv amyloidosis between 2006 and 2018 (median age, 72.8 years; 68.8% men; 95.7% Val30Met [p.Val50Met] mutation). The incidence rate per 100,000 persons and year increased from 1.50 (95% confidence interval [CI], 0.84-2.47) cases in 2006-2009 to 4.92 (95%CI, 3.46-6.78) cases in 2016-2018. The SMR in the ATTRv amyloidosis cohort was 2.64 times higher than in the general population in 2006-2018 (95%CI, 1.78-3.77). However, there were indications of lower SMRs over time (2006-2012, 2.96 [95%CI, 1.73-4.74]; 2013-2018, 2.32 [95%CI, 1.23-3.96]) and by use of disease-modifying drugs (no, 3.21 [95%CI, 1.87-5.13]; yes, 2.09 [95%CI, 1.08-3.64]). CONCLUSION: The incidence of ATTRv amyloidosis increased 3-fold in Norrbotten between 2006 and 2018, most likely due to a previous underdiagnosis - with suggestions of lowered mortality during later years, possibly due to the introduction of disease-modifying drugs.
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Neuropatias Amiloides Familiares , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genética , Feminino , Humanos , Masculino , Mutação , Pré-Albumina/genética , Estudos Retrospectivos , Suécia/epidemiologiaRESUMO
INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRv) is endemic in northern Sweden (Västerbotten). The awareness of ATTRv amyloidosis is lower in Stockholm, a non-endemic region in Sweden. The aim of this study was to compare the possible differences in diagnostic delay, disease phenotypes, treatment and survival between a non-endemic and an endemic region in Sweden. METHODS: The in- and outpatient diagnosis registry at the Department of Neurology at Karolinska University Hospital and the Amyloidosis Centre at University Hospital of Umeå were used to identify patients between January 2006 and November 2017. RESULTS: In total, 21 patients in Stockholm and 134 patients in Västerbotten were included. The time between symptom onset to time-point of diagnosis was significantly longer in Stockholm vs Västerbotten. This corresponded to a longer median time between first visit at amyloidosis centre to time-point of diagnosis in Stockholm vs in Västerbotten. The most common reason for a diagnostic delay was negative tissue biopsies. CONCLUSION: There was a diagnostic-, but no patient-delay in non-endemic Stockholm vs endemic Västerbotten. Despite a more severe neuropathic phenotype in Stockholm at the onset, the systemic affection over the course of disease and of survival seems not to be influenced by the diagnosis delay in Stockholm.
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Neuropatias Amiloides Familiares , Diagnóstico Tardio , Humanos , Suécia/epidemiologia , Pré-Albumina/genética , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , Neuropatias Amiloides Familiares/genéticaRESUMO
Amyloid formation is a pathological process associated with a wide range of degenerative disorders, including Alzheimer's disease, Parkinson's disease, and diabetes mellitus type 2. During disease progression, abnormal accumulation and deposition of proteinaceous material are accompanied by tissue degradation, inflammation, and dysfunction. Agents that can interfere with the process of amyloid formation or target already formed amyloid assemblies are consequently of therapeutic interest. In this context, a few endogenous proteins have been associated with an anti-amyloidogenic activity. Here, we review the properties of transthyretin, apolipoprotein E, clusterin, and BRICHOS protein domain which all effectively interfere with amyloid in vitro, as well as displaying a clinical impact in humans or animal models. Their involvement in the amyloid formation process is discussed, which may aid and inspire new strategies for therapeutic interventions.
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Doença de Alzheimer , Amiloidose , Doença de Parkinson , Amiloide/metabolismo , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas/metabolismo , Animais , Humanos , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismoRESUMO
BACKGROUND: We have previously shown that transthyretin (TTR) amyloidosis patients have amyloid fibrils of either of two compositions; type A fibrils consisting of large amounts of C-terminal TTR fragments in addition to full-length TTR, or type B fibrils consisting of only full-length TTR. Since type A fibrils are associated with an older age in ATTRVal30Met (p.Val50Met) amyloidosis patients, it has been discussed if the TTR fragments are derived from degradation of the amyloid deposits as the patients are aging. The present study aimed to investigate if the fibril composition type changes over time, especially if type B fibrils can shift to type A fibrils as the disease progresses. MATERIAL AND METHODS: Abdominal adipose tissue biopsies from 29 Swedish ATTRVal30Met amyloidosis patients were investigated. The fibril type in the patients´ initial biopsy taken for diagnostic purposes was compared to a biopsy taken several years later (ranging between 2 and 13 years). The fibril composition type was determined by western blot. RESULTS: All 29 patients had the same fibril composition type in both the initial and the follow-up biopsy (8 type A and 21 type B). Even patients with a disease duration of more than 12 years and an age over 75 years at the time of the follow-up biopsy had type B fibrils in both biopsies. DISCUSSION: The result clearly shows that the amyloid fibril composition containing large amounts of C-terminal fragments (fibril type A) is a consequence of other factors than a slow degradation process occurring over time.
Assuntos
Neuropatias Amiloides Familiares , Amiloide , Gordura Abdominal/metabolismo , Idoso , Envelhecimento/patologia , Amiloide/metabolismo , Neuropatias Amiloides Familiares/metabolismo , Humanos , Pré-Albumina/metabolismoRESUMO
Hereditary transthyretin (ATTRv) amyloidosis is a rare but life-threatening multi-systemic disease with clustering areas in, for example, northern Sweden. Until the 1990s, only symptomatic treatments were available but liver transplantation has, in selected patients, been a good therapeutic option since. The first disease-modifying drug for ATTRv amyloidosis was approved in 2011 and since then, the development of new therapeutic drugs has been rapid and successful. Two gene silencing therapies were approved for the disease in 2018, both showing a robust reduction in serum transthyretin levels and a satisfactory safety profile. Recently, CRISPR-Cas9 gene editing has also shown promising results in patients with ATTRv amyloidosis. The recent developments have had a paramount effect on the management of these patients, and will probably also have a significant positive effect on their life expectancy. However, treatment costs have skyrocketed, which implies future challenges.
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Neuropatias Amiloides Familiares , Transplante de Fígado , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/terapia , Edição de Genes , Humanos , Pré-Albumina/genética , Pré-Albumina/uso terapêuticoRESUMO
Introduction: Hereditary transthyretin (ATTRv) amyloidosis caused by the V30M (p. V50M) mutation is a fatal, neuropathic systemic amyloidosis. Liver transplantation has prolonged the survival of patients and central nervous system (CNS) complications, attributed to amyloid angiopathy caused by CNS synthesis of variant transthyretin, have emerged. The study aimed to ascertain amyloid deposition within the brain in long-term ATTRv amyloidosis survivors with neurological symptoms from the CNS. Methods: A total of 20 patients with ATTR V30M having symptoms from the CNS and a median disease duration of 16 years (8-25 years) were included in this study. The cognitive and peripheral nervous functions were determined for 18 patients cross-sectionally at the time of the investigation. Amyloid brain deposits were examined by [18F]flutemetamol PET/CT. Five patients with Alzheimer's disease (AD) served as positive controls. Result: 60% of the patients with ATTRv had a pathological Z-score in the cerebellum, compared to only 20% in the patients with AD. 75% of the patients with transient focal neurological episodes (TFNEs) displayed a pathological uptake only in the cerebellum. Increased cerebellar uptake was related to an early age of onset of the ATTRv disease. 55% of the patients with ATTRv had a pathological Z-score in the global cerebral region compared to 100% of the patients with AD. Conclusion: Amyloid deposition within the brain after long-standing ATTRv amyloidosis is common, especially in the cerebellum. A cerebellar amyloid uptake profile seems to be related to TFNE symptoms.
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Untargeted metabolomics is a well-established technique and a powerful tool to find potential plasma biomarkers for early diagnosing hereditary transthyretin amyloidosis. Hereditary transthyretin amyloidosis (ATTRv) is a disabling and fatal disease with different clinical features such as polyneuropathy, cardiomyopathy, different gastrointestinal symptoms and renal failure. Plasma specimens collected from 27 patients with ATTRv (ATTRV30M), 26 asymptomatic TTRV30M carriers and 26 control individuals were subjected to gas chromatography (GC)- and liquid chromatography (LC)-mass spectrometry (MS)-based metabolomics analysis. Partial least squares discriminant and univariate analysis was used to analyse the data. The models constructed by Partial least squares-discriminant analysis (PLS-DA) could clearly discriminate ATTRV30M patients from controls and asymptomatic TTRV30M carriers. In total, 24 plasma metabolites (VIP > 1.0 and p < .05) were significantly altered in ATTRV30M patient group (6 increased and 18 decreased). Eleven of these distinguished the ATTRV30M group from both controls and TTRV30M carriers. Plasma metabolomics analysis revealed marked changes in several pathways in patients with ATTRV30M amyloidosis. Statistical analysis identified a panel of biomarkers that could effectively separate controls/TTRV30M carriers from ATTRV30M patients. These biomarkers can potentially be used to diagnose patients at an early stage of the disease.
Assuntos
Neuropatias Amiloides Familiares , Polineuropatias , Neuropatias Amiloides Familiares/diagnóstico , Biomarcadores , Humanos , MetabolômicaRESUMO
Amyloid transthyretin (ATTR) amyloidosis is characterized by the abnormal accumulation of ATTR fibrils in multiple organs. However, the structure of ATTR fibrils from the eye is poorly understood. Here, we used cryo-EM to structurally characterize vitreous body ATTR fibrils. These structures were distinct from previously characterized heart fibrils, even though both have the same mutation and type A pathology. Differences were observed at several structural levels: in both the number and arrangement of protofilaments, and the conformation of the protein fibril in each layer of protofilaments. Thus, our results show that ATTR protein structure and its assembly into protofilaments in the type A fibrils can vary between patients carrying the same mutation. By analyzing and matching the interfaces between the amino acids in the ATTR fibril with those in the natively folded TTR, we are able to propose a mechanism for the structural conversion of TTR into a fibrillar form.
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Neuropatias Amiloides Familiares/metabolismo , Amiloide/química , Amiloide/metabolismo , Pré-Albumina/química , Pré-Albumina/metabolismo , Corpo Vítreo/metabolismo , Idoso , Microscopia Crioeletrônica , Oftalmopatias Hereditárias , Humanos , Masculino , Estrutura Secundária de ProteínaRESUMO
INTRODUCTION: Hereditary transthyretin (ATTRv) amyloidosis is of autosomal dominant transmission, caused by a spectrum of mutations in the transthyretin (TTR) gene. The ATTRV30M (p.Val50Met) is the most frequent substitution in Europe. Northern Sweden is a known cluster for ATTRV30M amyloidosis patients due to high prevalence of the mutation rate, with homozygous cases. First symptoms occur generally during the 6th decade. Previous studies reported low penetrance in this area and possible anticipation in families. In order to refine our knowledge of the genetic aspects, penetrance and factors that influence the disease's risk, we performed a comprehensive study of ATTRV30M families in Sweden. METHODS: To assess anticipation, well-established age at onset (AO) was compared in all informative parent-offspring pairs and in subgroups, after excluding ascertainment biases. Penetrance was estimated using a non-parametric method that enables to study covariates' effect on the disease's risk. RESULTS: We analysed 114 ATTRV30M Swedish families, including 12 homozygous individuals. Among 131 parent-offspring pairs, we found an average anticipation of 11.7 [Standard Deviation (SD) =10.03] years, higher in case of maternal transmission (mean ± SD = 13.7 ± 8.4 years), compared to paternal transmission (mean ± SD = 7.9 ± 11.5 years, p < .003). Anticipation remained significant, after exclusion of ascertainment biases. In heterozygous ATTRV30M kindred, penetrance was low, estimated below 10% [95% confidence interval (CI) = 6-10] at 40 years-old, increasing to 71% [95% CI= 65-76] at age 90 years. The risk was found to be higher in male patients (p < .01) and in case of maternal transmission (p < .01), reflecting a parent of origin effect. We observed no difference of penetrance according the geographical origin. Finally, the disease risk was similar in heterozygous and homozygous ATTRV30M amyloidosis individuals. CONCLUSIONS: Our study provides new data on the genetics of ATTRV30M families in Sweden, including the occurrence of anticipation and on penetrance. Both are increased in case of maternal inheritance and in male patients. Overall, gender seems to be a factor that substantially modulates the AO of the disease, in this area. Clinically, these findings are of importance to guide the management of sibships and the monitoring of mutation carriers.
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Neuropatias Amiloides Familiares , Perfil Genético , Adulto , Idoso de 80 Anos ou mais , Neuropatias Amiloides Familiares/genética , Humanos , Masculino , Mutação , Penetrância , Pré-Albumina/genética , Suécia/epidemiologiaRESUMO
AIMS/BACKGROUND: Transthyretin amyloid (ATTR) amyloidosis cardiomyopathy is an underdiagnosed, causatively treatable cause of heart failure (HF). The aim of this study was to evaluate the efficacy of electrocardiogram (ECG) and echocardiography on patients with increased interventricular septum diameter (IVSd) to identify ATTR cardiac amyloidosis (ATTR-CA) patients. METHODS: We investigated 58 patients with HF and an IVSd > 14 mm. Included were 33 ATTR-CA patients and 25 controls that consisted of non-amyloidosis HFpatients with negative 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) scintigraphy. We used echocardiography including 2D speckle-tracking strain and a 12-lead ECG to test the accuracy to differentiate the groups. RESULTS: We found high diagnostic accuracy (98%) for differentiating ATTR-CA from HF controls using a combination of R amplitude in -aVR from ECG and relative wall thickness acquired from echocardiography. With this combined model (RWT/R in -aVR), the sensitivity was 100% and specificity was 95% using a cut-off value of 0.90. Furthermore, the area under the curve was 99% and the negative predictive value was 100%. CONCLUSION: We found that a simple combination of ECG and echocardiographic parameters used in clinical settings was able to differentiate ATTR-CA from other aetiologies of HF with increased interventricular septum thickness. The high sensitivity and negative predictive value render the algorithm useful for selection of patients for further diagnostic procedures for ATTR-CA.
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Amiloidose , Cardiomiopatias , Insuficiência Cardíaca , Amiloidose/diagnóstico por imagem , Cardiomiopatias/diagnóstico por imagem , Ecocardiografia , Eletrocardiografia , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/etiologia , Humanos , Pré-AlbuminaRESUMO
Amyloid-formation by the islet amyloid polypeptide (IAPP), produced by the ß-cells in the human pancreas, has been associated with the development of type II diabetes mellitus (T2DM). The human plasma-protein transthyretin (TTR), a well-known amyloid-inhibiting protein, is interestingly also expressed within the IAPP producing ß-cells. In the present study, we have characterized the ability of TTR to interfere with IAPP amyloid-formation, both in terms of its intrinsic stability as well as with regard to the effect of TTR-stabilizing drugs. The results show that TTR can prolong the lag-phase as well as impair elongation in the course of IAPP-amyloid formation. We also show that the interfering ability correlates inversely with the thermodynamic stability of TTR, while no such correlation was observed as a function of kinetic stability. Furthermore, we demonstrate that the ability of TTR to interfere is maintained also at the low pH environment within the IAPP-containing granules of the pancreatic ß-cells. However, at both neutral and low pH, the addition of TTR-stabilizing drugs partly impaired its efficacy. Taken together, these results expose mechanisms of TTR-mediated inhibition of IAPP amyloid-formation and highlights a potential therapeutic target to prevent the onset of T2DM.
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Polipeptídeo Amiloide das Ilhotas Pancreáticas/antagonistas & inibidores , Pré-Albumina/metabolismo , Benzotiazóis/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Pré-Albumina/química , Estabilidade ProteicaRESUMO
BACKGROUND: The diagnostic accuracy of histopathological detection of transthyretin amyloid (ATTR) by Congo red staining of abdominal fat samples has been questioned since low sensitivity has been reported, especially for patients with ATTR cardiomyopathy. However, the outcome of surgically obtained fat pad biopsies has not yet been evaluated. The aim was to evaluate the diagnostic accuracy of skin punch biopsies from abdominal fat in patients with suspected ATTR amyloidosis. MATERIAL AND METHODS: Data were evaluated from patients who had undergone abdominal fat pad biopsies using a skin punch due to suspected amyloidosis from 2006 to 2015. The biopsies had been analysed using Congo red staining to determine the presence of amyloid, and immunohistochemistry or Western blot to determine the type of amyloidosis. The final diagnosis was based on the clinical picture, biopsy results and DNA sequencing. Minimum follow-up after the initial biopsy was 3 years. RESULTS: Two hundred seventy-four patients (61% males) were identified, and in 132 (48%), a final diagnosis of amyloidosis had been settled. The majority (93%) had been diagnosed with hereditary transthyretin (ATTRv) amyloidosis, and therefore subsequent analyses were focused on these patients. Overall, our data showed a test specificity of 99% and a sensitivity of 91%. Ninety-eight (94%) of the patients had neuropathic symptoms at diagnosis, whereas 57 (55%) had signs of amyloid cardiomyopathy. Subgroup analyses showed that patients with merely neuropathic symptoms displayed the highest test sensitivity of 91%, whereas patients with pure cardiomyopathy displayed the lowest sensitivity of 83%. However, no significant differences in sensitivity were found between patients with or without cardiomyopathy or between the sexes. CONCLUSIONS: Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspect ATTRv amyloidosis, including patients presenting with cardiomyopathy. In addition, the method enables typing not only of the precursor protein but also of the amyloid fibril type, which is related to the phenotype and to the outcome of the disease.
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Neuropatias Amiloides Familiares , Gordura Abdominal , Tecido Adiposo , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Biópsia , Feminino , Humanos , Masculino , Pré-Albumina/genéticaRESUMO
BACKGROUND: The amyloid fibril in hereditary transthyretin (TTR) Val30Met (pVal50Met) amyloid (ATTR Val30Met) amyloidosis is composed of either a mixture of full-length and TTR fragments (Type A) or of only full-length TTR (Type B). The type of amyloid fibril exerts an impact on the phenotype of the disease, and on the outcome of diagnostic procedures and therapy. The aim of the present study was to investigate if the type of amyloid fibril remains the same within ATTR Val30Met amyloidosis families. METHODS: Fifteen families were identified in whom at least two first-degree relatives had their amyloid fibril composition determined. The type of ATTR was determined by Western blot in all but two patients. For these two patients a positive 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy indicated ATTR Type A. RESULTS: In 14 of the 15 families, the same amyloid fibril composition was noted irrespective of differences in age at onset. In the one family, different ATTR fibril types was found in two brothers with similar ages at onset. CONCLUSIONS: Family predisposition appears to have an impact on amyloid fibril composition in members of the family irrespective of their age at onset of disease, but if genetically determined, the gene/genes are likely to be situated at another location than the TTR gene in the genome.
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Substituição de Aminoácidos , Neuropatias Amiloides Familiares/metabolismo , Amiloide/metabolismo , Pré-Albumina/metabolismo , Adulto , Idade de Início , Idoso , Amiloide/genética , Neuropatias Amiloides Familiares/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Pré-Albumina/genéticaRESUMO
BACKGROUND: Differences in the gastrointestinal manifestations have emerged between Swedish and Japanese familial amyloidotic polyneuropathy amyloidogenic transthyretin Valine30Methionine (FAP ATTR Val30Met) patients. To elucidate the cause of the differences, we investigated the associations between serotonin transporter gene-linked polymorphic region (5-HTTLPR) and/or catechol-O-methyl transferase (COMT) gene polymorphism and their gastrointestinal in these patients. METHODS: Twenty-six Swedish and 24 Japanese patients with gastrointestinal disturbances, in whom genetic material was available, were included in the study. The initial gastrointestinal manifestations of the disease were classified as constipation, constipation alternating with diarrhoea, continuous diarrhoea, and nausea/vomiting. 5-HTTLPR and COMT gene polymorphism were assessed by polymerase chain reaction and enzymatic digestion. RESULTS: A significantly higher LA allele frequency of 5-HTTLPR was noted in the Swedish population compared with that of the Japanese. Moreover, the LA allele frequency tended to be lower in the continuous diarrhoea group than in that of the remaining groups of both Swedish and Japanese patients. No association between COMT genotype and initial gastrointestinal symptoms was noted. CONCLUSION: A high expression of serotonin transporter induced by LA allele of 5-HTTLPR may be one of the factors implicated with the inhibition of severe diarrhoea in early stages of Swedish FAP ATTR Val30Met patients.
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Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/genética , Catecol O-Metiltransferase/genética , Gastroenteropatias/etiologia , Gastroenteropatias/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Alelos , Neuropatias Amiloides Familiares/epidemiologia , Constipação Intestinal/etiologia , DNA/genética , Diarreia/etiologia , Feminino , Gastroenteropatias/epidemiologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Polimorfismo Genético/genética , Pré-Albumina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suécia/epidemiologia , Vômito/etiologiaRESUMO
INTRODUCTION: Hereditary transthyretin amyloidosis (ATTRm amyloidosis) is a rare disease caused by the deposition and accumulation of insoluble non-native transthyretin fibrils in the body. The disease inevitably results in widespread organ disruption, and poor life expectancy. The GI tract is one organ system vulnerable to disruption and, although the clinical presentation of the disease varies, GI involvement affects most patients with ATTRm amyloidosis. Areas covered: This article presents our experience with diagnosing and treating the GI symptoms of ATTRm amyloidosis patients at our center over the last 40 years, in the Swedish clustering area of the disease. Our aim is to help other physicians to better manage GI complications in patients with this rare but widespread condition. Expert commentary: GI symptoms are debilitating complications for ATTRm amyloidosis patients to experience, yet with the appropriate questioning and diagnosis methods, symptomatic treatments of these symptoms can be implemented to provide relief. Further, patients with fewer GI complications and a good nutritional status are also better candidates for liver transplantation which, in selected cases, is the best disease-modifying treatment of ATTRm amyloidosis to date.