Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center

Next-generation sequencing (NGS) technologies have been proposed as a first-line test for the diagnosis of inborn errors of metabolism (IEM), a group of genetically heterogeneous disorders with overlapping or nonspecific phenotypes. Over a 3-year period, we prospectively analyzed 311 pediatric patients with a suspected IEM using four targeted gene panels. The rate of positive diagnosis was 61.86% for intermediary metabolism defects, 32.84% for complex molecular defects, 19% for hypoglycemic/hyperglycemic events, and 17% for mitochondrial diseases, and a conclusive molecular diagnosis was established in 2-4 weeks. Forty-one patients for whom negative results were obtained with the mitochondrial diseases panel underwent subsequent analyses using the NeuroSeq panel, which groups all genes from the individual panels together with genes associated with neurological disorders (1870 genes in total). This achieved a diagnostic rate of 32%. We next evaluated the utility of a tool, Phenomizer, for differential diagnosis, and established a correlation between phenotype and molecular findings in 39.3% of patients. Finally, we evaluated the mutational architecture of the genes analyzed by determining z-scores, loss-of-function observed/expected upper bound fraction (LOEUF), and haploinsufficiency (HI) scores. In summary, targeted gene panels for specific groups of IEMs enabled rapid and effective diagnosis, which is critical for the therapeutic management of IEM patients.info:eu-repo/semantics/publishedVersio

Compliance with current dietary recommendations and geographical variability of diet in women participating in 7 screening programs for breast cancer in Spain

Introducción: Una dieta saludable es especialmente importante durante la menopausia, periodo en el que aumenta el riesgo de varios problemas de salud. Analizamos la dieta de mujeres peri y postmenopáusicas españolas y el grado de cumplimiento de las recomendaciones actuales. Material y métodos: Estudio transversal en 3.574 mujeres de 45-68 años que acuden al cribado de cáncer de mama en 7 centros (A Coruña, Barcelona, Burgos, Palma de Mallorca, Pamplona, Valencia y Zaragoza). Se recogió la dieta mediante un cuestionario de frecuencia de alimentos validado para población española. Para la valoración del cumplimiento de las recomendaciones actuales se utilizaron los rangos recomendados por la Sociedad Española de Nutrición Comunitaria para ingesta de grupos de alimentos y las Ingestas Diarias Recomendadas (IDR) para energía, vitaminas y minerales de la Federación Española de Nutrición, Alimentación y Dietética. Resultados: El 29% de las mujeres eran obesas y un 42% tenía sobrepeso. El aporte calórico medio fue de 2.053 kcal (DE: 480). El perfil calórico general fue de: 43% de la energía aportada por lo carbohidratos, 36% por las grasas, 20% por las proteínas. Se evidenció una ingesta deficiente de vitamina D en todos los nodos del estudio, con una ingesta media general de 2,14 μg/día. Se detectó a su vez una ingesta deficitaria de vitamina E en A Coruña y Burgos. Todos los centros presentaron una ingesta elevada de productos lácteos y de legumbres. El consumo de frutas y verduras fue muy heterogéneo siendo especialmente elevada su ingesta en Mallorca y Valencia mientras que fue baja para ambos grupos de alimentos en A Coruña. La ingesta de aceite de oliva fue elevada en todos los centros exceptuando Burgos con un 74,3% de las mujeres estudiadas por debajo de las 3 raciones al día recomendadas. Conclusiones: Una dieta con menos grasas y proteínas y más rica en vegetales, frutos secos y alimentos ricos en hidratos de carbono equilibraría el balance energético y mejoraría la calidad de la dieta corrigiendo las bajas ingestas de vitaminas D y E. Estas recomendaciones son especialmente importantes en las ciudades más alejadas de la costa mediterránea donde se han detectado mayores incumplimientos de las recomendaciones vigentes y una dieta más alejada de la dieta mediterránea.Introduction: A healthy diet is especially important during menopause, a period which increases the risk of various health problems. We analyzed the diet of periand postmenopausal Spanish women and the degree of compliance with current recommendations. Material and methods: We studied 3574 women 45-68 years old who attended breast cancer screening programmes in 7 centres (A Coruña, Barcelona, Burgos, Palma de Mallorca, Pamplona, Valencia and Zaragoza). Diet information was collected using a food frequency questionnaire validated for the Spanish population. For the assessment of compliance with current guidelines we used the recommendations by the Spanish Society of Community Nutrition for food groups intake and by the Spanish Federation of Nutrition, Food and Dietetics for energy, vitamins and minerals intake. Results: The 29% of women were obese and 42% overweight. The average caloric intake was 2.053 kcal (SD 480). The general energy profile was: 43% of the energy from the carbohydrates, 36% from fats, and 20% from proteins. There was a low vitamin D intake in all centres of the study, with an overall mean intake of 2.14 mg/day. A deficit of vitamin E intake in A Coruña and Burgos was also detected. Intake of dairy products and vegetables was high in all the study centers. The consumption of fruits and vegetables was very heterogeneous, with high intakes observed in Mallorca and Valencia and low for both food groups in A Coruña. The olive oil intake was high in all centers except Burgos with 74.3% of the women studied below the recommended 3 servings per day. Conclusions: A diet with less fat and protein and a higher consumption of vegetables, nuts and foods rich in carbohydrate might balance the energy intake and improve the quality of the diet correcting the low intakes of vitamins D and E. These recommendations are especially important in cities far from the Mediterranean coast where more breaches have been detected over the current recommendations with a lower adherence to the Mediterranean diet.Este estudio ha recibido financiación del Fondo de Investigación Sanitaria (proyecto PI060386) y de Astra-Zéneca (convenio de colaboración entre Astra- Zeneca y el Instituto de salud Carlos III 1306-1306 EPY

Limited dCTP Availability Accounts for Mitochondrial DNA Depletion in Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a severe human disease caused by mutations in TYMP, the gene encoding thymidine phosphorylase (TP). It belongs to a broader group of disorders characterized by a pronounced reduction in mitochondrial DNA (mtDNA) copy number in one or more tissues. In most cases, these disorders are caused by mutations in genes involved in deoxyribonucleoside triphosphate (dNTP) metabolism. It is generally accepted that imbalances in mitochondrial dNTP pools resulting from these mutations interfere with mtDNA replication. Nonetheless, the precise mechanistic details of this effect, in particular, how an excess of a given dNTP (e.g., imbalanced dTTP excess observed in TP deficiency) might lead to mtDNA depletion, remain largely unclear. Using an in organello replication experimental model with isolated murine liver mitochondria, we observed that overloads of dATP, dGTP, or dCTP did not reduce the mtDNA replication rate. In contrast, an excess of dTTP decreased mtDNA synthesis, but this effect was due to secondary dCTP depletion rather than to the dTTP excess in itself. This was confirmed in human cultured cells, demonstrating that our conclusions do not depend on the experimental model. Our results demonstrate that the mtDNA replication rate is unaffected by an excess of any of the 4 separate dNTPs and is limited by the availability of the dNTP present at the lowest concentration. Therefore, the availability of dNTP is the key factor that leads to mtDNA depletion rather than dNTP imbalances. These results provide the first test of the mechanism that accounts for mtDNA depletion in MNGIE and provide evidence that limited dNTP availability is the common cause of mtDNA depletion due to impaired anabolic or catabolic dNTP pathways. Thus, therapy approaches focusing on restoring the deficient substrates should be explored

POLG1 p.R722H mutation associated with multiple mtDNA deletions and a neurological phenotype

<p>Abstract</p> <p>Background</p> <p>The c.2447G>A (p.R722H) mutation in the gene <it>POLG1 </it>of the catalytic subunit of human mitochondrial polymerase gamma has been previously found in a few occasions but its pathogenicity has remained uncertain. We set out to ascertain its contribution to neuromuscular disease.</p> <p>Methods</p> <p>Probands from two families with probable mitochondrial disease were examined clinically, muscle and buccal epithelial DNA were analyzed for mtDNA deletions, and the <it>POLG1, POLG2, ANT1 </it>and <it>Twinkle </it>genes were sequenced.</p> <p>Results</p> <p>An adult proband presented with progressive external ophthalmoplegia, sensorineural hearing impairment, diabetes mellitus, dysphagia, a limb myopathy and dementia. Brain MRI showed central and cortical atrophy, and ¹⁸F-deoxyglucose PET revealed reduced glucose uptake. Histochemical analysis of muscle disclosed ragged red fibers and cytochrome c oxidase-negative fibers. Electron microscopy showed subsarcolemmal aggregates of morphologically normal mitochondria. Multiple mtDNA deletions were found in the muscle, and sequencing of the <it>POLG1 </it>gene revealed a homozygous c.2447G>A (p.R722H) mutation. His two siblings were also homozygous with respect to the p.R722H mutation and presented with dementia and sensorineural hearing impairment. In another family the p.R722H mutation was found as compound heterozygosity with the common p.W748S mutation in two siblings with mental retardation, ptosis, epilepsy and psychiatric symptoms. The estimated carrier frequency of the p.R722H mutation was 1:135 in the Finnish population. No mutations in <it>POLG2</it>, <it>ANT1 </it>and <it>Twinkle </it>genes were found. Analysis of the POLG1 sequence by homology modeling supported the notion that the p.R722H mutation is pathogenic.</p> <p>Conclusions</p> <p>The recessive c.2447G>A (p.R722H) mutation in the linker region of the <it>POLG1 </it>gene is pathogenic for multiple mtDNA deletions in muscle and is associated with a late-onset neurological phenotype as a homozygous state. The onset of the disease can be earlier in compound heterozygotes.</p

Prospective associations between a priori dietary patterns adherence and kidney function in an elderly Mediterranean population at high cardiovascular risk.

PURPOSE: To assess the association between three different a priori dietary patterns adherence (17-item energy reduced-Mediterranean Diet (MedDiet), Trichopoulou-MedDiet and Dietary Approach to Stop Hypertension (DASH)), as well as the Protein Diet Score and kidney function decline after one year of follow-up in elderly individuals with overweight/obesity and metabolic syndrome (MetS). METHODS: We prospectively analyzed 5675 participants (55-75 years) from the PREDIMED-Plus study. At baseline and at one year, we evaluated the creatinine-based estimated glomerular filtration rate (eGFR) and food-frequency questionnaires-derived dietary scores. Associations between four categories (decrease/maintenance and tertiles of increase) of each dietary pattern and changes in eGFR (ml/min/1.73m2) or ≥ 10% eGFR decline were assessed by fitting multivariable linear or logistic regression models, as appropriate. RESULTS: Participants in the highest tertile of increase in 17-item erMedDiet Score showed higher upward changes in eGFR (β: 1.87 ml/min/1.73m2; 95% CI: 1.00-2.73) and had lower odds of ≥ 10% eGFR decline (OR: 0.62; 95% CI: 0.47-0.82) compared to individuals in the decrease/maintenance category, while Trichopoulou-MedDiet and DASH Scores were not associated with any renal outcomes. Those in the highest tertile of increase in Protein Diet Score had greater downward changes in eGFR (β: - 0.87 ml/min/1.73m2; 95% CI: - 1.73 to - 0.01) and 32% higher odds of eGFR decline (OR: 1.32; 95% CI: 1.00-1.75). CONCLUSIONS: Among elderly individuals with overweight/obesity and MetS, only higher upward change in the 17-item erMedDiet score adherence was associated with better kidney function after one year. However, increasing Protein Diet Score appeared to have an adverse impact on kidney health. TRIAL REGISTRATION NUMBER: ISRCTN89898870 (Data of registration: 2014)

Compliance with current dietary recommendations and geographical variability of diet in women participating in 7 screening programs for breast cancer in Spain.

[ES] Introducción:Una dieta saludable es especialmenteimportante durante la menopausia, periodo en el queaumenta el riesgo de varios problemas de salud. Analiza-mos la dieta de mujeres peri y postmenopáusicas españo-las y el grado de cumplimiento de las recomendacionesactuales. Material y métodos:Estudio transversal en 3.574 muje-res de 45-68 años que acuden al cribado de cáncer demama en 7 centros (A Coruña, Barcelona, Burgos, Palmade Mallorca, Pamplona, Valencia y Zaragoza). Se recogióla dieta mediante un cuestionario de frecuencia de ali-mentos validado para población española. Para la valora-ción del cumplimiento de las recomendaciones actuales seutilizaron los rangos recomendados por la SociedadEspañola de Nutrición Comunitaria para ingesta de gru-pos de alimentos y las Ingestas Diarias Recomendadas(IDR) para energía, vitaminas y minerales de la Federa-ción Española de Nutrición, Alimentación y Dietética. Resultados:El 29% de las mujeres eran obesas y un42% tenía sobrepeso. El aporte calórico medio fue de2.053 kcal (DE: 480). El perfil calórico general fue de: 43% de la energía aportada por lo carbohidratos, 36%por las grasas, 20% por las proteínas. Se evidenció unaingesta deficiente de vitamina D en todos los nodos delestudio, con una ingesta media general de 2,14 μg/día. Sedetectó a su vez una ingesta deficitaria de vitamina E en ACoruña y Burgos. Todos los centros presentaron unaingesta elevada de productos lácteos y de legumbres. Elconsumo de frutas y verduras fue muy heterogéneosiendo especialmente elevada su ingesta en Mallorca yValencia mientras que fue baja para ambos grupos de ali-mentos en A Coruña. La ingesta de aceite de oliva fue ele-vada en todos los centros exceptuando Burgos con un74,3% de las mujeres estudiadas por debajo de las 3raciones al día recomendadas. Conclusiones:Una dieta con menos grasas y proteínasy más rica en vegetales, frutos secos y alimentos ricos enhidratos de carbono equilibraría el balance energético ymejoraría la calidad de la dieta corrigiendo las bajasingestas de vitaminas D y E. Estas recomendaciones sonespecialmente importantes en las ciudades más alejadasde la costa mediterránea donde se han detectado mayoresincumplimientos de las recomendaciones vigentes y unadieta más alejada de la dieta mediterránea. [EN] A healthy diet is especially important during menopause, a period which increases the risk of various health problems. We analyzed the diet of periand postmenopausal Spanish women and the degree of compliance with current recommendations. We studied 3574 women 45-68 years old who attended breast cancer screening programmes in 7 centres (A Coruña, Barcelona, Burgos, Palma de Mallorca, Pamplona, Valencia and Zaragoza). Diet information was collected using a food frequency questionnaire validated for the Spanish population. For the assessment of compliance with current guidelines we used the recommendations by the Spanish Society of Community Nutrition for food groups intake and by the Spanish Federation of Nutrition, Food and Dietetics for energy, vitamins and minerals intake. The 29% of women were obese and 42% overweight. The average caloric intake was 2.053 kcal (SD 480). The general energy profile was: 43% of the energy from the carbohydrates, 36% from fats, and 20% from proteins. There was a low vitamin D intake in all centres of the study, with an overall mean intake of 2.14 mg/day. A deficit of vitamin E intake in A Coruña and Burgos was also detected. Intake of dairy products and vegetables was high in all the study centers. The consumption of fruits and vegetables was very heterogeneous, with high intakes observed in Mallorca and Valencia and low for both food groups in A Coruña. The olive oil intake was high in all centers except Burgos with 74.3% of the women studied below the recommended 3 servings per day. A diet with less fat and protein and a higher consumption of vegetables, nuts and foods rich in carbohydrate might balance the energy intake and improve the quality of the diet correcting the low intakes of vitamins D and E. These recommendations are especially important in cities far from the Mediterranean coast where more breaches have been detected over the current recommendations with a lower adherence to the Mediterranean diet.Este estudio ha recibido financiación del Fondo deInvestigación Ssanitaria (proyecto PI060386) y de Astra-Zéneca (convenio de colaboración entre Astra-Zeneca y el Instituto de salud Carlos III 1306-1306EPY).S

Relationship between olive oil consumption and ankle-brachial pressure index in a population at high cardiovascular risk

The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome. Methods: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure. Results: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48]). Conclusions: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed

Long daytime napping is associated with increased adiposity and type 2 diabetes in an elderly population with metabolic syndrome

Research examining associations between objectively-measured napping time and type 2 diabetes (T2D) is lacking. This study aimed to evaluate daytime napping in relation to T2D and adiposity measures in elderly individuals from the Mediterranean region. A cross-sectional analysis of baseline data from 2190 elderly participants with overweight/obesity and metabolic syndrome, in the PREDIMED-Plus trial, was carried out. Accelerometer-derived napping was measured. Prevalence ratios (PR) and 95% confidence intervals (CI) for T2D were obtained using multivariable-adjusted Cox regression with constant time. Linear regression models were fitted to examine associations of napping with body mass index (BMI) and waist circumference (WC). Participants napping ≥90 min had a higher prevalence of T2D (PR 1.37 (1.06, 1.78)) compared with those napping 5 to <30 min per day. Significant positive associations with BMI and WC were found in those participants napping ≥30 min as compared to those napping 5 to <30 min per day. The findings of this study suggest that longer daytime napping is associated with higher T2D prevalence and greater adiposity measures in an elderly Spanish population at high cardiovascular risk

Isotemporal substitution of inactive time with physical activity and time in bed: Cross-sectional associations with cardiometabolic health in the PREDIMED-Plus study

© 2019 The Author(s). Background: This study explored the association between inactive time and measures of adiposity, clinical parameters, obesity, type 2 diabetes and metabolic syndrome components. It further examined the impact of reallocating inactive time to time in bed, light physical activity (LPA) or moderate-To-vigorous physical activity (MVPA) on cardio-metabolic risk factors, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Methods: This is a cross-sectional analysis of baseline data from 2189 Caucasian men and women (age 55-75 years, BMI 27-40 Kg/m2) from the PREDIMED-Plus study (http://www.predimedplus.com/). All participants had ≥3 components of the metabolic syndrome. Inactive time, physical activity and time in bed were objectively determined using triaxial accelerometers GENEActiv during 7 days (ActivInsights Ltd., Kimbolton, United Kingdom). Multiple adjusted linear and logistic regression models were used. Isotemporal substitution regression modelling was performed to assess the relationship of replacing the amount of time spent in one activity for another, on each outcome, including measures of adiposity and body composition, biochemical parameters and blood pressure in older adults. Results: Inactive time was associated with indicators of obesity and the metabolic syndrome. Reallocating 30 min per day of inactive time to 30 min per day of time in bed was associated with lower BMI, waist circumference and glycated hemoglobin (HbA1c) (all p-values < 0.05). Reallocating 30 min per day of inactive time with 30 min per day of LPA or MVPA was associated with lower BMI, waist circumference, total fat, visceral adipose tissue, HbA1c, glucose, triglycerides, and higher body muscle mass and HDL cholesterol (all p-values < 0.05). Conclusions: Inactive time was associated with a poor cardio-metabolic profile. Isotemporal substitution of inactive time with MVPA and LPA or time in bed could have beneficial impact on cardio-metabolic health. Trial registration: The trial was registered at the International Standard Randomized Controlled Trial (ISRCTN: http://www.isrctn.com/ISRCTN89898870) with number 89898870 and registration date of 24 July 2014, retrospectively registered