Search

Patient registries for rare diseases enable systematic data collection and can also be used to facilitate post-authorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane®), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects (E-HOD) and the marketing authorization holder (MAH). Prospective data collection, 2013-2016, in a non-interventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. 130 individuals with vitamin B(6) non-responsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B(6) non-responsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 µmoL/L to 81 ± 51 µmoL/L (P < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals older than 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

INTRODUCTION: Neuronal Ceroid Lipofuscinosis (NCL) comprises a clinically and genetically heterogeneous group of 13 neurodegenerative lysosomal storage disorders. Neuronal Ceroid lipofuscinosis type 2 disease (NCL2), caused by the deficient lysosomal enzyme tripeptidyl peptidase 1 (TPP1), is the only one with an approved enzyme replacement treatment (ERT). Early initiation of ERT appears to modify significantly the natural history of the disease. We aimed to shorten the time to diagnosis of NCL2. METHODS: In March 2017, we started per first time in Spain a selective screening program, the LINCE project, in pediatric patients with clinical symptoms compatible with NCL2 disease. The program covered the whole country. We distributed kits to pediatricians with the necessary material to assess patients. All samples in this study were received within one week of collection. Enzymatic activity determined on dried blood spots was the main method used to screen for TPP1 and palmitoyl protein thioesterase 1 (PPT1) for the differential diagnosis with neuronal ceroid lipofuscinosis type 1 (NCL1). RESULTS: Over a period of three years, we received 71 samples. The analysis was minimally invasive, relatively cheap and fast-executing. Three cases identified as a direct result of the selective screening strategy were confirmed by genetic study of NCL2 disease with a median age of 4.5 years. Our screening method has a specificity of 100%, and, with the absence to date of false negatives. We did not detect any NCL1-positive cases. CONCLUSIONS: LINCE proved to be a simple, useful, and reliable tool for the diagnosis of NCL2, enabling clinicians to diagnose NCL2 faster. The presence of NCL2-positive cases in our population and availability of treatment may facilitate the inclusion of NCL2 in neonatal screening programs for early diagnosis.

Glucose transporter 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder caused by haploinsufficiency of the GLUT1 glucose transporter (encoded by SLC2A1) leading to defective glucose transport across the blood-brain barrier. This work describes the genetic analysis of 56 patients with clinical or biochemical GLUT1DS hallmarks. 55.4% of these patients had a pathogenic variant of SLC2A1, and 23.2% had a variant in one of 13 different genes. No pathogenic variant was identified for the remaining patients. Expression analysis of SLC2A1 indicated a reduction in SLC2A1 mRNA in patients with pathogenic variants of this gene, as well as in one patient with a pathogenic variant in SLC9A6, and in three for whom no candidate variant was identified. Thus, the clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1.

Mitochondrial functional integrity depends on protein and lipid homeostasis in the mitochondrial membranes and disturbances in their accumulation can cause disease. AGK, a mitochondrial acylglycerol kinase, is not only involved in lipid signaling but is also a component of the TIM22 complex in the inner mitochondrial membrane, which mediates the import of a subset of membrane proteins. AGK mutations can alter both phospholipid metabolism and mitochondrial protein biogenesis, contributing to the pathogenesis of Sengers syndrome. We describe the case of an infant carrying a novel homozygous AGK variant, c.518+1G>A, who was born with congenital cataracts, pielic ectasia, critical congenital dilated myocardiopathy, and hyperlactacidemia and died 20 h after birth. Using the patient's DNA, we performed targeted sequencing of 314 nuclear genes encoding respiratory chain complex subunits and proteins implicated in mitochondrial oxidative phosphorylation (OXPHOS). A decrease of 96-bp in the length of the AGK cDNA sequence was detected. Decreases in the oxygen consumption rate (OCR) and the OCR:ECAR (extracellular acidification rate) ratio in the patient's fibroblasts indicated reduced electron flow through the respiratory chain, and spectrophotometry revealed decreased activity of OXPHOS complexes I and V. We demonstrate a clear defect in mitochondrial function in the patient's fibroblasts and describe the possible molecular mechanism underlying the pathogenicity of this novel AGK variant. Experimental validation using in vitro analysis allowed an accurate characterization of the disease-causing variant.

Pain recognition and management continues to be a challenge for health professionals in Neonatal Intensive Care Units. They are routinely exposed to repeated painful experiences with demonstrated short- and long-term consequences. Preterm babies are a vulnerable high-risk population. Despite international recommendations, pain remains poorly assessed and managed in many Neonatal Intensive Care Units. Due to there being no general protocol, there is significant variability as regards the guidelines for the approach and treatment of pain between the different Neonatal Intensive Care Units. The objective of this article is to review and assess the general principles of pain in the initial stages of development, its recognition through the use of standardised scales. It also includes its prevention and management with the combination of pharmacological and non-pharmacological measures, as well as to establish recommendations that help alleviate pain in daily clinical practice by optimising pain and stress control in the Neonatal Intensive Care Units.

The first hours of life of a sick or premature newborn are crucial for its prognosis andtherefore delivery should take place in a center prepared for that degree of complexity. Whenthis condition is not met, the newborn must be transferred in an optimal and safe way to thecenter that can offer the necessary care. The training, staffing, organization and coordinationof the neonatal transport team are essential to guarantee a safe transfer. Being aware of theinterest and the advances that are currently taking place in this area of pediatrics, the StandardsCommission and the Neonatal Transport Commission of the Spanish Society of Neonatology haveprepared this document. In it, both the provision of human and material resources necessary aswell as the bases of clinical stabilization in transport to carry out the neonatal transfer in a safeway and proportionate to the needs of the critical newborn have been exhaustively reviewedand detailed. (C) 2021 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L.U.

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns.

Data are limited on the association between the use of donor human milk and improvements in feeding tolerance.

Patients with inborn errors of amino acid metabolism frequently show neuropsychiatric symptoms despite accurate metabolic control. This study aimed to gain insight into the underlying mechanisms of neural dysfunction. Here we analyzed the expression of brain-derived neurotrophic factor (BDNF) and 10 genes required for correct brain functioning in plasma and blood of patients with Urea Cycle Disorders (UCD), Maple Syrup Urine Disease (MSUD) and controls. Receiver-operating characteristic (ROC) analysis was used to evaluate sensitivity and specificity of potential biomarkers. CACNA2D2 (a2d2 subunit of voltage-gated calcium channels) and MECP2 (methyl-CpG binding protein 2) mRNA and protein showed an excellent neural function biomarker signature (AUC = 0,925) for recognition of MSUD. THBS3 (thrombospondin 3) mRNA and AABA gave a very good biomarker signature (AUC 0,911) for executive-attention deficits. THBS3, LIN28A mRNA, and alanine showed a perfect biomarker signature (AUC 1) for behavioral and mood disorders. Finally, a panel of BDNF protein and at least two large neural AAs showed a perfect biomarker signature (AUC 1) for recognition of psychomotor delay, pointing to excessive protein restriction as central causative of psychomotor delay. To conclude, our study has identified promising biomarker panels for neural function evaluation, providing a base for future studies with larger samples.

We describe the postnatal weight gain, linear and head growth trends of surviving preterm infants from 2005 to 2017.

Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 4.9 and 10.6 5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 4.43 vs 24.30 6.10; P = .08) and those with good pharmacological adherence (21.19 4.68 vs 28.58 213.79).intellectual quotient was =85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 GT.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.

Postnatal steroids, often used to prevent and treat bronchopulmonary dysplasia, may influence the growth of preterm infants, although data are scarce in the literature. This is a multicenter cohort study including surviving preterm infants 32 weeks at birth ( n = 17,621) from the Spanish Neonatal Network SEN1500 database, without major congenital malformations. Linear regression models were adjusted for postnatal steroids, respiratory severity course (invasive mechanical ventilation at 28 days), progression to moderate-severe bronchopulmonary dysplasia (O 2 at 36 weeks), length of stay, sex, gestational age and z-scores at birth. A subgroup analysis depending on the timing of administration, ventilation status at 28 days and moderate-severe BPD diagnosis was also performed. Overall, systemic postnatal steroids were not independently associated with poorer weight gain (0.1; 95% CI: -0.05 to 0.2 g/kg/day), linear growth (0; 95% CI: -0.03 to 0.01 cm/week) or head circumference growth (-0.01; 95% CI: -0.02 to 0 cm/week). Patients who received steroids after 28 days or who were not O 2 dependent at 36 weeks after having received steroids gained more weight (0.22; 95% CI: 0.04 to 0.4 and 0.2; 95% CI: 0.004 to 0.5 g/kg/day, respectively). Globally, systemic postnatal steroids had no significant adjusted effect on postnatal growth.

Hypophosphatasia is a very rare bone metabolism disorder caused by a deficiency in alkaline phosphatase activity, due to mutations in the ALPL gene. Its clinical hallmark is the impairment of skeletal and teeth mineralisation, although extra-skeletal manifestations are frequent. Its phenotypic spectrum is widely variable from a subtype with exclusive odontological impairment (odontohypophosphatasia) to five subtypes with systemic involvement, classified according to the age at the onset of the first symptoms (four of them in the paediatric age range: perinatal lethal, perinatal benign, infant and childhood hypophosphatasia). Those subtypes of hypophosphatasia with an earliest onset usually involve a worse prognosis, due to the risk of developing potentially lethal complications, such as seizures or severe respiratory insufficiency, secondary to rib cage malformations. Due to the extremely low prevalence of the severe forms of hypophosphatasia, its clinical variability and overlapping phenotypic features with several more prevalent conditions, the diagnosis of hypophosphatasia in the clinical setting is challenging. However, its potential lethality and impact on the patient's quality of life, along with the recent availability of an enzyme replacement therapy, increases the relevance of the early and accurate identification of patients affected with hypophosphatasia. On the basis of published evidence and clinical experience, this article suggests an algorithm with practical recommendations for the differential diagnosis of childhood hypophosphatasia, as well as an updated review of current therapeutic options.

Mucopolysaccharidosis IVA (Morquio A) is a rare inherited metabolic disease caused by deficiency of the lysosomal enzyme N-acetylgalatosamine-6-sulfate-sulfatase (GALNS). Until now, treatments employed included hematopoietic stem cell transplantation and enzyme replacement therapy (ERT), the latter being the most commonly used to treat mucopolysaccharidoses, but with serious disadvantages due to rapid degradation and clearance. The purpose of this study was to develop and evaluate the potential of nanostructured lipid carriers (NLCs) by encapsulating elosulfase alfa and preserving its enzyme activity, leading to enhancement of its biological effect in chondrocyte cells. A pegylated elosulfase alfa-loaded NLC was characterized in terms of size, &zeta, potential, structural lipid composition (DSC and XRD), morphology (TEM microscopy), and stability in human plasma. The final formulation was freeze-dried by selecting the appropriate cryoprotective agent. Viability assays confirmed that NLCs were non-cytotoxic to human fibroblasts. Imaging techniques (confocal and TEM) were used to assess the cellular uptake of NLCs loaded with elosulfase alfa. This study provides evidence that the encapsulated drug exhibits enzyme activity inside the cells. Overall, this study provides a new approach regarding NLCs as a promising delivery system for the encapsulation of elosulfase alfa or other enzymes and the preservation of its activity and stability to be used in enzymatic replacement therapy (ERT).

Oxidative phosphorylation dysfunction has been found in many different disorders. This biochemical pathway depends on mitochondrial protein synthesis. Thus, mutations in components of the mitochondrial translation system can be responsible for some of these pathologies. We identified a new homozygous missense mutation in the mitochondrial translation elongation factor Ts gene in a patient suffering from slowly progressive childhood ataxia and hypertrophic cardiomyopathy. Using cell, biochemical and molecular-genetic protocols, we confirm it as the etiologic factor of this phenotype. Moreover, as an important functional confirmation, we rescued the normal molecular phenotype by expression of the wild-type TSFM cDNA in patient's fibroblasts. Different TSFM mutations can produce the same or very different clinical phenotypes, going from abortions to moderately severe presentations. On the other hand, the same TSFM mutation can also produce same or different phenotypes within the same range of presentations, therefore suggesting the involvement of unknown factors.

The rapid analysis of genomic data is providing effective mutational confirmation in patients with clinical and biochemical hallmarks of a specific disease. This is the case for nonketotic hyperglycinemia (NKH), a Mendelian disorder causing seizures in neonates and early-infants, primarily due to mutations in the GLDC gene. However, understanding the impact of missense variants identified in this gene is a major challenge for the application of genomics into clinical practice. Herein, a comprehensive functional and structural analysis of 19 GLDC missense variants identified in a cohort of 26 NKH patients was performed. Mutant cDNA constructs were expressed in COS7 cells followed by enzymatic assays and Western blot analysis of the GCS P-protein to assess the residual activity and mutant protein stability. Structural analysis, based on molecular modeling of the 3D structure of GCS P-protein, was also performed. We identify hypomorphic variants that produce attenuated phenotypes with improved prognosis of the disease. Structural analysis allows us to interpret the effects of mutations on protein stability and catalytic activity, providing molecular evidence for clinical outcome and disease severity. Moreover, we identify an important number of mutants whose loss-of-functionality is associated with instability and, thus, are potential targets for rescue using folding therapeutic approaches.

Isovaleric acidemia (IVA) is a rare disorder of leucine metabolism. We carried out a multicenter study of IVA patients diagnosed by newborn screening (NBS) or symptoms clinics over a period of 28 years in Spain. Evaluated at diagnosis, data included age, detection method, levels of C5 and IVG, enzymatic studies, clinical presentation parameters and genotype in 16 patients. Follow-up data included C5 levels, intellectual quotient and correlation genotype-phenotype. IVA was detected by NBS in 8 patients (prevalence of 1/326 629). Except 1, all the 8 patients identified by NBS were asymptomatic at diagnosis and had isovalerylcarnitine (C5) levels of 1.6-6.4 mu M and isovalerylglycine (IVG) levels = 1.5 g kg(-1) per day. Symptomatic patients with chronic intermittent or acute neonatal IVA had C5 levels of 3.9-16.3 mu M and IVG levels >3400 mmol per mol creatinine. The percentage of isovalerate incorporation in fibroblasts was 64-80% in patients detected by NBS and 4.9-13% in symptomatic patients. Cognitive function was within normal ranges in all patients but was negatively correlated with IVG at detection (-0.592; P < 0.05). The genetic analysis revealed nine novel mutations. The clinical/biochemical phenotype correlated fairly well with the phenotype predicted by the mutations found. In conclusion, although blood C5 levels have traditionally been considered the prognostic marker of choice, urine IVG levels would appear to be a better predictor, as they correlated well with severity of mutations and were associated with a lower incorporation rate of IVA in fibroblasts and a less favorable clinical course.

The mucopolysaccharidoses (MPSs) are underdiagnosed but they are evaluated in few newborn screening programs, probably due to the many challenges remaining, such as the identification of late-onset phenotypes. Systematic screening at the onset of clinical symptoms could help to early identify patients who may benefit from specific treatments. The aim of this prospective study was to assess a novel selective screening program, the FIND project, targeting patients aged 0 to 16 years with clinical manifestations of MPS. The project was designed to increase awareness of these diseases among pediatricians and allow early diagnosis.From July 2014 to June 2016, glycosaminoglycan (GAG) levels normalized to creatinine levels were determined in urine-impregnated analytical paper submitted by pediatricians who had patients with clinical signs and/or symptoms compatible with MPS. When high GAG concentrations were detected, a new liquid urine sample was requested to confirm and identify the GAG present. When a specific form of MPS was suspected, enzyme activity was analyzed using blood-impregnated paper to determine MPS type (I, IIIB, IIIC, IVA, IVB, VI, or VII). Age-specific reference values for GAG were previously established using 145 urine samples from healthy children.GAG levels were normal in 147 (81.7%) of the 180 initial samples received. A liquid sample was requested for the other 33 cases (18.3%); GAG levels were normal in 13 of these and slightly elevated in 12, although the electrophoresis study showed no evidence of MPS. Elevated levels with corresponding low enzymatic activity were confirmed in 8 cases. The mean time from onset of clinical symptoms to detection of MPS was 22 months, and just 2 cases were detected at the beginning of the project were detected with 35 and 71 months of evolution of clinical symptoms. Our screening strategy for MPS had a sensitivity of 100%, a specificity of 85%, and a positive predictive value of 24%.The FIND project is a useful and cost-effective screening method for increasing awareness of MPS among pediatricians and enabling the detection of MPS at onset of clinical symptoms.

We report the case of a newborn with arthrogrypbsis multiplex congenita and severe axial hypotonia without cardiac involvement in which, using a customized targeted next-generation sequencing assay for 64 myopathy-associated genes, we detected a novel homozygous truncating mutation, c.38661_38665de1, in exon 197 of the TTN gene that is expressed only in the fetal skeletal isoform. Its pathogenicity is supported by evidence of maternal isodisomy for chromosome 2. Muscle pathology showed fibers with core-like areas devoid of oxidative staining and cytoplasmic bodies. Electron microscopy showed the replacement of the sarcomeric structure with filamentous material. Identification of this mutation expands the phenotypic spectrum of the TTN gene and shows for the first time that a mutation not found in adult TTN isoforms is involved in the development of a neuromuscular disorder. TTN mutations should be considered in all severe congenital myopathies with arthrogryposis without cardiac involvement. (C) 2016 Elsevier B.V. All rights reserved.

The KCNQ2 gene codifies a subunit of the voltage-gated potassium M channel underlying the neuronal M-current. Classically, mutations in this gene have been associated with benign familial neonatal seizures, however, in recent years KCNQ2 mutations have been reported associated to early-onset epileptic encephalopathy. In this work, detailed familiar, clinical and genetic data were collected for 13 KCNQ2-positive patients revealed among a cohort of 80 epileptic pediatric probands from Spain who were analyzed through a targeted next-generation sequencing assay for 155 epilepsy-associated genes. This work shows for the first time the association between KCNQ2 mutations and startle attacks in 38% of patients, which opens the possibility to define electroclinical phenotypes associated to KCNQ2 mutations. It also demonstrates that KCNQ2 mutations contribute to an important percentage of Spanish patients with epilepsy. The study confirm the high genetic heterogeneity of this gene with 13 different mutations found, 10 of them novel and the better outcome of patients treated with sodium channel blockers.

BACKGROUND AND OBJECTIVE: The transition process from paediatric to adult care is a subject of great interest in recent years, especially in chronic diseases with childhood onset, such as inborn errors of metabolism (IEM). Advances in diagnosis and treatment of these diseases have improved their prognosis, with a high number of patients with IEM who currently reach adult age and need to be attended to by non-paediatric professionals. The objective of this work is to establish action guidelines so that the specialists involved can guarantee a successful transition of these patients' healthcare. METHODOLOGY: After carrying out a bibliographic review of the subject, the authors, beginning with their own experience, produced an initial document which was subjected to successive debates until the final document was obtained. The consensus recommendation was decided by the majority in case of criterion discrepancy. RESULTS: A series of recommendations are presented for the best clinical management of the transitions of care of patients with IEM from the paediatric to adult care setting in order to achieve the best results in this process given the special characteristics of this patient subgroup and the main difficulties entailed in the transition process. CONCLUSIONS: The role of the internal medicine doctor in this transition process and correct interrelation with the paediatric and social setting is stressed. Furthermore, actions and attitudes are suggested to improve the quality of said transition.

Background and Aims: Phenylalanine-restricted diets have proven effective in treating phenylketonuria. However, such diets have occasionally been reported to hinder normal development. Our study aimed to assess whether treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin might prevent growth retardation later in life. Methods: We conducted a longitudinal retrospective study which examined anthropometric characteristics of phenylketonuric patients on 6R-tetrahydrobiopterin therapy (22 subjects), and compared them with a group of phenylketonuric patients on protein-restricted diets (44 subjects). Nutritional issues were also considered. We further explored possible relationships between mutations in the PAH gene, BH4 responsiveness and growth outcome. Results: No significant growth improvements were observed in either the group on 6R-tetrahydrobiopterin treatment (height Z-score: initial = -0.57 +/- 1.54; final = -0.52 +/- 1.29; BMI Z-score: initial = 0.17 +/- 1.05; final = 0.18 +/- 1.00) or the diet-only group (height Z-score: initial = -0.92 +/- 0.96; final = -0.78 +/- 1.08; BMI Z-score: initial = 0.17 +/- 0.97; final = -0.07 +/- 1.03) over the 1-year observation period. Furthermore, we found no significant differences (p > 0.05) between the two groups at any of the time points considered (0, 6 and 12 months). Patients on 6R-tetrahydrobiopterin increased their phenylalanine intake (from 49.1 [25.6-60.3] to 56.5 [39.8-68.3] mg kg(-1) day(-1)) and natural protein intake (from 1.0 [0.8-1.7] to 1.5 [1.0-1.8] g kg(-1) day(-1)), and some patients managed to adopt normal diets. Higher phenylalanine and natural protein intakes were positively correlated with better physical outcomes in the diet-only group (p < 0.05). No correlation was found between patient genotype and physical outcomes, results being similar regardless of the nutritional approach used. We did not detect any side effects due to 6R-tetrahydrobiopterin administration. Conclusions: Our study indicates that treating 0-4-year-old phenylketonuric patients with 6R-tetrahydrobiopterin is safe. However, poor developmental outcomes were observed, despite increasing the intake of natural proteins. Genotype could be a valid predictor of tetrahydrobiopterin-responsiveness, since patients who carried the same genotype responded similarly to the 6R-tetrahydrobiopterin loading test. On the other hand, harbouring 6R-tetrahydrobiopterin responsive genotypes did not predispose patients to better physical outcomes. (C) 2015 Elsevier Inc. All rights reserved.

Natural sources of protein and some vitamins and minerals are limited in phenylketonuria (PKU) treated patients, who should receive optimal supplementation although this is not yet fully established. We conducted a cross-sectional observational multicenter study including 156 patients with hyperphenylalaninemia. Patients were stratified by age, phenotype, disease detection and type of treatment. Annual median blood phenylalanine (Phe) levels, Phe tolerance, anthropometric measurements, and biochemical parameters (total protein, prealbumin, electrolytes, selenium, zinc, B-12, folic acid, ferritin, 25-OH vitamin D) were collected in all patients. 81.4% of patients had biochemical markers out of recommended range but no clinical symptoms. Total protein, calcium, phosphorus, B-12, ferritin, and zinc levels were normal in most patients. Prealbumin was reduced in 34.6% of patients (74% with PKU phenotype and 94% below 18 years old), showing almost all (96.3%) an adequate adherence to diet. Selenium was diminished in 25% of patients (95% with PKU phenotype) and also 25-OHD in 14%. Surprisingly, folic acid levels were increased in 39% of patients, 66% with classic PKU. Phosphorus and 1352 levels were found diminished in patients with low adherence to diet. Patients under BH4 therapy only showed significant lower levels of B-12. This study shows a high percentage of prealbumin and selenium deficiencies as well as an increased level of folic acid in PKU treated patients, which should lead us to assess an adjustment for standards supplements formulated milks. (C) 2015 Elsevier Inc. All rights reserved.

The data presented here are the biochemical parameters of 156 patients with hyperphenylalaninemia. PKU patients, who, in order to maintain optimal serum Phe concentrations, receive dietary treatment consisting of a diet low in natural protein supplemented with special low protein foods and a Phe-free amino acid mixture, vitamins and minerals. The obtained data reflects a high percentage of patients with prealbumin and selenium deficiencies, as well as an increased level of folic acid. This data article is related to the research article entitled, "Vitamin and mineral status in patients with hyperphenylalaninemia", by Crujeiras et al. [1].

In order to investigate the effects produced by external CR on neuroendocrine systems,GH secretion, in response to hypothalamic stimulation (clonidine, 0.15 mg/m2, per os) and to direct pituitary challenge (GRF-29, Serono, Spain, 1 μg/kg, iv bolus), and TSH and PRL responses to TRH (200 ug, iv bolus) were evaluated in 7 children, 3 years after previous CR for LLA (dose= 2400 rads). Growth velocity was also periodically evaluated. Mean age at diagnosis was 4.2 years (range : 9 months to 8 y.). Hormones in plasma were measured by sensitive IRMA. RESULTS (mean ± SD).- Growth velocity, as expressed by SD under the mean for age, was impaired in all patients. -3.05 ± 1.8, GH peaks elicited by clonidine and GRF-29 were similar : 13.8 ± 6.1, and 15.5 ± 10.8,ng/ml,respectively. Either basal or stimulated TSH and PRL were between normal limits, TSH; O' = 1.6 ± 1.1, peak = 7.8 ± 5.3, μU/ml; PRL : O' = 5.4 ± 2.1, peak = 22.5 ± 14.8, ng/ml. Individually, while in 6 patients a normal GH response to clonidine was observed, 3 of them exhibited a poor response of the hormone to GRF challenge (peaks : 7.4, 9.2, 2, ng/ml). CONCLUSIONS.- The fact that GH secretion appeared to be normal when explored either from the hypothalamus or directly at pituitary level, suggests that CR (at the dcse utilised) did not affect the endogenous GHRH-GH pathway. Given that, in spite of the fact that thyroideal status was also normal, growth velocity is consistently impaired in these children it is tempting to speculate that CR affected the suprahypothalamic structures that, governing the interplay between GHRH and somatostatin, lead to the normal pattern of spontaneous GH secretion. Additionally, the fact that in 3 cases there was not observed significant GH response to GRF, but normal response to clonidine, supports our previous hypothesis on HSR and GRF tests (Bevesa, J Endoc Inv, 10, Suppl 3,27,87)

Childhood obesity is a global public health issue and is linked to metabolic syndrome, which increases the risk of comorbidities such as type 2 diabetes, cardiovascular diseases and cancer. Social, economic and cultural factors influence changes in nutrition and lifestyle characterized by poorer diets and reduced physical activity. This systematic review summarizes the evidence for nutritional education interventions to improve metabolic risks in children and adolescents. Systematic searches of the databases Medline (via PubMed) and Scopus were conducted following PRISMA guidelines. The risk of bias for each study was assessed following the methodology of the Cochrane Collaboration. Ten case-controlled and randomized controlled studies testing nutritional educational interventions targeting children and adolescents from the general population were eligible for inclusion. The sample size was 3915 and the age range was 7-20 years. The duration of intervention ranged from 12 weeks to 20 years. All the studies that provided data on abdominal obesity reported differences in favour of the intervention. However, data on the effects on the remaining components of metabolic syndrome remain inconclusive. These results support the role of nutritional education interventions as a strategy to reduce central adiposity and its possible unhealthy consequences in children and adolescents. Yes

BackgroundRecent attempts to refine the definition bronchopulmonary dysplasia (BPD) have based its predictive capacity on respiratory outcome in the first 2 years of life, eliminating the pre-existing requirement of 28 days of oxygen therapy prior to 36 weeks postmenstrual age (PMA). The objective of this study was to assess the utility of the 2001 consensus definition in predicting impaired lung function at preschool age.MethodsThis cohort study included children aged 4–6 years old who were born at gestational age (GA) ResultsGA, hemodynamically significant patent ductus arteriosus, and late sepsis were independent risk factors for the development of BPD. A total of 119 children underwent incentive spirometry. All lung function parameters were significantly altered relative to reference values. Greater impairment of lung function was observed in the mild BPD vs. the no BPD group (forced expiratory volume in the first 0.75 seconds [FEV0.75]: −1.18 ± 0.80 vs. −0.55 ± 1.13; p = 0.010), but no difference in forced vital capacity (FVC) was observed (−0.32 ± 0.90 vs. −0.18 ± 1; p = 0.534). The moderate-to-severe BPD group exhibited the most severe FEV0.75 reduction (FEV0.75: −2.63 ± 1.18 vs. −0.72 ± 1.08; p = 0.000) and was the only condition with FVC impairment (FVC: −1.82 ± 1.12 vs. −0.22 ± 0.87; p = 0.000). The multivariate analysis identified a diagnosis of moderate-to-severe BPD as an independent risk factor for lung function impairment.ConclusionThe 2001 consensus definition of BPD has adequate predictive capacity for lung function measured by spirometry at 4–6 years of age. Moderate-to-severe BPD was the best predictor of respiratory impairment. Children with mild BPD showed greater alteration of FEV0.75 than those without BPD.

Pain recognition and management continues to be a challenge for health professionals in Neonatal Intensive Care Units. Many of the patients are routinely exposed to repeated painful experiences with demonstrated short- and long-term consequences. Preterm babies are a vulnerable high-risk population. Despite international recommendations, pain remains poorly assessed and managed in many Neonatal Intensive Care Units. Due to there being no general protocol, there is significant variability as regards the guidelines for the approach and treatment of pain between the different Neonatal Intensive Care Units. The objective of this article is to review and assess the general principles of pain in the initial stages of development, its recognition through the use of standardised scales. It also includes its prevention and management with the combination of pharmacological and non-pharmacological measures, as well as to establish recommendations that help alleviate pain in daily clinical practice by optimising pain and stress control in the Neonatal Intensive Care Units. Resumen: El reconocimiento del dolor y su tratamiento en las unidades de cuidados intensivos neonatales continúa siendo un desafío para los profesionales sanitarios responsables de la atención de estos niños. Las exposiciones dolorosas repetidas a las que se someten muchos de estos pacientes de manera rutinaria han demostrado presentar efectos deletéreos a corto y largo plazo. Los recién nacidos prematuros, especialmente vulnerables, suponen una población de alto riesgo. Pese a las recomendaciones internacionales, el dolor sigue siendo evaluado actualmente en muchas ocasiones de manera inconsistente, sin protocolización, siendo patente, además, entre las diferentes unidades de cuidados intensivos neonatales una variabilidad importante en cuanto a las pautas para el abordaje y tratamiento del mismo. El objetivo de este artículo es revisar y valorar los principios generales del dolor en las etapas iniciales del desarrollo, su reconocimiento mediante el uso de escalas protocolizadas, y su prevención y manejo, con la combinación de medidas farmacológicas y no farmacológicas; con el fin de establecer recomendaciones que ayuden a aliviar el dolor en la práctica clínica diaria optimizando el control del dolor y el estrés en las unidades de cuidados intensivos neonatales.

The classical dogma states that brown adipose tissue (BAT) plays a major role in the regulation of temperature in neonates. However, although BAT has been studied in infants for more than a century, the knowledge about its physiological features at this stage of life is rather limited. This has been mainly due to the lack of appropriate investigation methods, ethically suitable for neonates. Here, we have applied non-invasive infrared thermography (IRT) to investigate neonatal BAT activity. Our data show that BAT temperature correlates with body temperature and that mild cold stimulus promotes BAT activation in newborns. Notably, a single short-term cold stimulus during the first day of life improves the body temperature adaption to a subsequent cold event. Finally, we identify that bone morphogenic protein 8B (BMP8B) is associated with the BAT thermogenic response in neonates. Overall, our data uncover key features of the setup of BAT thermogenesis in newborns., Brown adipose tissue (BAT) in infants has been studied for more than a century, however, the knowledge about its physiological features is limited. Here, the authors investigate the link between BAT thermogenesis and the regulation of temperature in human new-borns with non-invasive infrared thermography.

Virus adeno associat; Lentivirus; Vectors virals Virus adenoasociado; Lentivirus; Vectores virales Adeno-associated virus; Lentivirus; Viral vectors The need for long-lasting and transformative therapies for mucopolysaccharidoses (MPS) cannot be understated. Currently, many forms of MPS lack a specific treatment and in other cases available therapies, such as enzyme replacement therapy (ERT), do not reach important areas such as the central nervous system (CNS). The advent of newborn screening procedures represents a major step forward in early identification and treatment of individuals with MPS. However, the treatment of brain disease in neuronopathic MPS has been a major challenge to date, mainly because the blood brain barrier (BBB) prevents penetration of the brain by large molecules, including enzymes. Over the last years several novel experimental therapies for neuronopathic MPS have been investigated. Gene therapy and gene editing constitute potentially curative treatments. However, despite recent progress in the field, several considerations should be taken into account. This review focuses on the state of the art of in vivo and ex vivo gene therapy-based approaches targeting the CNS in neuronopathic MPS, discusses clinical trials conducted to date, and provides a vision for the future implications of these therapies for the medical community. Recent advances in the field, as well as limitations relating to efficacy, potential toxicity, and immunogenicity, are also discussed. This research received no external funding.

Transporte neonatal; Transporte intraútero; Recién nacido de alto riesgo In utero transport; Neonatal transport; High risk newborn Transport neonatal; Transport intraúter; Nounat de risc alt The first hours of life of a sick or premature newborn are crucial for its prognosis and therefore delivery should take place in a center prepared for that degree of complexity. When this condition is not met, the newborn must be transferred in an optimal and safe way to the center that can offer the necessary care. The training, staffing, organization and coordination of the neonatal transport team are essential to guarantee a safe transfer. Being aware of the interest and the advances that are currently taking place in this area of ​​pediatrics, the Standards Commission and the Neonatal Transport Commission of the Spanish Society of Neonatology have prepared this document. In it, both the provision of human and material resources necessary as well as the bases of clinical stabilization in transport to carry out the neonatal transfer in a safe way and proportionate to the needs of the critical newborn have been exhaustively reviewed and detailed. Las primeras horas de vida de un recién nacido enfermo o prematuro son cruciales para su pronóstico y por lo tanto el parto debería acontecer en un centro preparado para ese grado de complejidad. Cuando no se cumple esta condición, el recién nacido debe ser trasladado de un modo óptimo y seguro al centro que pueda ofrecerle los cuidados necesarios. La formación, dotación, organización y coordinación del equipo de transporte neonatal son indispensables para garantizar un traslado en condiciones. Siendo conscientes del interés y los avances que en la actualidad se están produciendo en esta área de la pediatría, la Comisión de Estándares y la Comisión de Transporte Neonatal de la Sociedad Española de Neonatología han elaborado el presente documento. En él, se ha revisado y detallado de forma exhaustiva tanto la dotación de recursos humanos y materiales necesarios como las bases de la estabilización clínica en transporte para llevar a cabo el traslado neonatal de forma segura y proporcionada a las necesidades del recién nacido crítico.

Nephrocalcinosis; Phenotype; Severe liver dysfunction Nefrocalcinosis; Fenotipo; Disfunción hepática grave Nefrocalcinosi; Fenotip; Disfunció hepàtica greu Treatment with nitisinone (NTBC) has brought about a drastic improvement in the treatment and prognosis of hereditary tyrosinemia type I (HT1). We conducted a retrospective observational multicentric study in Spanish HT1 patients treated with NTBC to assess clinical and biochemical long-term evolution.We evaluated 52 patients, 7 adults and 45 children, treated with NTBC considering: age at diagnosis, diagnosis by clinical symptoms, or by newborn screening (NBS); phenotype (acute/subacute/chronic), mutational analysis; symptoms at diagnosis and clinical course; biochemical markers; doses of NTBC; treatment adherence; anthropometric evolution; and neurocognitive outcome.The average follow-up period was 6.1 ± 4.9 and 10.6 ± 5.4 years in patients with early and late diagnosis respectively. All patients received NTBC from diagnosis with an average dose of 0.82 mg/kg/d. All NBS-patients (n = 8) were asymptomatic at diagnosis except 1 case with acute liver failure, and all remain free of liver and renal disease in follow-up. Liver and renal affectation was markedly more frequent at diagnosis in patients with late diagnosis (P < .001 and .03, respectively), with ulterior positive hepatic and renal course in 86.4% and 93.2% of no-NBS patients, although 1 patient with good metabolic control developed hepatocarcinoma.Despite a satisfactory global nutritional evolution, 46.1% of patients showed overweight/obesity. Interestingly lower body mass index was observed in patients with good dietary adherence (20.40 ± 4.43 vs 24.30 ± 6.10; P = .08) and those with good pharmacological adherence (21.19 ± 4.68 vs 28.58 ± 213.79).intellectual quotient was ≥85 in all NBS- and 68.75% of late diagnosis cases evaluated, 15% of which need pedagogical support, and 6.8% (3/44) showed school failure.Among the 12 variants identified in fumarylacetoacetate hydrolase gene, 1 of them novel (H63D), the most prevalent in Spanish population is c.554-1 G>T.After NTBC treatment a reduction in tyrosine and alpha-fetoprotein levels was observed in all the study groups, significant for alpha-fetoprotein in no NBS-group (P = .03), especially in subacute/chronic forms (P = .018).This series confirms that NTBC treatment had clearly improved the prognosis and quality of life of HT1 patients, but it also shows frequent cognitive dysfunctions and learning difficulties in medium-term follow-up, and, in a novel way, a high percentage of overweight/obesity.

Background: Advances in the diagnosis and treatment of urea cycle disorders (UCDs) have led to a higher survival rate. The purpose of this study is to describe the characteristics of patients with urea cycle disorders in Spain. Methods: Observational, cross-sectional and multicenter study. Clinical, biochemical and genetic data were collected from patients with UCDs, treated in the metabolic diseases centers in Spain between February 2012 and February 2013, covering the entire Spanish population. Heterozygous mothers of patients with OTC deficiency were only included if they were on treatment due to being symptomatic or having biochemistry abnormalities. Results: 104 patients from 98 families were included. Ornithine transcarbamylase deficiency was the most frequent condition (64.4%) (61.2% female) followed by type 1 citrullinemia (21.1%) and argininosuccinic aciduria (9.6%). Only 13 patients (12.5%) were diagnosed in a pre-symptomatic state. 63% of the cases presented with type intoxication encephalopathy. The median ammonia level at onset was 298 mu mol/L (169-615). The genotype of 75 patients is known, with 18 new mutations having been described. During the data collection period four patients died, three of them in the early days of life. The median current age is 9.96 years (5.29-18), with 25 patients over 18 years of age. Anthropometric data, expressed as median and z-score for the Spanish population is shown. 52.5% of the cases present neurological sequelae, which have been linked to the type of disease, neonatal onset, hepatic failure at diagnosis and ammonia values at diagnosis. 93 patients are following a protein restrictive diet, 0.84 g/kg/day (0.67-1.10), 50 are receiving essential amino acid supplements, 0.25 g/kg/day (0.20-0.45), 58 arginine, 156 mg/kg/day (109-305) and 45 citrulline, 150 mg/kg/day (105-199). 65 patients are being treated with drugs: 4 with sodium benzoate, 50 with sodium phenylbutyrate, 10 with both drugs and 1 with carglumic acid. Conclusions: Studies like this make it possible to analyze the frequency, natural history and clinical practices in the area of rare diseases, with the purpose of knowing the needs of the patients and thus planning their care.