Anticipation on age at onset in kindreds with hereditary ATTRV30M amyloidosis from the Majorcan cluster

Cisneros-Barroso, Eugenia; González-Moreno, Juan; Rodríguez, Adrián; Ripoll‐Vera, Tomás; Alvarez, Jorge A.; Usón, Mercedes; Figuerola, Antoni; Descals, Cristina; Montalá, Carles; Ferrer-Nadal, María Asunción; Losada, Inés

doi:10.1080/13506129.2020.1789580

Cited by 8 publications

(8 citation statements)

References 38 publications

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“…Phenotypic variations are observed between populations of patients with the Val30Met mutation. As previously published [ 8 ], the ATTR amyloidosis Val30Met population in Spain presents with a “middle-age” disease onset. Clinically, this finding is reflected in the high proportion of patients showing autonomic neuropathy (typical of early disease onset) and sensorimotor neuropathy or mixed phenotype (typical of late disease onset) [ 3 ].…”

Section: Discussionmentioning

confidence: 76%

“…In Spain there are two large endemic foci of ATTRv amyloidosis (Majorca and Huelva), and additional cases occur across the country; however, these data may be incomplete, as there is no centralized patient registry. In Majorca, the largest focus in Spain, the prevalence has been estimated to be 5/100,000 inhabitants [8,9], considered the fifth largest focus worldwide. In Majorca, the mean age at onset has previously been reported as 46 years [8]; epidemiological data of ATTRv amyloidosis in other areas of Spain is scarce.…”

Section: Introductionmentioning

confidence: 99%

“…In Majorca, the largest focus in Spain, the prevalence has been estimated to be 5/100,000 inhabitants [8,9], considered the fifth largest focus worldwide. In Majorca, the mean age at onset has previously been reported as 46 years [8]; epidemiological data of ATTRv amyloidosis in other areas of Spain is scarce.…”

Section: Introductionmentioning

confidence: 99%

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A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey

González-Moreno¹,

Losada-López²,

Cisneros-Barroso³

et al. 2021

Neurol Ther

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Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene or aggregation of wild-type transthyretin (ATTRwt). In Spain, there are two large endemic foci of ATTR amyloidosis caused by the Val30Met variant, with additional cases across the country; however, these data may be incomplete, as there is no centralized patient registry. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. This analysis aimed to gain a deeper understanding of the clinical profile of patients with ATTR amyloidosis in Spain. Methods: This was a descriptive analysis of the demographic and clinical characteristics of symptomatic patients enrolled at six sites geographically dispersed throughout Spain (data cutoff: January 6, 2020). Patient data at enrollment, including genotype, demographics, and clinical presentation for symptomatic patients, were recorded. Patients were grouped by predominant phenotype based on clinical measures at enrollment: predominantly cardiac,

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Section: Discussionmentioning

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey

González-Moreno¹,

Losada-López²,

Cisneros-Barroso³

et al. 2021

Neurol Ther

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“…This theory of "founder effect" should be investigated in the future. A pooled analysis of the Austro-Hungarian patients would further refine our knowledge on the clinical characteristics of ATTRHis88Arg ATTRv, such as expected penetrance, age of onset, rate of progression in asymptomatic individuals as it is shown in other ATTRv-s [36,37].…”

Section: Discussionmentioning

confidence: 96%

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features

Pozsonyi

Peskó

Takács

et al. 2021

Genes

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Background: Variant transthyretin amyloidosis (ATTRv) is an autosomal dominant inherited disease, where the mutation of the transthyretin gene (TTR) results in the deposition of pathogenic protein fibrils in various tissues. The mutation type influences the clinical course. Until now, no data were available on the genotype, phenotype, and prevalence of Hungarian ATTRv patients. The aim of our study was to assess the prevalence, regional distribution, genotypes, and phenotypes of Hungarian patients with ATTRv. Methods: With the collaboration of Hungarian regional and university centers, we identified patients diagnosed with ATTRv. We also searched prior publications for case studies of Hungarian ATTRv patients. Results: 40 individuals in 23 families with ATTRv were identified within the borders of Hungary. At the time of the diagnosis, 24 of them were symptomatic. The two most common mutations were ATTRHis88Arg (nine families) and ATTRIle107Val (8 families). ATTRVal30Met was demonstrated in 2 families, and ATTRVal122del, ATTRPhe33Leu, ATTRIle84Ser, and ATTRAsp18Gly in one family each. The median age of the symptomatic patients at the time of clinical diagnosis was 65 years. The most common clinically significant organ involvement was restrictive cardiomyopathy, found in 24 patients. Polyneuropathy was diagnosed in 20 patients. A total of 19 patients showed a mixed phenotype. The leading symptom was heart failure in 8 cases (3 of them had only cardiac symptoms), polyneuropathy in 11 cases (all of them also had cardiac symptoms), and equally severe cardiac and neuropathy symptoms were present in 3 cases. Out of 24 symptomatic patients, 10 received targeted pharmacological therapy. The follow-up period ranged from 1 to 195 months. At the time of the retrospective analysis, 12 patients had already died, and 1 patient underwent heart transplantation. Conclusions: As TTR genotype influences the phenotype and clinical course of ATTRv, it is important to know the regional data. In Hungary, ATTRHis88Arg and ATTRIle107Val are the most common mutations in ATTRv, both presenting with mixed phenotype, but the median age at the time of the diagnosis is 9 years lower in patients with ATTRHis88Arg than in patients with ATTRIle107Val.

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“…In the first study, authors studied the evolution of the age of onset in a group of families and found the existence of an anticipation mechanism ( 26 ), a common factor in hereditary diseases. This fact has been studied for ATTRv amyloidosis in other geographic areas with the studies of Drugge et al ( 27 ), Tashima et al ( 28 ), and Cisneros-Barroso et al ( 29 ). This study, which used a large enough pool set of patient records, presents a statistically based foundation that can foster the development of a wide range of analytical inferences focused on the distribution of the age of onset of ATTRv patients and its genealogical influence.…”

Section: Discussionmentioning

confidence: 99%

Clinical model for Hereditary Transthyretin Amyloidosis age of onset prediction

et al. 2023

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IntroductionHereditary transthyretin amyloidosis (ATTRv amyloidosis) is a rare neurological hereditary disease clinically characterized as severe, progressive, and life-threatening while the age of onset represents the moment in time when the first symptoms are felt. In this study, we present and discuss our results on the study, development, and evaluation of an approach that allows for time-to-event prediction of the age of onset, while focusing on genealogical feature construction.Materials and methodsThis research was triggered by the need to answer the medical problem of when will an asymptomatic ATTRv patient show symptoms of the disease. To do so, we defined and studied the impact of 77 features (ranging from demographic and genealogical to familial disease history) we studied and compared a pool of prediction algorithms, namely, linear regression (LR), elastic net (EN), lasso (LA), ridge (RI), support vector machines (SV), decision tree (DT), random forest (RF), and XGboost (XG), both in a classification as well as a regression setting; we assembled a baseline (BL) which corresponds to the current medical knowledge of the disease; we studied the problem of predicting the age of onset of ATTRv patients; we assessed the viability of predicting age of onset on short term horizons, with a classification framing, on localized sets of patients (currently symptomatic and asymptomatic carriers, with and without genealogical information); and we compared the results with an out-of-bag evaluation set and assembled in a different time-frame than the original data in order to account for data leakage.ResultsCurrently, we observe that our approach outperforms the BL model, which follows a set of clinical heuristics and represents current medical practice. Overall, our results show the supremacy of SV and XG for both the prediction tasks although impacted by data characteristics, namely, the existence of missing values, complex data, and small-sized available inputs.DiscussionWith this study, we defined a predictive model approach capable to be well-understood by medical professionals, compared with the current practice, namely, the baseline approach (BL), and successfully showed the improvement achieved to the current medical knowledge.

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Anticipation on age at onset in kindreds with hereditary ATTRV30M amyloidosis from the Majorcan cluster

Cited by 8 publications

References 38 publications

A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey

A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey

Variant Transthyretin Amyloidosis (ATTRv) in Hungary: First Data on Epidemiology and Clinical Features

Clinical model for Hereditary Transthyretin Amyloidosis age of onset prediction

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