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Taming molecular flexibility to tackle rare diseases.

ABSTRACT: Many mutations responsible of Fabry disease destabilize lysosomal alpha-galactosidase, but retain the enzymatic activity. These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis. We demonstrate the effectiveness of molecular dynamics simulations to correlate the genotype to the severity of the disease. We studied the relation between protein flexibility and residual enzymatic activity of pathological missense mutants in the cell. We found that mutations occurring at flexible sites are likely to retain activity in vivo. The usefulness of molecular dynamics for diagnostic purposes is not limited to lysosomal galactosidase because destabilizing mutations are widely encountered in other proteins, too, and represent a large share of all the ones associated to human diseases.

SUBMITTER: Cubellis MV

PROVIDER: S-EPMC4441037 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Taming molecular flexibility to tackle rare diseases.

Cubellis Maria Vittoria MV Baaden Marc M Andreotti Giuseppina G

Biochimie 20150402

Many mutations responsible of Fabry disease destabilize lysosomal alpha-galactosidase, but retain the enzymatic activity. These mutations are associated to a milder phenotype and are potentially curable with a pharmacological therapy either with chaperones or with drugs that modulate proteostasis. We demonstrate the effectiveness of molecular dynamics simulations to correlate the genotype to the severity of the disease. We studied the relation between protein flexibility and residual enzymatic a ...[more]

PMID: 25841341

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Project description:BackgroundThe multiplicity of issues, including uncertainty and ethical dilemmas, and policies involved in appraising interventions for rare diseases suggests that multicriteria decision analysis (MCDA) based on a holistic definition of value is uniquely suited for this purpose. The objective of this study was to analyze and further develop a comprehensive MCDA framework (EVIDEM) to address rare disease issues and policies, while maintaining its applicability across disease areas.MethodsSpecific issues and policies for rare diseases were identified through literature review. Ethical and methodological foundations of the EVIDEM framework v3.0 were systematically analyzed from the perspective of these issues, and policies and modifications of the framework were performed accordingly to ensure their integration.ResultsAnalysis showed that the framework integrates ethical dilemmas and issues inherent to appraising interventions for rare diseases but required further integration of specific aspects. Modification thus included the addition of subcriteria to further differentiate disease severity, disease-specific treatment outcomes, and economic consequences of interventions for rare diseases. Scoring scales were further developed to include negative scales for all comparative criteria. A methodology was established to incorporate context-specific population priorities and policies, such as those for rare diseases, into the quantitative part of the framework. This design allows making more explicit trade-offs between competing ethical positions of fairness (prioritization of those who are worst off), the goal of benefiting as many people as possible, the imperative to help, and wise use of knowledge and resources. It also allows addressing variability in institutional policies regarding prioritization of specific disease areas, in addition to existing uncertainty analysis available from EVIDEM.ConclusionThe adapted framework measures value in its widest sense, while being responsive to rare disease issues and policies. It provides an operationalizable platform to integrate values, competing ethical dilemmas, and uncertainty in appraising healthcare interventions.

Project description:Non-communicable diseases (NCDs) and their risk factors are the leading cause of death worldwide and contribute to 74.3% of deaths globally in 2019. The burden of NCDs is escalating in Afghanistan. Currently, every seconds, people in Afghanistan are dying of NCDs. Addressing this challenge in Afghanistan needs effective and practical interventions. This study aimed to identify the strategies developed and implemented in countries with low non-communicable premature death. To conduct a scoping review, we followed the six-step Arksey and O'Malley protocol and searched for eligible articles on eight international databases and the gray literature. The study followed the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) guidelines. The inclusion criteria were English documents and evidence produced up to 30 November 2021 for the control of NCDs. We excluded incomplete texts, duplicates, and dissertations due to lack of access. We used EndNote X9 and MaxQDA software for data management and analysis. We conducted content analysis for this study. A total of 122 documents developed between 1984 and 2021 met the inclusion criteria. We identified 35 strategies from which the most used strategies were related to unhealthy diets and smoking cessation programs. Canada (26.4%), Korea (19.8%), and the United Kingdom (19%) have the most publications on the control and prevention of NCDs among the countries included in the study. Most strategies were implemented over 2 years (41%). This study recommends specific interventions to control and prevent NCDs for the main risk factors of tobacco use, unhealthy diet, physical inactivity, and the main non-communicable diseases such as heart diseases, cancers, diabetes, and chronic obstructive pulmonary diseases. Afghanistan Ministry of Public Health, the WHO country office, and other involved stakeholders can use the findings of this review to design and implement strategies for controlling and preventing NCDs in Afghanistan. International organizations such as the World Health Organization, United Nations Agencies, the World Bank, and other involving communities should invest in strengthening good health governance in Afghanistan. The Afghan Government should focus on promoting and funding health literacy among the public and self-care to control and prevent NCDs.

Project description:BackgroundAccording to the International Rare Diseases Research Consortium (IRDiRC), a known rare disease (RD) should be diagnosable within a year. This study sought: firstly, to ascertain how long it takes to obtain the diagnosis of a RD in Spain, along with its associated time trend; and secondly, to identify and measure diagnostic delay (defined by the IRDiRC as any period exceeding a year) by reference to the characteristics of RDs and the persons affected by them.MethodsUsing data sourced from the Spanish Rare Diseases Patient Registry, we performed a descriptive analysis of the time elapsed between symptom onset and diagnosis of each RD, by sex, age and date of symptom onset, and type of RD. We analysed the time trend across the period 1960-2021 and possible change points, using a Joinpoint regression model and assuming a Poisson distribution. The multivariate analysis was completed with backward stepwise logistic regression.ResultsDetailed information was obtained on 3304 persons with RDs: 56.4% had experienced delay in diagnosis of their RDs, with the mean time taken being 6.18 years (median = 2; IQR 0.2-7.5). Both the percentage of patients with diagnostic delay and the average time to diagnosis underwent a significant reduction across the study period (p < 0.001). There was a higher percentage of diagnostic delays: in women (OR 1.25; 95% CI 1.07-1.45); in cases with symptom onset at age 30-44 years (OR 1.48; 95% CI 1.19-1.84): and when analysed by type of RD, in mental and behavioural disorders (OR 4.21; 95% CI 2.26-7.85), followed by RDs of the nervous system (OR 1.39; 95% CI 1.02-1.88).ConclusionsThis is the first study to quantify time to diagnosis of RDs in Spain, based on data from a national registry open to any RD. Since over half of all persons affected by RDs experience delay in diagnosis, new studies are needed to ascertain the factors associated with this delay and the implications this has on the lives of patients and their families.

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Taming molecular flexibility to tackle rare diseases.

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Taming molecular flexibility to tackle rare diseases.

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