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Abstract Background Human milk banks are essential facilities to provide donated human milk (DHM) to preterm and term infants with health complications. Little is known regarding milk bank donors and how their characteristics may influence the particularities of the donation process. The present study aims to assess characteristics of donors and their newborns to identify associations with the amount of DHM and initiation and donation time, during the first and second year of the milk bank operation in Córdoba, Spain. Methods This cross-sectional study was conducted in three periods: pre-opening of the milk bank (PRE) including all women who gave birth to a newborn between January – May 2017 and were hospital users; donors in the first year after the opening (Period 1 (P1): April 2019 – March 2020); and in the second year (P2: April 2020 – March 2021). For P1 and P2, DHM data were recorded. The relationships between donor and newborn characteristics and the donation process were examined using univariable and regression models. Results From 391 women interviewed in the PRE period, 55 (14%) showed intention to donate. In P1 and P2, there were 51 and 25 human milk (HM) donors, respectively. Age, gestational age (GA) and parity were similar between periods. In P2, a higher proportion of donors had higher education (P1: 46%; P2: 70.8%, p = 0.045). Around 40% of donors in both periods were on maternity leave. In P1, donors who had low birth weight infants (

Abstract This study aimed to investigate if the duration of breastfeeding and the method at initiation of complementary feeding affect eating behaviour in children aged 3−6 years. This is a cross‐sectional analysis from the Childhood Obesity Risk Assessment Longitudinal Study project, an ongoing longitudinal cohort study that aims to identify childhood obesity risk factors in Spanish children. A total of 1215 children aged 3−6 years were included. Breastfeeding duration and the method of initiation of complementary feeding [baby‐led weaning (BLW), traditional/spoon or mixed method] were evaluated. Eating behaviour at 3−6 years was assessed with the Child Eating Behaviour Questionnaire. Generalized linear models were fitted to assess the association between the aforementioned exposures and eating behaviour. Children breastfed for ≥4 months were less likely to be fussy eaters at 3−6 years compared to those breastfed for

Abstract Background Enoyl-CoA hydratase short-chain 1 (ECHS1) is a key mitochondrial enzyme that is involved in valine catabolism and fatty acid beta-oxidation. Mutations in the ECHS1 gene lead to enzymatic deficiency, resulting in the accumulation of certain intermediates from the valine catabolism pathway. This disrupts the pyruvate dehydrogenase complex and the mitochondrial respiratory chain, with consequent cellular damage. Patients present with a variable age of onset and a wide spectrum of clinical features. The Leigh syndrome phenotype is the most frequently reported form of the disease. Herein, we report a case of a male with ECHS1 deficiency who was diagnosed at 8 years of age. He presented severe dystonia, hyperlordosis, moderate to severe kyphoscoliosis, great difficulty in walking, and severe dysarthria. A valine-restricted and total fat-restricted diet was considered as a therapeutic option after the genetic diagnosis. An available formula that restricted branched-chain amino acids and especially restricted valine was used. We also restricted animal protein intake and provided a low-fat diet that was particularly low in dairy fat. Results This protein- and fat-restricted diet was initiated with adequate tolerance and adherence. After three years, the patient noticed an improvement in dystonia, especially in walking. He currently requires minimal support to walk or stand. Therefore, he has enhanced his autonomy to go to school or establish a career for himself. His quality of life and motivation for treatment have greatly increased. Conclusions There is still a substantial lack of knowledge about this rare disorder, especially knowledge about future effective treatments. However, early diagnosis and treatment with a valine- and fat-restricted diet, particularly dairy fat-restricted diet, appeared to limit disease progression in this patient with ECHS1 deficiency.

Abstract Due to the absence of easily applicable cut‐off points to determine high blood pressure or hypertension in children, as in the adult population, blood pressure is rarely measured in the pediatrician's clinical routine. This has led to an underdiagnosis of high blood pressure or hypertension in children. For this reason, the present study evaluate the utility of five equations for the screening of high blood pressure in children: blood pressure to height ratio, modified blood pressure to height ratio, new modified blood pressure to height ratio, new simple formula and height‐based equations. The authors evaluated 1599 children between 5 and 18 years. The performance of the five equations was analyzed using the receiver‐operating characteristics curves for identifying blood pressure above P90th according to the American Academy of Pediatrics Clinical Practice Guideline 2017. All equations showed an area under the curve above 0.882. The new modified blood pressure to height ratio revealed a high sensitivity whereas the height‐based equations showed the best performance, with a positive predictive value above 88.2%. Finally, all equations showed higher positive predictive values in children with overweight or obesity. The height‐based equation obtained the highest PPV values above 71.1% in children with normal weight and above 90.2% in children with overweight or obesity. In conclusions, the authors recommend the use of the height‐based equations equation because it showed the best positive predictive values to identify children with elevated blood pressure, independently of their sex, pubertal and weight status.

IntroductionMetabolic syndrome (MetS) is a cluster of clinical and metabolic alterations related to the risk of cardiovascular diseases (CVD). Metabolic changes occurring during puberty, especially in children with overweight and obesity, can influence the risk of developing chronic diseases, especially CVD.MethodsLongitudinal study based on the follow-up until puberty of a cohort of 191 prepubertal Spanish boys and girls without congenital, chronic, or inflammatory diseases: undernutrition: or intake of any drug that could alter blood glucose, blood pressure, or lipid metabolism. The following parameters were used to determine the presence of MetS: obesity, hypertension, hyperglycemia, hypertriglyceridemia, and low HDL-c.ResultsA total of 75·5% of participants stayed in the same BMI category from prepuberty to puberty, whereas 6·3% increased by at least one category. The prevalence of MetS was 9·1% (prepubertal stage) and 11·9% (pubertal stage). The risk of presenting alterations in puberty for systolic blood pressure (SBP), plasma triacylglycerols, HDL cholesterol (HDL-c), and HOMA-IR was significantly higher in those participants who had the same alterations in prepuberty. MetS prevalence in puberty was predicted by sex and levels of HOMA-IR, BMI-z, and waist circumference in the prepubertal stage, in the whole sample: in puberty, the predictors were levels of HOMA-IR, BMI-z, and diastolic blood pressure in participants with obesity. Two fast-and-frugal decision trees were built to predict the risk of MetS in puberty based on prepuberty HOMA-IR (cutoff 2·5), SBP (cutoff 106 mm of Hg), and TAG (cutoff 53 mg/dl).DiscussionControlling obesity and cardiometabolic risk factors, especially HOMA-IR and blood pressure, in children during the prepubertal stage appears critical to preventing pubertal MetS effectively.

IntroductionEating behavior is often established during the first years of life. Therefore, it is important to make a research on it to understand the relationships that children have with food and how this can contribute to prevent the development of childhood obesity. An appropriate assessment of eating behavior can be achieved using the “Child Eating Behavior Questionnaire” (CEBQ). This questionnaire has been validated in several populations and languages, but it has never been translated, adapted, and validated for Spanish children.AimTo evaluate the reliability and internal consistency of the CEBQ questionnaire, culturally adapted and translated into Spanish (Spain), in Spanish families with children aged 3 to 6 years, as well as its association with children’s body mass index (BMI) to test its construct validity.Materials and MethodsChildren between 3 and 6 years old were recruited from the ongoing MELI-POP randomized controlled clinical trial, as well as from public schools located in middle class neighborhoods of Zaragoza, Spain, to complete the sample. Sociodemographic characteristics and anthropometric measures were obtained according to standardized methods. The 35-item CEBQ questionnaire was completed twice with a time difference of 3 weeks between each response. Statistical analyses included the evaluation of internal consistency and reliability of the questionnaire, a confirmatory factor analysis, and the association between the different CEBQ scales and the children’s BMI.ResultsA total of 197 children completed variables; 97 of them were boys (49.2%) and 100 girls (50.8%). Mean age of the total sample was 4.7 ± 0.9 years. There was a high test-re-test reliability of the questionnaire with values close to 1, with an average of 0.66 and a good internal consistency (Cronbach alpha with values above 0.7), so that a high reliability is established between the items in each scale. A gradual positive association was found between the score of different “pro-intake” scales of the CEBQ: “Food Responsiveness,” “Emotional Overeating,” and “Enjoyment of food” and the children’s BMI; at the opposite, negative associations were observed between BMI and the score of anti-intake scales “Satiety Responsiveness,” “Slowness in Eating,” and “Emotional Undereating.”ConclusionThe Spanish version of the CEBQ is a useful tool to assess the eating behavior of Spanish children because the high reliability and internal validity. There is a significant association between eating behavior and BMI in Spanish children.

Background and AimChanges in adipokines have been related with the development of metabolic syndrome, frequently associated with obesity, and other risk factors. Fitness seems to promote a healthy cardiovascular status and could be a protector factor, just from childhood. Therefore, the present study aimed to evaluate the relationship between fitness levels with plasma adipokines and inflammatory biomarkers in prepubertal children.MethodsOne hundred and thirty-seven healthy normal-weight prepubertal children were recruited from local schools and divided after performing the fitness tests, into two groups according to fitness level—low cardiovascular fitness group (LF) and equal or higher cardiovascular fitness group (HF). Anthropometric variables, blood pressure (BP) and plasma insulin, and leptin, resistin, adiponectin, tumor necrosis factor-alpha, hepatic growth factor, interleukin (IL)-8, monocyte chemoattractant protein-1, nerve growth factor (NGF), and plasminogen activator inhibitor-1 (PAI-1) were measured fasting in both groups to be compared. Univariate analysis of variance, comparative analysis, binary logistic regression, stepwise linear regression, and principal component analysis were conducted to evaluate the association between fitness, BMI, gender, and the biochemical parameters.ResultsGirls and boys with HF presented lower waist circumference Z-score, BMI Z-score, systolic BP (only boys) as well as lower levels of leptin and NGF compared with their respective LF group. Regarding the association between variables, fitness showed an inverse relationship with BMI Z-score, leptin, PAI-1, HOMA-IR, resistin, IL-8, and NGF.ConclusionAn adequate level of fitness seems to protect against risk factors related to low-grade inflammation and altered adipokines that are related to the onset of obesity just from the prepubertal stage.

Background and AimThe association of a metabolically healthy status with the practice of physical activity (PA) remains unclear. Sedentarism and low PA have been linked to increased cardiometabolic risk. The aim of this study was to evaluate the PA levels in metabolically healthy (MH) or unhealthy (MU) prepubertal children with or without overweight/obesity.MethodsA total 275 children (144 boys) with 9 ± 2 years old were selected for the GENOBOX study. PA times and intensities were evaluated by accelerometry, and anthropometry, blood pressure, and blood biochemical markers were analyzed. Children were considered to have normal weight or obesity, and further classified as MH or MU upon fulfillment of the considered metabolic criteria.ResultsClassification resulted in 119 MH children (21% with overweight/obesity, referred to as MHO) and 156 MU children (47% with overweight/obesity, referred to as MUO). Regarding metabolic profile, MHO showed lower blood pressure levels, both systolic and diastolic and biochemical markers levels, such as glucose, Homeostatic Model Assessment of Insulin Resistance, triglycerides and higher HDL-c levels than MUO (P < 0.001). In addition, MHO children spent more time in PA of moderate intensity compared with MUO children. In relation to vigorous PA, MH normal weight (MHN) children showed higher levels than MUO children. Considering sex, boys spent more time engaged in moderate, vigorous, and moderate–vigorous (MV) PA than girls, and the number of boys in the MH group was also higher.ConclusionPrepubertal MHO children are less sedentary, more active, and have better metabolic profiles than their MUO peers. However, all children, especially girls, should increase their PA engagement, both in terms of time and intensity because PA appears to be beneficial for metabolic health status itself.

Abstract Background Alpha-mannosidosis is a lysosomal storage disorder caused by reduced enzymatic activity of alpha-mannosidase. SPARKLE is an alpha-mannosidosis registry intended to obtain long-term safety and effectiveness data on the use of velmanase alfa during routine clinical care in patients with alpha-mannosidosis. It is a post-approval commitment to European marketing authorization for Velmanase alfa (Lamzede®), the first enzyme replacement therapy for the treatment of non-neurologic manifestations in patients with mild to moderate alpha-mannosidosis. In addition, SPARKLE will expand the current understanding of alpha-mannosidosis by collecting data on the clinical manifestations, progression, and natural history of the disease in treated and untreated patients, respectively. Results The SPARKLE registry is designed as a multicenter, multinational, noninterventional, prospective cohort study of patients with alpha-mannosidosis, starting patient enrollment in 2020. Patients will be followed for up to 15 years. Safety and effectiveness as post-authorization outcomes under routine clinical care in patients with treatment will be evaluated. The primary safety outcomes are the rate of adverse events (anti-velmanase alfa-immunoglobulin G antibody development, infusion-related reactions, and hypersensitivity). Secondary safety outcomes include the evaluation of medical events, change in vital signs, laboratory tests, physical examination, and electrocardiogram results. The primary effectiveness outcome is a global treatment response rate, evaluated as the individual aggregate of single endpoints from pharmacodynamic, functional, and quality-of-life effectiveness outcomes; secondary effectiveness outcomes are to characterize the population of patients with alpha-mannosidosis with regard to clinical manifestation, progression, and natural history of the disease. Any patient in the European Union with a diagnosis of alpha-mannosidosis who is willing to participate will likely be eligible for inclusion in the registry. Publications to disseminate scientific insights from the registry are planned. Conclusion This study will provide real-world data on the long-term safety and effectiveness of velmanase alfa in patients with alpha-mannosidosis during routine clinical care and increase the understanding of the natural course, clinical manifestations, and progression of this ultra-rare disease.

Abstract Background The pathophysiological etiologies related with the development of Autism Spectrum Disorders (ASD) remain controversial. Different authors have studied neurotoxins such as mercury (Hg) and their relationship with ADS. The objective of this study was to assess the levels of Hg in hair in a group of ASD children (chronic exposure) and in urinary excretion (acute exposure), in comparison to a healthy group. Methods A case-control study was conducted in Spanish children. We compared 54 ASD children (aged 2–6) with no other associated pathology to a normally-developing control group (54 subjects). Results There were no differences in urine (p:0.631) and hair (p:1.000) samples percentages below the limits of detection between the control and the ASD groups, and also between patients in the regression ASD subgroup (AMR) (p:0.08) and the non-regression ASD subgroup (ANMR) (p:0.705). When the analysis was adjusted for age and sex, the differences between Hg levels maintained not significant. There were no correlations between Hg concentrations in the ASD group as a whole (p: 0.739), or when they were subdivided into ASD-AMR (p: 0.739) and ASD-ANMR (p: 0.363). Conclusions The present study shows no evidence in our geographical area to support an association between mercury neurotoxicity and the etiopathogenesis of ASD.

BackgroundThe pathogenesis of autism spectrum disorder (ASD) is under investigation and one of the main alterations relates to the metabolic and inflammatory system dysfunctions. Indeed, based on a possible deficit of omega-3 fatty acids (FAs) of patients with ASD and looking for an anti-inflammatory effect, dietary supplements with omega-3 fatty acids have been proposed. We aimed to evaluate differences in plasma and erythrocyte FA profiles and plasma cytokines in patients with infantile ASD after supplementation with docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids or placebo and both compared at baseline with a reference healthy group.MethodsA double-blind, randomized placebo-controlled intervention with DHA/EPA for 6 months was carried out in 54 children between 2 and 6 years diagnosed with ASD. They were selected and randomly assigned into two groups: 19 children received 800 mg/day of DHA and 25 mg/day of EPA, or placebo. In addition, another reference group of 59 healthy children of the same age was included. Plasma lipids and cytokines, and FA profiles in plasma and erythrocytes were measured at baseline and after 6 months of treatment in ASD children, and at baseline in the reference group.ResultsThere were no differences in demographic, anthropometric characteristics, and omega-3 intake between the healthy reference group and the ASD children at baseline. Children with ASD showed the higher plasma percentages of palmitic acid and total saturated FA and lower total omega-6 polyunsaturated FA (PUFA) compared with healthy children. An increased level of DHA and reduced EPA level in erythrocytes were detected in the ASD group vs. the reference group. After 6 months of treatment, the ASD group that received DHA enriched product significantly increased the plasma and erythrocyte percentages of DHA, but no differences were observed in the clinical test scores and other parameters as plasma cytokines between the two groups of ASD related to the intervention.ConclusionSpanish children with ASD exhibit an appropriate omega-3 FA status in plasma and erythrocytes. Neither a clinical improvement of ASD children nor a better anti-inflammatory or fatty acid state has been found after an intervention with DHA/EPA for 6 months. So, the prescription of n-3 LC-PUFA and other dietary supplements in ASD should be only indicated after a confirmed alteration of FA metabolism or omega-3 LC-PUFA deficiency evaluated by specific erythrocyte FA.Clinical Trial Registration[www.ClinicalTrials.gov], identifier [NCT03620097].

Introduction: An impaired antioxidant status has been described during foetal growth restriction (FGR). Similarly, the antioxidant defence system can be compromised in preterm children with extrauterine growth restriction (EUGR). The aim of this prospective study was to evaluate the antioxidant status in prepubertal children with a history of prematurity without FGR, with and without EUGR, compared to a healthy group.Methods: In total, 211 children were recruited and classified into three groups: 38 with a history of prematurity and EUGR; 50 with a history of prematurity and adequate extrauterine growth (AEUG); and 123 control children born at term. Catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GR) activities were assessed in lysed erythrocytes with spectrophotometric methods. Plasma levels of the antioxidants α-tocopherol, retinol and β-carotene were determined through solvent extraction and ultra-high-pressure liquid chromatography coupled to mass spectrometry.Results: Children with the antecedent of EUGR and prematurity had lower CAT activity than the other two groups and lower GPx activity than the control children. Lower SOD, GPx and GR activities were observed in the AEUG group compared to the controls. However, higher concentrations of α-tocopherol and β-carotene were found in the EUGR group compared to the other groups; retinol levels were also higher in EUGR than in AEUG children. In EUGR and AEUG children, enzymatic antioxidant activities and plasma antioxidants were associated with metabolic syndrome components and pro-inflammatory biomarkers.Conclusions: This study reveals, for the first time, that the EUGR condition and prematurity appear to be linked to an impairment of the antioxidant defence status, which might condition an increased risk of adverse metabolic outcomes later in life.

The goal of this investigation was to determine whether there are alterations in DNA methylation patterns in children with autism spectrum disorder (ASD).Material and Methods: Controlled prospective observational case-control study. Within the ASD group, children were sub-classified based on the presence (AMR subgroup) or absence (ANMR subgroup) of neurodevelopmental regression during the first 2 years of life. We analyzed the global levels of DNA methylation, reflected in LINE-1, and the local DNA methylation pattern in two candidate genes, Neural Cell Adhesion Molecule (NCAM1) and Nerve Growth Factor (NGF) that, according to our previous studies, might be associated to an increased risk for ASD. For this purpose, we utilized blood samples from pediatric patients with ASD (n = 53) and their corresponding controls (n = 45).Results: We observed a slight decrease in methylation levels of LINE-1 in the ASD group, compared to the control group. One of the CpG in LINE-1 (GenBank accession no.X58075, nucleotide position 329) was the main responsible for such reduction, highly significant in the ASD subgroup of children with AMR (p < 0.05). Furthermore, we detected higher NCAM1 methylation levels in ASD children, compared to healthy children (p < 0.001). The data, moreover, showed higher NGF methylation levels in the AMR subgroup, compared to the control group and the ANMR subgroup. These results are consistent with our prior study, in which lower plasma levels of NCAM1 and higher levels of NGF were found in the ANMR subgroup, compared to the subgroup that comprised neurotypically developing children.Conclusions: We have provided new clues about the epigenetic changes that occur in ASD, and suggest two potential epigenetic biomarkers that would facilitate the diagnosis of the disorder. We similarly present with evidence of a clear differentiation in DNA methylation between the ASD subgroups, with or without mental regression.

Resumen: Introducción: Las enfermedades raras suponen un reto para la salud pública debido a la escasa información sobre su magnitud. Entre ellas destacan los errores congénitos del metabolismo. El presente estudio pretende valorar la calidad de vida y las posibles necesidades sanitarias, socioeducativas y económicas de los pacientes pediátricos con diagnóstico de ER de tipo metabólico y de sus familiares o cuidadores principales, atendidos habitualmente en un hospital de tercer nivel. Material y método: Se desarrolló un cuestionario basado en las necesidades y expectativas recogidas fundamentalmente en el Plan Andaluz para las Enfermedades Raras. Se analizaron variables de los órdenes sociosanitario, económico y educativo en 65 pacientes pediátricos con errores congénitos del metabolismo. Resultados: Los encuestados manifestaron escasas posibilidades para afrontar el gasto de la medicación (61%), alimentación especial (86%) y otras prestaciones sanitarias (79%). El 43% consideraron que la calidad de vida familiar se afectó bastante desde la aparición de la enfermedad. En el 61,5% la cuidadora principal fue la madre, frente al 1,5% de casos en los que fue el padre. El cuidador principal redujo su jornada laboral o abandonó su trabajo en el 77% de los casos. Conclusiones: El tratamiento multidisciplinar se ve afectado por la imposibilidad de las familias para hacer frente a su elevado coste, junto a una difícil accesibilidad a dichos recursos. Además, existe gran repercusión en la calidad de vida de los pacientes y sus cuidadores. Por tanto, deberían evaluarse los resultados de los planes gubernamentales de apoyo sanitario y socioeconómico a pacientes con enfermedades raras, y conseguir una respuesta real a sus necesidades. Abstract: Introduction: Rare diseases are a challenge for public health due to the lack of information on their magnitude. These include inborn errors of metabolism. The objective of this study was to assess the quality of life and social, health, economic, and educational needs of a group of paediatric patients with inborn errors of metabolism attended to in a hospital. Material and method: A questionnaire was developed based on the needs and expectations, based mainly on the Andalusian Plan for Rare Diseases. An analysis was performed on the variables of health, socioeconomic, and educational needs of 65 paediatric patients with inborn errors of metabolism. Results: The respondents showed few possibilities to cope with medication (61%), special diet (86%), and other health benefits (79%). Just under half of them (43%) believed that the quality of family life had been greatly reduced since the onset of the disease. The main caregiver was the mother in 61.5% of cases, compared to 1.5% of cases in which it was the father. The primary caregivers had to reduce their working hours or give up their job in 77% of cases. Conclusions: The multidisciplinary treatment is affected by the inability of families to cope with a high cost, as well as with difficult access to these resources. In addition, there is great impact on the quality of life of patients, and their caregivers. Therefore, there is a need to evaluate the results of government health and socio-economic support plans for patients with rare diseases, and make a real response to their needs.

Introduction: Rare diseases are a challenge for public health due to the lack of information on their magnitude. These include inborn errors of metabolism. The objective of this study was to assess the quality of life and social, health, economic, and educational needs of a group of paediatric patients with inborn errors of metabolism attended to in a hospital. Material and method: A questionnaire was developed based on the needs and expectations, based mainly on the Andalusian Plan for Rare Diseases. An analysis was performed on the variables of health, socioeconomic, and educational needs of 65 paediatric patients with inborn errors of metabolism. Results: The respondents showed few possibilities to cope with medication (61%), special diet (86%), and other health benefits (79%). Just under half of them (43%) believed that the quality of family life had been greatly reduced since the onset of the disease. The main caregiver was the mother in 61.5% of cases, compared to 1.5% of cases in which it was the father. The primary caregivers had to reduce their working hours or give up their job in 77% of cases. Conclusions: The multidisciplinary treatment is affected by the inability of families to cope with a high cost, as well as with difficult access to these resources. In addition, there is great impact on the quality of life of patients, and their caregivers. Therefore, there is a need to evaluate the results of government health and socio-economic support plans for patients with rare diseases, and make a real response to their needs. Resumen: Introducción: Las enfermedades raras suponen un reto para la salud pública debido a la escasa información sobre su magnitud. Entre ellas destacan los errores congénitos del metabolismo. El objetivo de este estudio fue valorar la calidad de vida y las posibles necesidades de un grupo de pacientes pediátricos con errores congénitos del metabolismo asistidos en un hospital de tercer nivel, y de sus familiares o cuidadores principales. Material y método: Se desarrolló un cuestionario basado en las necesidades y expectativas recogidas fundamentalmente en el Plan Andaluz para las Enfermedades Raras. Se analizaron variables de los órdenes sociosanitario, económico y educativo en 65 pacientes pediátricos con errores congénitos del metabolismo. Resultados: Los encuestados manifestaron escasas posibilidades para afrontar el gasto de la medicación (61%), alimentación especial (86%) y otras prestaciones sanitarias (79%). El 43% consideraron que la calidad de vida familiar se afectó bastante desde la aparición de la enfermedad. En el 61,5% la cuidadora principal fue la madre, frente al 1,5% de casos en los que fue el padre. El cuidador principal redujo su jornada laboral o abandonó su trabajo en el 77% de los casos. Conclusiones: El tratamiento multidisciplinar se ve afectado por la imposibilidad de las familias para hacer frente a su elevado coste, junto a una difícil accesibilidad a dichos recursos. Además, existe gran repercusión en la calidad de vida de los pacientes y sus cuidadores. Por tanto, deberían evaluarse los resultados de los planes gubernamentales de apoyo sanitario y socioeconómico a pacientes con enfermedades raras, y conseguir una respuesta real a sus necesidades.

This study examined the presence of neurodevelopmental regression and its effects on the clinical manifestations and the severity of autism spectrum disorder (ASD) in a group of children with autism compared with those without neurodevelopmental regression at the time of initial classification and subsequently.Methods and Subjects: ASD patients were classified into two subgroups, neurodevelopmental regressive (AMR) and non-regressive (ANMR), using a questionnaire based on the Autism Diagnostic Interview-Revised test. The severity of ASD and neurodevelopment were assessed with the Childhood Autism Rating Scale Test-2, Strengths and Difficulties Questionnaire, and Pervasive Developmental Disorders Behavior Inventory Parent Ratings (PDDBI) and with the Battelle Developmental Inventory tests at the beginning of the study and after 24 months of follow-up. Fifty-two patients aged 2–6 years with ASD were included. Nineteen were classified with AMR, and 33 were classified with ANMR.Results: The AMR subgroup presented greater severity of autistic symptoms and higher autism scores. Additionally, they showed lower overall neurodevelopment. The AMR subgroup at 24 months had poorer scores on the Battelle Developmental Inventory test in the following areas: Total personal/social (p < 0.03), Total Motor (p < 0.04), Expressive (p < 0.01), and Battelle Total (p < 0.04). On the PDDBI test, the AMR subgroup had scores indicating significantly more severe ASD symptoms in the variables: ritual score (p < 0.038), social approach behaviors (p < 0.048), expressive language (p < 0.002), and autism score (p < 0.003).Conclusions: ASD patients exhibited a set of different neurological phenotypes. The AMR and ANMR subgroups presented different clinical manifestations and prognoses in terms of the severity of autistic symptoms and neurodevelopment.

Introduction: Prematurity, a well-established risk factor for various intestinal diseases in newborns, results in increased morbidity and mortality. However, the intestinal inflammatory status of preterm (PT) infants has been poorly characterized. Here we have broadly described the intestinal and systemic inflammatory status of PT children.Materials and Methods: Meconium and plasma from 39 PT and 32 full term (T) newborns were studied. Fecal calprotectin, polymorphonuclear leukocyte elastase (PMN-E), TNF, IL-17A, IL-8, IP-10, MCP-1, MIP-1, IL-1β, IL-1α, and E-selectin and the enzymatic activities of myeloperoxidase (MPO) and alkaline phosphatase (AP) in meconium were measured. Plasma levels of AP, hepatocyte growth factor, nerve growth factor (NGF), proinflammatory cytokines, leptin, adiponectin, PAI-1, and resistin were also determined. Correlations with gestational age (GA) and birth weight (BW) were studied.Results: Neutrophil derived PMN-E, MPO and calprotectin were increased in the meconium of PT compared to T newborns, while AP was decreased. No significant differences were found in other inflammatory parameters. Considering data from all children, GA and BW showed inverse correlation with neutrophil markers, while AP directly correlated with BW. Plasma levels of IL-1β and NGF were enhanced in PT infants, and were also negatively correlated with BW. PT children additionally showed neutropenia and decreased adiponectin, leptin, haematocrit, and haemoglobin. These parameters (neutrophils, adiponectin, and so forth) were positively correlated with GA and BW, while IL-8, MCP-1, PAI-1, and plasma AP were negatively correlated. PT children showing postnatal morbidity exhibited increased meconium MPO and MIP-1α.Conclusion: PT neonates present a significant elevation of intestinal inflammatory parameters, characterized by the presence of neutrophil markers, associated with mild systemic inflammation.

Objectives: Alpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder resulting from deficient lysosomal alpha-mannosidase activity. Clinical manifestations include progressive balance disorders, immune deficiency, skeletal abnormalities and cognitive deficits beginning in early childhood. Enzyme replacement therapy with recombinant human alpha-mannosidase (velmanase alfa) is scheduled for clinical development in the US beginning in 2020 and has been approved in the EU for treatment of non-neurological manifestations in cases of mild to moderate disease. This study assessed effects of velmanase alfa on fine and gross motor proficiency in children and adults. Methods: Integrated Bruininks-Oseretsky (BOT-2) test of Motor Proficiency data from velmanase alfa clinical trials was stratified by age for 14 adults and 19 children treated for up to 4 years. Results: Patients showed global developmental delays at baseline. For the combined adult and pediatric group there was a statistically significant increase (improvement) in BOT-2 total point score of 13% (p = .035, 95% CI 1.0, 25.0) from baseline to last observation. When stratified by pediatric versus adult patients, there was improvement in BOT-2 total point score in patients

Introduction: An adipose tissue programming mechanism could be implicated in the extrauterine growth restriction (EUGR) of very preterm infants with morbidity in the cardiometabolic status later in life, as has been reported in intrauterine growth restriction. The aim of this study was to assess whether children with a history of prematurity and EUGR, but also with an adequate growth, showed alterations in the metabolic and inflammatory status.Methods: This was a case–control study. A total of 88 prepubertal children with prematurity antecedents were selected: 38 with EUGR and 50 with an adequate growth pattern (PREM group). They were compared with 123 healthy children born at term. Anthropometry, metabolic parameters, blood pressure (BP), C-reactive protein, hepatocyte growth factor (HGF), interleukin-6 (IL-6), IL-8, monocyte chemotactic protein type 1 (MCP-1), neural growth factor, tumour necrosis factor-alpha (TNF-α) and plasminogen activator inhibitor type-1 were analysed at the prepubertal age.Results: EUGR children exhibited higher BP levels and a higher prevalence of hypertension (46%) compared with both PREM (10%) and control (2.5%) groups. Moreover, there was a positive relationship between BP levels and values for glucose, insulin and HOMA-IR only in children with a EUGR history. The EUGR group showed higher concentrations of most of the cytokines analysed, markedly higher TNF-α, HGF and MCP-1 levels compared with the other two groups.Conclusion: EUGR status leads to cardiometabolic changes and a low-grade inflammatory status in children with a history of prematurity, and that could be related with cardiovascular risk later in life.

Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation.

Resumen: Introducción: La obesidad infantil es un problema de salud de alta prevalencia. Aunque existen guías clínicas para su manejo, la variabilidad en su abordaje clínico es un hecho. El objetivo de este estudio es describir la práctica clínica habitual en unidades de Endocrinología Pediátrica y evaluar su adecuación a la guía recomendada. Material y métodos: Se realizó un estudio observacional, transversal y descriptivo mediante encuesta a endocrinólogos infantiles de la Sociedad Española de Endocrinología Pediátrica. Las preguntas fueron formuladas en base a las recomendaciones de la «Guía de Práctica Clínica sobre la Prevención y el Tratamiento de la Obesidad Infantojuvenil» del Ministerio de Sanidad español. Resultados: Se obtuvieron 125 encuestas de todas la Comunidades Autónomas. Se observó variabilidad en el número de pacientes atendidos al mes y en la frecuencia de las visitas. El 70% de los encuestados no dispone de un nutricionista ni de psicólogo o psiquiatra al que derivar a los pacientes. En el tratamiento, las medidas dietéticas son las más empleadas; un 69% nunca ha prescrito fármacos para perder peso. De los que prescriben, el 52,6% no utilizan el consentimiento informado como paso previo a su empleo. Conclusiones: Pocos centros cumplen las recomendaciones de la Guía de Práctica Clínica sobre la Prevención y el Tratamiento de la Obesidad Infantil en un plan de calidad establecido. La práctica clínica difiere mucho entre los endocrinólogos pediátricos encuestados, sin existir protocolos unificados de actuación, y con escasa disponibilidad de recursos para el tratamiento integral que precisa esta enfermedad. Abstract: Introduction: Childhood obesity is a high prevalence health problem. Although there are clinical guidelines for its management, there is variability in its clinical approach. The aim of this study is to describe the usual clinical practice in Paediatric Endocrinology Units in Spain and to evaluate if it resembles the recommended guidelines. Material and methods: An observational, cross-sectional and descriptive study was carried out by means of a questionnaire sent to paediatric endocrinologists of the Spanish Society of Paediatric Endocrinology. The questions were formulated based on the recommendations of “Clinical Practice Guidelines on the Prevention and Treatment of Childhood Obesity” issued by the Spanish Ministry of Health. Results: A total of 125 completed questionnaires were obtained from all Autonomous Communities. Variability was observed both in the number of patients attended and in the frequency of the visits. The majority (70%) of the paediatricians who responded did not have a dietitian, psychologist or psychiatrist, in their centre to share the treatment for obese children. As regards treatment, dietary advice is the most used, and 69% have never prescribed weight-loss drugs. Of those who have prescribed them, 52.6% did not use informed consent as a prior step to them being used. Conclusions: There are few centres that comply with the recommendations of the clinical practice guidelines on prevention and treatment of childhood obesity as an established quality plan. Clinical practice differs widely among the paediatric endocrinologists surveyed. There are no uniform protocols of action, and in general there is limited availability of resources for the multidisciplinary treatment required by this condition.

Introduction: Childhood obesity is a high prevalence health problem. Although there are clinical guidelines for its management, there is variability in its clinical approach. The aim of this study is to describe the usual clinical practice in Paediatric Endocrinology Units in Spain and to evaluate if it resembles the recommended guidelines. Material and methods: An observational, cross-sectional and descriptive study was carried out by means of a questionnaire sent to paediatric endocrinologists of the Spanish Society of Paediatric Endocrinology. The questions were formulated based on the recommendations of “Clinical Practice Guidelines on the Prevention and Treatment of Childhood Obesity” issued by the Spanish Ministry of Health. Results: A total of 125 completed questionnaires were obtained from all Autonomous Communities. Variability was observed both in the number of patients attended and in the frequency of the visits. The majority (70%) of the paediatricians who responded did not have a dietitian, psychologist or psychiatrist, in their centre to share the treatment for obese children. As regards treatment, dietary advice is the most used, and 69% have never prescribed weight-loss drugs. Of those who have prescribed them, 52.6% did not use informed consent as a prior step to them being used. Conclusions: There are few centres that comply with the recommendations of the clinical practice guidelines on prevention and treatment of childhood obesity as an established quality plan. Clinical practice differs widely among the paediatric endocrinologists surveyed. There are no uniform protocols of action, and in general there is limited availability of resources for the multidisciplinary treatment required by this condition. Resumen: Introducción: La obesidad infantil es un problema de salud de alta prevalencia. Aunque existen guías clínicas para su manejo, la variabilidad en su abordaje clínico es un hecho. El objetivo de este estudio es describir la práctica clínica habitual en unidades de Endocrinología Pediátrica y evaluar su adecuación a la guía recomendada. Material y métodos: Se realizó un estudio observacional, transversal y descriptivo mediante encuesta a endocrinólogos infantiles de la Sociedad Española de Endocrinología Pediátrica. Las preguntas fueron formuladas en base a las recomendaciones de la «Guía de Práctica Clínica sobre la Prevención y el Tratamiento de la Obesidad Infantojuvenil» del Ministerio de Sanidad español. Resultados: Se obtuvieron 125 encuestas de todas la Comunidades Autónomas. Se observó variabilidad en el número de pacientes atendidos al mes y en la frecuencia de las visitas. El 70% de los encuestados no dispone de un nutricionista ni de psicólogo o psiquiatra al que derivar los pacientes. En el tratamiento, las medidas dietéticas son las más empleadas; un 69% nunca ha prescrito fármacos para perder peso. De los que prescriben, el 52,6% no utilizan el consentimiento informado como paso previo a su empleo. Conclusiones: Pocos centros cumplen las recomendaciones de la Guía de Práctica Clínica sobre la Prevención y el Tratamiento de la Obesidad Infantil en un plan de calidad establecido. La práctica clínica difiere mucho entre los endocrinólogos pediátricos encuestados, sin existir protocolos unificados de actuación, y con escasa disponibilidad de recursos para el tratamiento integral que precisa esta enfermedad.

The World Health Organization has recommended performing at least 60 min a day of moderate-to-vigorous physical activity (MVPA) and reducing sedentarism in children and adolescents to offer significant health benefits and mitigate health risks. Physical fitness and sports practice seem to improve oxidative stress (OS) status during childhood. However, to our knowledge, there are no data regarding the influence of objectively-measured physical activity (PA) and sedentarism on OS status in children and adolescents. The present study aimed to evaluate the influence of moderate and vigorous PA and sedentarism on OS and plasma total antioxidant capacity (TAC) in a selected Spanish population of 216 children and adolescents from the GENOBOX study. PA (light, moderate, and vigorous) and sedentarism (i.e., sedentary time (ST)) were measured by accelerometry. A Physical Activity-Sedentarism Score (PASS) was developed integrating moderate and vigorous PA and ST levels. Urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and isoprostane F2α (F2-IsoPs), as markers of OS, were determined by ELISA; and TAC was estimated by colorimetry using an antioxidant kit. A higher PASS was associated with lower plasma TAC and urinary 8-OHdG and F2-IsoPs, showing a better redox profile. Reduced OS markers (8-OHdG and F2-IsoPs) in children with higher PASS may diminish the need of maintaining high concentrations of antioxidants in plasma during rest to achieve redox homeostasis.

Background: Asthma is a multifactorial condition where patients with identical clinical diagnoses do not have the same clinical history or respond to treatment. This clinical heterogeneity is reflected in the definition of two main endotypes. We aimed to explore the metabolic and microbiota signatures that characterize the clinical allergic asthma phenotype in obese children. Methods: We used a multi-omics approach combining clinical data, plasma and fecal inflammatory biomarkers, metagenomics, and metabolomics data in a cohort of allergic asthmatic children. Results: We observed that the obese allergic asthmatic phenotype was markedly associated with higher levels of leptin and lower relative proportions of plasma acetate and a member from the Clostridiales order. Moreover, allergic children with a worse asthma outcome showed higher levels of large unstained cells, fecal D lactate and D/L lactate ratio, and with a higher relative proportion of plasma creatinine and an unclassified family member from the RF39 order belonging to the Mollicutes class. Otherwise, children with persistent asthma presented lower levels of plasma citrate and dimethylsulfone. Conclusion: Our integrative approach shows the molecular heterogeneity of the allergic asthma phenotype while highlighting the use of omics technologies to examine the clinical phenotype at a more holistic level.

Oxidative stress could help explain the relationship between childhood obesity and a metabolically unhealthy (MU) status. Moreover, puberty could also influence this relationship, since it entails physiological cardiometabolic changes. We aimed to evaluate plasma antioxidants and oxidative stress biomarkers in MU and metabolically healthy (MH) prepubertal and pubertal children and their associations with pro-inflammatory and endothelial damage biomarkers, taking puberty into account. A total of 1444 Spanish children aged 3–17 years (48.9% males, 66% prepubertal, 47.1% with obesity) were recruited. Blood pressure, anthropometric and biochemical parameters were measured, and children were categorized as having a MU or MH status according to risk factors. Retinol, carotenes, tocopherols, total antioxidant capacity (TAC), oxidized low-density lipoprotein and selected pro-inflammatory and endothelial damage biomarkers were analyzed. General linear models adjusted for age, sex, recruitment center and body mass index, partial correlations and stepwise linear regressions were performed. Lower carotenes and tocopherols levels were found in MU than in MH children. Plasma TAC was lower in prepubertal and higher in pubertal children with obesity compared to normal-weight children. Antioxidants and oxidative stress biomarkers showed novel associations with several pro-inflammatory and endothelial damage biomarkers, with pubertal differences, supporting the importance of considering both the antioxidant and oxidative stress status and puberty in the prevention of metabolic diseases in childhood.

Background: In the etiopathogenesis of autism spectrum disorder (ASD), it has been suggested that a proinflammatory condition, as well as an alteration in adhesion molecules in the early stages of neurodevelopment, may play a role in the pathophysiology of the disorder. This study set out to evaluate the plasma levels of certain inflammatory cytokines, adhesion molecules, and growth factors in a sample of pediatric patients with ASD and compare them to the levels in a control group of healthy children.Methods: Fifty-four children (45 males and nine females) aged 2-6, who were diagnosed with ASD, and a control group of 54 typically-developing children of similar ages were selected. The diagnosis of ASD was carried out in accordance with the DSM-5 criteria and the data obtained from a developmental semi-structured clinical interview and the ADOS evaluation test. Additional testing was carried out to identify the children's developmental level and severity of ASD symptomatology. Patients with ASD were further divided into two subgroups based on developmental parameters: ASD children with neurodevelopmental regression (AMR) and ASD children without neurodevelopmental regression (ANMR). Analyses of plasma molecules, such as cathepsin, IL1β, IL6, IL8, MPO, RANTES, MCP, BDNF, PAI NCAM, sICAM, sVCAM and NGF, were performed.Results: Higher levels of NGF were observed in the ASD group compared with the levels in the control group (p < 0.05). However, in the analysis of the ASD subgroups, lower plasma levels of NCAM and higher levels of NGF were found in the group of ASD children without developmental regression compared to the levels in the group of typically-developing children.Conclusions: These results suggest differences that could be related to different pathophysiological mechanisms in ASD. There is not a specific profile for the expression of relevant plasma cytokines, adhesion molecules or growth factors in children with ASD compared with that in typically-developing children. However, in the ANMR and AMR subgroups, some of the adhesion molecules and neuronal growth factors show differences that may be related to synaptogenesis.

Alpha-mannosidosis, a rare lysosomal storage disorder caused by deficiency of the lysosomal enzyme alpha-mannosidase, results in accumulation of mannose-rich glycoproteins in the tissues and sequelae leading to intellectual disability, ataxia, impaired hearing and speech, recurrent infections, skeletal abnormalities, muscular pain, and weakness. This study aimed to investigate disability, pain, and overall health using the Childhood Health Assessment Questionnaire (CHAQ) and the EuroQol 5 Dimension-5 Level Questionnaire (EQ-5D-5L) in patients with alpha-mannosidosis participating in rhLAMAN-10, a phase III open-label, clinical trial of velmanase alfa, a recombinant human lysosomal alpha-mannosidase. Long-term prognoses for most patients with untreated alpha-mannosidosis are poor due to progressive neuromuscular, skeletal, and intellectual deterioration, leading to increased dependence in mobility and activities of daily living and increased caregiver and health-care burden. Long-term CHAQ and EQ-5D-5L data highlight improvement trends in health-related quality of life and a reduction in disability and pain in patients receiving up to 48 months of velmanase alfa treatment.

ResumenEl ejercicio físico puede producir estrés oxidativo en el individuo lo que pueden condicionar el riesgo cardiovascular en niños y adolescentes. Este estudio pretende analizar el estrés oxidativo según la fuerza muscular isométrica de las extremidades superiores en la edad pediátrica. Se estudiaron 70 niños sanos con edades entre 10 y 14 años, y se analizaron en saliva los lipoperóxidos (LPO), el glutatión reducido (GSH), la ratio GSH/LPO y la catalasa, como marcadores de estrés oxidativo. La muestra se dividió en dos grupos según una condición física superior o inferior medida a través de dinamometría manual (TKK 5110); se diferenció la serie en sujetos prepuberales y puberales. Se encontraron niveles significativamente inferiores de GSH y GSH/LPO en el grupo de niños con fuerza superior, y en los puberales con la mismas características; estos resultados podrían indicar la existencia de un mayor estrés oxidativo en esta situación. En conclusión, los mayores niveles de fuerza músculo esquelética, medida a través de dinamometría manual, posiblemente pueden estar asociados a un mayor estrés oxidativo en niños púberes con condición física musculoesquelética superior.AbstractPhysical exercise can produce oxidative stress, this situation could contribute cardiovascular risk in children and adolescents. The following study tries to evaluate the oxidative stress produced according to the handgrip strength in infancy. 70 healthy male subjects, ages 10 to 14 years, were studied. In the saliva samples, lipoperoxides (LPO), reduced glutathione (GSH), glutathione/lipoperoxides ratio and catalase were analyzed as biomarkers of oxidative stress. Children were divided into two groups according to their handgrip strength (high or low) measured by handgrip strength (TKK 5110). The groups were also divided into prepubertal and pubertal subjects. We found GSH’s significantly low levels and of GSH/LPO in pubertal group with high handgrip strength. We could possibly conclude that the higher levels of handgrip strength could be associated with more oxidative stress in pubertal group with high fitness.doi:10.5232/ricyde2011.02205

Los objetivos de este estudio son, realizar una descripción de las características demográficas, antropométricas y de las alteraciones metabólicas de niños atendidos por obesidad resaltando las características aquellos casos de obesidad de inicio temprano (< 10 años) y los de inicio precoz (< 5 años), y evaluar la capacidad diagnóstica de la definición de síndrome metabólico (SM) según diferentes criterios. Métodos: Es un estudio retrospectivo, caso-control, transversal, multicéntrico. Han participado un total de 10 Unidades de Endocrinología Pediátrica de diferentes hospitales españoles con un grupo de 469 niños con obesidad de inicio temprano y otro grupo de 30 niños con obesidad de inicio precoz. El grupo control estuvo constituido por 224 niños sanos menores de 10 años. Se realizó una valoración antropométrica y determinación analítica de parámetros del metabolismo de los hidratos de carbono y lipidograma. Resultados: La presencia de alteraciones metabólicas asociadas a la obesidad en la etapa infanto-juvenil en España es notable, de forma aislada, o englobada bajo la definición de SM. La prevalencia de éste aumenta sustancialmente cuando se considera la resistencia periférica a la acción de la insulina como criterio diagnóstico. Se demuestra cómo en niños menores de 10 años, dichas alteraciones están presentes en un porcentaje reseñable, y se encuentran las primeras alteraciones metabólicas ya en niños obesos < 5 años. Conclusión: En los niños españoles existen alteraciones metabólicas asociadas a la obesidad en la etapa infanto-juvenil de forma aislada o englobada bajo la definición de SM, y ya están presentes a edades precoces.