Publications by authors named "Domingo González-Lamuño"

55 Publications

Comparison of COVID-19 and Non-COVID-19 Pneumonia in Down Syndrome.

J Clin Med 2021 Aug 23;10(16). Epub 2021 Aug 23.

Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.

Whether the increased risk for coronavirus disease 2019 (COVID-19) hospitalization and death observed in Down syndrome (DS) are disease specific or also occur in individuals with DS and non-COVID-19 pneumonias is unknown. This retrospective cohort study compared COVID-19 cases in persons with DS hospitalized in Spain reported to the Trisomy 21 Research Society COVID-19 survey ( = 86) with admissions for non-COVID-19 pneumonias from a retrospective clinical database of the Spanish Ministry of Health ( = 2832 patients). In-hospital mortality rates were significantly higher for COVID-19 patients (26.7% vs. 9.4%), especially among individuals over 40 and patients with obesity, dementia, and/or epilepsy. The mean length of stay of deceased patients with COVID-19 was significantly shorter than in those with non-COVID-19 pneumonias. The rate of admission to an ICU in patients with DS and COVID-19 (4.3%) was significantly lower than that reported for the general population with COVID-19. Our findings confirm that acute SARS-CoV-2 infection leads to higher mortality than non-COVID-19 pneumonias in individuals with DS, especially among adults over 40 and those with specific comorbidities. However, differences in access to respiratory support might also account for some of the heightened mortality of individuals with DS with COVID-19.
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http://dx.doi.org/10.3390/jcm10163748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397064PMC
August 2021

Urine Phenylacetylglutamine Determination in Patients with Hyperphenylalaninemia.

J Clin Med 2021 Aug 19;10(16). Epub 2021 Aug 19.

Metabolism Group, CIBER-ER, Biocruces Bizkaia Health Research Institute, 48903 Bizkaia, Spain.

Phenylketonuria (PKU), an autosomal-recessive inborn error of phenylalanine (Phe) metabolism is the most prevalent disorder of amino acid metabolism. Currently, clinical follow-up relies on frequent monitoring of Phe levels in blood. We hypothesize that the urine level of phenylacetylglutamine (PAG), a phenyl-group marker, could be used as a non-invasive biomarker. In this cross-sectional study, a validated liquid chromatography coupled to tandem mass spectrometry (LC-MS) method was used for urinary PAG quantification in 35 participants with hyperphenylalaninemia (HPA) and 33 age- and sex-matched healthy controls. We have found that (a) PKU patients present higher urine PAG levels than healthy control subjects, and that (b) there is a significant correlation between urine PAG and circulating Phe levels in patients with HPA. In addition, we show a significant strong correlation between Phe levels from venous blood samples and from capillary finger-prick dried blood spot (DBS) samples collected at the same time in patients with HPA. Further research in order to assess the potential role of urine PAG as a non-invasive biomarker in PKU is warranted.
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http://dx.doi.org/10.3390/jcm10163674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396897PMC
August 2021

PlA2 Polymorphism of Platelet Glycoprotein IIb/IIIa and C677T Polymorphism of Methylenetetrahydrofolate Reductase (), but Not Factor V Leiden and Prothrombin G20210A Polymorphisms, Are Associated with More Severe Forms of Legg-Calvé-Perthes Disease.

Children (Basel) 2021 Jul 20;8(7). Epub 2021 Jul 20.

Laboratorio de Pediatría, Departamento de Ciencias Médicas y Quirúrgicas, Universidad de Cantabria, Cardenal Herrera Oria s/n, 39011 Santander, Spain.

The possible association of common polymorphic variants related to thrombophilia (the rs6025(A) allele encoding the Leiden mutation, rs1799963(A), i.e., the G20210A mutation of the prothrombin gene, the rs1801133(T) variant of the methylenetetrahydrofolate reductase ( gene that encodes an enzyme involved in folate metabolism, and rs5918(C), i.e., the 'A2' allele of the platelet-specific alloantigen system that increases platelet aggregation induced by agonists), with the risk of Legg-Calvé-Perthes disease (LCPD) and the degree of hip involvement (Catterall stages I to IV) was analyzed in a cohort study, including 41 children of ages 2 to 10.9 (mean 5.4, SD 2.2), on the basis of clinical and radiological criteria of LCPD. In 10 of the cases, hip involvement was bilateral; thus, a total of 51 hips were followed-up for a mean of 75.5 months. The distribution of genotypes among patients and 118 controls showed no significant differences, with a slightly increased risk for LCPD in rs6025(A) carriers (OR: 2.9, CI: 0.2-47.8). Regarding the severity of LCPD based on Catterall classification, the rs1801133(T) variant of the gene and the rs5918(C) variant of the platelet glycoprotein IIb/IIIa were associated with more severe forms of Perthes disease (Catterall III-IV) ( < 0.05). The four children homozygous for mutated had a severe form of the disease (Stage IV of Catterall) and a higher risk of non-favorable outcome (Stulberg IV-V).
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http://dx.doi.org/10.3390/children8070614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307051PMC
July 2021

Translation and study of the measurement properties of the Early Feeding Skills Assessment tool in premature newborn.

An Pediatr (Engl Ed) 2021 Aug 7;95(2):72-77. Epub 2021 Jul 7.

Unidad Neonatal, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, Spain.

Introduction: With the aim of improving the care of the premature newborn during their hospital stay, and their well-being in the transition from enteral to independent feeding, it is proposed to incorporate an assessment system within a Spanish Neonatal Unit. The translation of the Early Feeding Skills Assessment (EFSA) tool is presented, along with a study of its measurement properties.

Patients And Method: A total of 104 assessments were made on premature babies of less than 34 + 6 weeks of gestational age, admitted to the neonatal unit with total or partial feeding, including a normal neurological examination for their age and with physiological stability.

Results: The EFSA 2010 tool achieved an acceptable value (0.76) as regards its internal consistency. The EFSA 2018 tool maintained an acceptable internal consistency value (0.751). As regards the reliability between two observers, the results showed a satisfactory and excellent reliability in 57.69% of the items in the EFSA 2010 tool, a property that improved in the EFSA 2018 tool (73.68%).

Conclusions: The Spanish version of the EFSA tool is consistent and reliable for use as a tool for the assessment of oral abilities for feeding premature babies admitted into a Spanish Neonatal Unit.
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http://dx.doi.org/10.1016/j.anpede.2020.05.018DOI Listing
August 2021

Treatment adherence in tyrosinemia type 1 patients.

Orphanet J Rare Dis 2021 06 3;16(1):256. Epub 2021 Jun 3.

CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, 15706, Santiago de Compostela, A Coruña, Spain.

Background: While therapeutic advances have significantly improved the prognosis of patients with hereditary tyrosinemia type 1 (HT1), adherence to dietary and pharmacological treatments is essential for an optimal clinical outcome. Poor treatment adherence is well documented among patients with chronic diseases, but data from HT1 patients are scarce. This study evaluated pharmacological and dietary adherence in HT1 patients both directly, by quantifying blood levels nitisinone (NTBC) levels and metabolic biomarkers of HT1 [tyrosine (Tyr), phenylalanine (Phe), and succinylacetone]; and indirectly, by analyzing NTBC prescriptions from hospital pharmacies and via clinical interviews including the Haynes-Sackett (or self-compliance) test and the adapted Battle test of patient knowledge of the disease.

Results: This observational study analyzed data collected over 4 years from 69 HT1 patients (7 adults and 62 children; age range, 7 months-35 years) who were treated with NTBC and a low-Tyr, low-Phe diet. Adherence to both pharmacological and, in particular, dietary treatment was poor. Annual data showed that NTBC levels were lower than recommended in more than one third of patients, and that initial Tyr levels were high (> 400 µM) in 54.2-64.4% of patients and exceeded 750 µM in 25.8% of them. Remarkably, annual normalization of NTBC levels was observed in 29.4-57.9% of patients for whom serial NTBC determinations were performed. Poor adherence to dietary treatment was more refractory to positive reinforcement: 36.2% of patients in the group who underwent multiple analyses per year maintained high Tyr levels during the entire study period, and, when considering each of the years individually this percentage ranged from 75 to 100% of them. Indirect methods revealed percentages of non-adherent patients of 7.3 and 15.9% (adapted Battle and Haynes tests, respectively).

Conclusions: Despite initially poor adherence to pharmacological and especially dietary treatment among HT1 patients, positive reinforcement at medical consultations resulted in a marked improvement in NTBC levels, indicating the importance of systematic positive reinforcement at medical visits.
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http://dx.doi.org/10.1186/s13023-021-01879-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173906PMC
June 2021

Impact of COVID-19 Confinement on Physical Activity and Sedentary Behaviour in Spanish University Students: Role of Gender.

Int J Environ Res Public Health 2021 01 6;18(2). Epub 2021 Jan 6.

AgeingOn Research Group, Department of Physiology, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.

During the COVID-19 pandemic, entire populations were instructed to live in home-confinement to prevent the expansion of the disease. Spain was one of the countries with the strictest conditions, as outdoor physical activity was banned for nearly two months. This study aimed to analyse the changes in physical activity and sedentary behaviours in Spanish university students before and during the confinement by COVID-19 with special focus on gender. We also analysed enjoyment, the tools used and motivation and impediments for doing physical activity. An online questionnaire, which included the International Physical Activity Questionnaire Short Form and certain "ad hoc" questions, was designed. Students were recruited by distributing an invitation through the administrative channels of 16 universities and a total of 13,754 valid surveys were collected. Overall, university students reduced moderate (-29.5%) and vigorous (-18.3%) physical activity during the confinement and increased sedentary time (+52.7%). However, they spent more time on high intensity interval training (HIIT) (+18.2%) and mind-body activities (e.g., yoga) (+80.0%). Adaptation to the confinement, in terms of physical activity, was handled better by women than by men. These results will help design strategies for each gender to promote physical activity and reduce sedentary behaviour during confinement periods.
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http://dx.doi.org/10.3390/ijerph18020369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825050PMC
January 2021

Modified Serum ALP Values and Timing of Apparition of Knee Epiphyseal Ossification Centers in Preterm Infants with Cholestasis and Risk of Concomitant Metabolic Bone Disease of Prematurity.

Nutrients 2020 Dec 17;12(12). Epub 2020 Dec 17.

Pediatric Department, University Hospital Marqués de Valdecilla-Research Institute Valdecilla (IDIVAL), 39008 Santander, Spain.

The usefulness of serum alkaline phosphatase (ALP) and phosphorous in screening and monitoring of metabolic bone disease of prematurity (MBDP) still has some limitations, especially in preterm infants with concomitant conditions such as cholestasis. We aimed to assess a modification of serum ALP (M-ALP) as a biomarker for MBDP in preterm infants, and the use of ultrasound monitoring for the apparition of knee ossification centers as marker of bone mineralization. Biochemical and clinical registers were taken from 94 preterm newborns <32 weeks. A significant correlation existed between serum ALP and direct bilirubin (DB), expressed by the regression equation: M-ALP (IU/L) = 302.1 + 96.9 (DB (mg/dL)). The ratio ALP/M-ALP > 1 was demonstrated to be more specific (87.5%) in the diagnosis of MBDP than the cut-off value of serum ALP > 500 IU/L (62.5%). ALP/M-ALP > 1 showed 100% sensitivity and specificity for the diagnosis of MBDP, and a good correlation with specific bone ALP (B-ALP). Patients with the knee nucleus by post-menstrual week 37 had lower B-ALP compared to patients with no nucleus, and no patients with MBDP presented the nucleus by the 40th week. In the absence of reliable specific B-ALP, reinterpreting serum ALP values by M-ALP plus monitoring of knee ossification centers contribute to better management of MBDP in preterm infants with cholestasis.
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http://dx.doi.org/10.3390/nu12123854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766077PMC
December 2020

Lessons from individuals with Down syndrome during COVID-19.

Lancet Neurol 2020 12;19(12):974-975

Center for Genomic Regulation, The Barcelona Institute for Science and Technology, University Pompeu Fabra, Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(20)30401-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836620PMC
December 2020

Metabolic Serendipities of Expanded Newborn Screening.

Genes (Basel) 2020 08 29;11(9). Epub 2020 Aug 29.

Department of Pediatrics, University of Cantabria-University Hospital Marqués de Valdecilla, 39008 Santander, Spain.

Incidental findings on newborn screening (NBS) are results that are not the target of screening within a given NBS program, but rather are found as a result of the screening and resulting diagnostic workup for that target. These findings may not have an immediate clinical impact on the newborn, but are sometimes an additional benefit of NBS programs and may be considered secondary targets of NBS programs. This work describes four case reports that had incidental findings on the NBS, which eventually led to the diagnosis of another metabolic disease instead of the one that was initially suspected. The first case was a new defect in the cationic amino acid transporter-2 (CAT-2), which was oriented as an arginase-1 deficiency in the newborn. The second case was a maternal glutaric aciduria type 1 (GA-1) that mimicked a carnitine transporter deficiency in the newborn. The third report was a case of lysinuric protein intolerance (LPI), which appeared as high levels of citrulline on the NBS. The fourth case was a mother with homocystinuria that was diagnosed during the biochemical study of vitamin B status. All cases provide new or interesting data that will help guide differential diagnosis in the future.
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http://dx.doi.org/10.3390/genes11091018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565434PMC
August 2020

Bone Status in Patients with Phenylketonuria: A Systematic Review.

Nutrients 2020 Jul 20;12(7). Epub 2020 Jul 20.

Department of Pediatrics, University Clinical Hospital of Santiago de Compostela, 15706 Santiago de Compostela, Spain.

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. Although dietary and, in some cases, pharmacological treatment has been successful in preventing intellectual disability in PKU patients who are treated early, suboptimal outcomes have been reported, including bone mineral disease. In this systematic review, we summarize the available evidence on bone health in PKU patients, including data on bone mineral density (BMD) and bone turnover marker data. Data from cohort and cross-sectional studies of children and adults (up to 40 years of age) were obtained by searching the MEDLINE and SCOPUS databases following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. For each selected study, quality assessment was performed applying the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS I) tool. We found that mean BMD was lower in PKU patients than in reference groups, but was within the normal range in most patients when expressed as Z-score values. Furthermore, data revealed a trend towards an imbalance between bone formation and bone resorption, favoring bone removal. Data on serum levels of minerals and hormones involved in bone metabolism were very heterogeneous, and the analyses were inconclusive. Clinical trials that include the analysis of fracture rates, especially in older patients, are needed to gather more evidence on the clinical implications of lower BMD in PKU patients.
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http://dx.doi.org/10.3390/nu12072154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400926PMC
July 2020

Strength plus Endurance Training and Individualized Diet Reduce Fat Mass in Overweight Subjects: A Randomized Clinical Trial.

Int J Environ Res Public Health 2020 04 10;17(7). Epub 2020 Apr 10.

Department of Nutrition, Hospital La Paz Health Research Institute (IdiPAZ), La Paz University Hospital, 28046 Madrid, Spain.

Studies with overweight people are a priority in order to observe the effect of the timing of intervention on pre-obesity people. The aim was to compare different physical activity programs plus an individualized hypocaloric diet on body composition in overweight subjects. A randomized controlled clinical trial was carried out in overweight adults with no history of relevant illness. Primary outcome was total fat mass (TFM). Participants were allocated into four activity programs with equal intensity and volume of exercise for 22 weeks: strength training (S), endurance training (E), strength + endurance training (SE), and 'adhering to physical activity recommendations' (C). Participants followed a diet with 25% less energy (50%-55% carbohydrates, 30%-35% fat) measured by accelerometer. Variables were assessed at baseline and at the end of the intervention. Body composition was measured by dual-energy X-ray absorptiometry. One hundred nineteen from 205 subjects were randomized in the four exercise groups (S = 30/E = 30/SE = 30/C = 29) and 84 participants (36 men/48 women) ended the intervention (S = 19/E = 25/SE = 22/C = 18). At the end of the experiment, all groups except C increased their total physical activity (S = 1159 ± 1740; E = 1625 ± 1790; SE = 1699 ± 2516; C = 724 ± 1979 MET-min/week). Using an ANOVA-test, improvements were observed in body weight (S = -4.6 ± 4.5; E = -6.6 ± 4.6; SE = -8.5 ± 2.8; C = -6.1 ± 5.6 kg, = 0.059) and TFM (S = -4.24 ± 2.02; E = -4.74 ± 2.96; SE = -6.74 ± 3.27; C = -3.94 ± 4.18%; < 0.05). The main conclusion was that there were no adverse events. Strength and endurance training with a balanced, individualized hypocaloric diet was the most effective at reducing weight loss and fat mass in overweight subjects. Trial registration: NCT01116856.
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http://dx.doi.org/10.3390/ijerph17072596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177353PMC
April 2020

Hypophosphataemic Rickets: Diagnosis Algorithm-How Not to Make a Mistake.

Adv Ther 2020 05 31;37(Suppl 2):95-104. Epub 2020 Mar 31.

Profesor Titular de Pediatría, Universidad de Cantabria, Servicio de Pediatría, Hospital Universitario Marqués de Valdecilla, Santander, Spain.

Hypophosphataemic rickets is a heterogeneous group of entities characterized by rickets or osteomalacia due to a phosphate deficit caused mainly by decreased renal reabsorption. They are also characterized by defective intestinal absorption of calcium and rickets or osteomalacia unresponsive to cholecalciferol. These metabolic alterations lead to growth retardation, bone pain and deformities, and short stature. For a correct diagnosis and treatment of all forms of rickets, the basic aspects of pathophysiology of the calcium-phosphorus metabolism and the relevance of the bone-kidney axis modulated by the presence of phosphaturic agents need to be known. Diagnosis of these diseases includes clinical assessment, blood and urine analytical tests, and bone x-ray. The aim of this article is to briefly describe the pathophysiology, signs, symptoms, and clinical forms of hypophosphataemic rickets, proposing a diagnosis algorithm that can help in the clinical practice.
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http://dx.doi.org/10.1007/s12325-019-01184-1DOI Listing
May 2020

Implementation of an Affordable Method for MPS Diagnosis from Urine Screening to Enzymatic Confirmation: Results of a Pilot Study in Morocco.

Clin Lab 2020 03;66(3)

Background: Rapid and accurate diagnosis of mucopolysaccharidoses (MPS) is still a challenge due to poor access to screening and diagnostic methods and to their extensive clinical heterogeneity. The aim of this work is to perform laboratory biochemical testing for confirming the diagnosis of mucopolysaccharidosis (MPS) for the first time in Morocco.

Methods: Over a period of twelve months, 88 patients suspected of having Mucopolysaccharidosis (MPS) were referred to our laboratory. Quantitative and qualitative urine glycosaminoglycan (GAG) analyses were performed, and enzyme activity was assayed on dried blood spots (DBS) using fluorogenic substrates. Enzyme activity was measured as normal, low, or undetectable.

Results: Of the 88 patients studied, 26 were confirmed to have MPS; 19 MPS I (Hurler syndrome; OMIM #607014/Hurler-Scheie syndrome; OMIM #607015), 2 MPS II (Hunter syndrome; OMIM #309900), 2 MPS IIIA (Sanfilippo syndrome; OMIM #252900), 1 MPS IIIB (Sanfilippo syndrome; OMIM #252920) and 2 MPS VI (Maroteaux-Lamy syndrome; OMIM #253200). Parental consanguinity was present in 80.76% of cases. Qualitative urinary glycosaminoglycan (uGAGs) assays showed abnormal profiles in 31 cases, and further quantitative urinary GAG evaluation and Thin Layer Chromatography (TLC) provided important additional information about the likely MPS diagnosis. The final diagnosis was confirmed by specific enzyme activity analysis in the DBS samples.

Conclusions: The present study shows that the adoption of combined urinary substrate analysis and enzyme assays using dried blood spots can facilitate such diagnosis, offer an important tool for an appropriate supporting care, and a specific therapy, when available.
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http://dx.doi.org/10.7754/Clin.Lab.2019.190720DOI Listing
March 2020

The Effects of the Type of Exercise and Physical Activity on Eating Behavior and Body Composition in Overweight and Obese Subjects.

Nutrients 2020 Feb 20;12(2). Epub 2020 Feb 20.

LFE Research Group, Faculty of Physical Activity and Sport Sciences, Universidad Politécnica de Madrid, 28040 Madrid, Spain.

The aim of this study was to examine whether a type of exercise favors better compliance with a prescribed diet, higher eating-related motivation, healthier diet composition or greater changes in body composition in overweight and obese subjects. One hundred and sixty-two (males = 79), aged 18-50 years, were randomized into four intervention groups during 24 weeks: strength, endurance, combined strength + endurance and guideline-based physical activity; all in combination with a 25-30% caloric restriction diet. A food frequency questionnaire and a "3-day food and drink record" were applied pre- and post-intervention. Diet and exercise-related motivation levels were evaluated with a questionnaire developed for this study. Body composition was assessed by DXA and habitual physical activity was measured by accelerometry. Body weight, body mass index (BMI) and body fat percentage decreased and lean body mass increased after the intervention, without differences by groups. No interactions were observed between intervention groups and time; all showing a decreased in energy intake ( < 0.001). Carbohydrate and protein intakes increased, and fat intake decreased from pre- to post-intervention without significant interactions with intervention groups, BMI category or gender ( < 0.001). Diet-related motivation showed a tendency to increase from pre- to post-intervention (70.0 ± 0.5 vs 71.0 ± 0.6, = 0.053), without significant interactions with intervention groups, BMI or gender. Regarding motivation for exercise, gender x time interactions were observed ( = 7.452, = 0.007): Women increased their motivation after the intervention (pre: 17.6 ± 0.3, post: 18.2 ± 0.3), while men maintained it. These findings suggest that there are no substantial effects of exercise type on energy intake, macronutrient selection or body composition changes. After a six-month weight loss program, individuals did not reduce their motivation related to diet or exercise, especially women. Individuals who initiate a long-term exercise program do not increase their energy intake in a compensatory fashion, if diet advices are included.
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http://dx.doi.org/10.3390/nu12020557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071486PMC
February 2020

[Newborn screening for metabolic disorders in Spain and worldwide].

An Pediatr (Engl Ed) 2019 Aug 21;91(2):128.e1-128.e14. Epub 2019 Jun 21.

Comisión de Diagnóstico Perinatal, Sociedad Española de Medicina de Laboratorio, Barcelona, España; Unidade de Rastreio Neonatal, Metabolismo e Genética, Departamento de Genética Humana do Instituto Nacional de Saúde Doutor Ricardo Jorge, Porto, Portugal. Electronic address:

Newborn screening programs are key players in a country's public health strategies, preventing the burden of care associated with the screened disorders. Its importance has dramatically intensified in recent years due to the increasing number of disorders that fulfil criteria for screening. Since the 1960's, many countries implemented newborn screening programs that are now, at least in developed countries, universal, well established, and with excellent results. Nevertheless, much work is still to be done, mainly in developing countries of Africa, Asia, and South America. In some European countries, including Spain, uniformity of screening panels between different regions is still a challenge, being a source of health inequalities between citizens. The authors will present the current status of newborn screening programs in Spain and integrate it into the current European and world scenario.
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http://dx.doi.org/10.1016/j.anpedi.2019.05.007DOI Listing
August 2019

GENYOi004-A: An induced pluripotent stem cells (iPSCs) line generated from a patient with autism-related ADNP syndrome carrying a pTyr719* mutation.

Stem Cell Res 2019 05 22;37:101446. Epub 2019 Apr 22.

Gene Regulation, Stem Cells and Development Group, Department of Genomic Oncology, GENYO: Centre for Genomics and Oncological Research-Pfizer, University of Granada, Junta de Andalucía, PTS, 18016 Granada, Spain; Department of Biochemistry and Molecular Biology I, Faculty of Science, University of Granada, 18016 Granada, Spain. Electronic address:

ADNP syndrome is an intellectual disability associated with Autism spectrum disorder caused by mutations in ADNP. We generated an iPSC line from an ADNP syndrome pediatric patient harboring the mutation p.Trp719* (GENYOi004-A). Peripheral blood mononuclear cells were reprogrammed using a non-transmissible form of Sendai viruses expressing the four Yamanaka factors (Oct3/4, SOX2, KLF4 and c-MYC). Characterization of GENYOi004-A included mutation analysis of ADNP by allele-specific PCR, genetic identity by Short Tandem Repeats polymorphism profiling, alkaline phosphatase enzymatic activity, expression of pluripotency-associated factors and pluripotency studies in vivo. GENYOi004-A will be useful to evaluate ADNP syndrome alterations at early developmental stages.
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http://dx.doi.org/10.1016/j.scr.2019.101446DOI Listing
May 2019

[Neonatal abstinence syndrome: Management and therapy in 25 hospitals in Spain].

An Pediatr (Engl Ed) 2019 Sep 11;91(3):215-216. Epub 2019 Mar 11.

Servicio de Pediatría, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, España; Unidad de Enfermedades Metabólicas, Servicio de Pediatría, Hospital Universitario Marqués de Valdecilla, Santander, Cantabria, España.

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http://dx.doi.org/10.1016/j.anpedi.2019.02.003DOI Listing
September 2019

Phenotype, treatment practice and outcome in the cobalamin-dependent remethylation disorders and MTHFR deficiency: Data from the E-HOD registry.

J Inherit Metab Dis 2019 03 17;42(2):333-352. Epub 2019 Feb 17.

Hospital Infantil Miguel Servet, Zaragoza, Spain.

Aim: To explore the clinical presentation, course, treatment and impact of early treatment in patients with remethylation disorders from the European Network and Registry for Homocystinurias and Methylation Defects (E-HOD) international web-based registry.

Results: This review comprises 238 patients (cobalamin C defect n = 161; methylenetetrahydrofolate reductase deficiency n = 50; cobalamin G defect n = 11; cobalamin E defect n = 10; cobalamin D defect n = 5; and cobalamin J defect n = 1) from 47 centres for whom the E-HOD registry includes, as a minimum, data on medical history and enrolment visit. The duration of observation was 127 patient years. In 181 clinically diagnosed patients, the median age at presentation was 30 days (range 1 day to 42 years) and the median age at diagnosis was 3.7 months (range 3 days to 56 years). Seventy-five percent of pre-clinically diagnosed patients with cobalamin C disease became symptomatic within the first 15 days of life. Total homocysteine (tHcy), amino acids and urinary methylmalonic acid (MMA) were the most frequently assessed disease markers; confirmatory diagnostics were mainly molecular genetic studies. Remethylation disorders are multisystem diseases dominated by neurological and eye disease and failure to thrive. In this cohort, mortality, thromboembolic, psychiatric and renal disease were rarer than reported elsewhere. Early treatment correlates with lower overall morbidity but is less effective in preventing eye disease and cognitive impairment. The wide variation in treatment hampers the evaluation of particular therapeutic modalities.

Conclusion: Treatment improves the clinical course of remethylation disorders and reduces morbidity, especially if started early, but neurocognitive and eye symptoms are less responsive. Current treatment is highly variable. This study has the inevitable limitations of a retrospective, registry-based design.
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http://dx.doi.org/10.1002/jimd.12041DOI Listing
March 2019

Cellular and animal models of skin alterations in the autism-related ADNP syndrome.

Sci Rep 2019 01 24;9(1):736. Epub 2019 Jan 24.

Genetics Unit, Hospital Valdecilla, 39008, Santander, Spain.

Mutations in ADNP have been recently associated with intellectual disability and autism spectrum disorder. However, the clinical features of patients with this syndrome are not fully identified, and no treatment currently exists for these patients. Here, we extended the ADNP syndrome phenotype describing skin abnormalities in both a patient with ADNP syndrome and an Adnp haploinsufficient mice. The patient displayed thin dermis, hyperkeratotic lesions in periarticular areas and delayed wound healing. Patient-derived skin keratinocytes showed reduced proliferation and increased differentiation. Additionally, detection of cell cycle markers indicated that mutant cells exhibited impaired cell cycle progression. Treatment of ADNP-deficient keratinocytes with the ADNP-derived NAP peptide significantly reduced the expression of differentiation markers. Sonography and immunofluorescence staining of epidermal layers revealed that the dermis was thinner in the patient than in a healthy control. Adnp haploinsufficient mice (Adnp) mimicked the human condition showing reduced dermal thickness. Intranasal administration of NAP significantly increased dermal thickness and normalized the levels of cell cycle and differentiation markers. Our observations provide a novel activity of the autism-linked ADNP in the skin that may serve to define the clinical phenotype of patients with ADNP syndrome and provide an attractive therapeutic option for skin alterations in these patients.
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http://dx.doi.org/10.1038/s41598-018-36859-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346103PMC
January 2019

Determinants of Plasma Docosahexaenoic Acid Levels and Their Relationship to Neurological and Cognitive Functions in PKU Patients: A Double Blind Randomized Supplementation Study.

Nutrients 2018 Dec 7;10(12). Epub 2018 Dec 7.

Division Metabolic and Nutritional Medicine, LMU-Ludwig-Maximilians-Universität Munich, Dr. von Hauner Children's Hospital, 80337 Munich, Germany.

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.
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http://dx.doi.org/10.3390/nu10121944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6316534PMC
December 2018

Factors associated with grip strength among adolescents: An observational study.

J Hand Ther 2020 Jan - Mar;33(1):96-102. Epub 2018 Nov 30.

Department of Pediatrics, University of Cantabria, Santander, Cantabria, Spain.

Study Design: Cross-sectional.

Introduction: The muscle strength has been studied in different populations in relation with individual and other factors.

Purpose Of The Study: The purpose of this study was to determine values of grip strength in adolescents and to examine its association with sex, age, weight, height, nutritional status, handedness, and academic performance.

Methods: A total of 452 adolescents (246 men and 206 women) aged 12 to 17 years were included in the study. Grip strength was measured using a Takei dynamometer.

Results: Boys were significantly stronger than girls with both the dominant hand (33.1 kgf vs 25.0 kgf; mean difference = 8.1 kgf; P < .001) and the nondominant hand (30.9 kgf vs 23.1 kgf; mean difference = 7.8 kgf; P < .001), and there was a significant increase in strength values as the age rises in both sexes (P < .001). The dominant hand was stronger than the nondominant one (29.4 kgf vs 27.3 kgf; mean difference = 2.1 kgf; P < .001), except for left-handed subjects who were significantly stronger than right-handed ones in their nondominant hand. Furthermore, strength was positively associated with nutritional status and negatively associated with academic performance in men.

Conclusions: Sex, age, handedness, nutritional status, and academic performance have a significant influence on the grip strength values. There seems to be a sexual dimorphism in the relationship between strength and both nutritional status and academic performance.
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http://dx.doi.org/10.1016/j.jht.2018.10.005DOI Listing
May 2021

Rehydration during exercise prevents the increase of homocysteine concentrations.

Amino Acids 2019 Feb 27;51(2):193-204. Epub 2018 Sep 27.

Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

This study aimed to assess the effect of rehydration during and after acute aerobic submaximal exercise on total homocysteine (tHcy) concentrations and related parameters in physically active adult males. Twenty trained males (29.4 ± 7.9 years old) completed four exercise tests: two without rehydration during exercise (NH1 and NH2), one with rehydration during exercise using water (H1) and one with rehydration during exercise using an isotonic sports drink (H2). After finishing the exercise tests, subjects followed a rehydration protocol for 2 h. Serum tHcy, vitamin B12, folate, creatine and creatinine were analysed before, after and at 2, 6 and 24 h after exercise. Data were analysed with and without correcting for haemoconcentration to assess the changes in tHcy related. The methylenetetrahydrofolate reductase (MTHFR) 677TT genotype was also analysed. THcy (uncorrected by haemoconcentration) increased significantly after exercise (P < 0.05) in the NH1 and NH2 tests [mean increase ± SD: 1.55 ± 0.33 (15.18%) and 1.76 ± 0.25 (17.69%) µmol/L, respectively], while no significant differences were found in the H1 and H2 tests [mean increase: 0.65 (6.29%) and 0.90 (8.69%) μmol/L, respectively]. The increase was partly due to haemoconcentration and partly due to the metabolism underlying acute exercise. THcy concentrations recovered to baseline after 24 h in all tests. In conclusion, adequate rehydration during acute aerobic exercise using either water or a sports drink maintains tHcy concentrations at baseline and for up to 2 h after exercise in physically active male adults and prevents further increases when compared to no rehydration.
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http://dx.doi.org/10.1007/s00726-018-2655-yDOI Listing
February 2019

Retrospective study to identify risk factors for chronic kidney disease in children with congenital solitary functioning kidney detected by neonatal renal ultrasound screening.

Medicine (Baltimore) 2018 Aug;97(32):e11819

Neonatal Service. Department of Pediatrics, Santiago de Compostela University Hospital, IDIS (Health Research Institute of Santiago de Compostela), CIBERER, Travesia Choupana Pediatric Nephrology Unit, Santiago de Compostela University Hospital, Santiago de Compostela Metabolism Unit, Clinical University Hospital of Cruces, Bilbao Department of Pediatrics, University Hospital Marqués de Valdecilla-Universidad de Cantabria, Santander, Spain.

To evaluate the prognostic significance of factors frequently associated with a reduction in renal mass, such as prematurity, low birth weight, and congenital anomalies of kidney and urinary tract (CAKUT), in patients with solitary functioning kidney (SFK) and investigate signs of early renal injury due to glomerular hyperfiltration damage or dysplasia in the remaining kidney.Retrospective observational study of congenital SFK diagnosed and followed at a tertiary care hospital over a period of 10 years in which 32,900 newborns underwent routine neonatal abdominal ultrasound screening. We analyzed age at diagnosis, sex, gestational age, anthropometric measurements at birth and prenatal and neonatal ultrasound findings, in addition to follow-up data corresponding to imaging findings (ultrasound, micturating cystourethrography, dimercaptosuccinic acid renal, and scintigraphy), ipsilateral CAKUT, compensatory hypertrophy, and renal injury in the form of albuminuria, blood pressure, and estimated glomerular filtration rate (eGFR).In total, 128 congenital SFK cases were detected (1 per 257 live births). Of these, 117 (91.4%) were diagnosed by neonatal ultrasound screening and 44.5% of these had been previously identified by prenatal ultrasound. Neonatal ultrasound had a specificity of 100% and a sensitivity of 92.1%. Forty-five patients (35.2%) had ipsilateral CAKUT and the most common type was urinary collecting system anomalies (75.5%). Over a median follow-up of 6.3 years (1-10 years), compensatory renal hypertrophy was observed in 81 patients (63.7%), most of whom had ipsilateral CAKUT (76.1% vs 56.6% of patients without ipsilateral CAKUT). Albuminuria and hypertension were observed in 3.12% and 5% of patients, respectively, and both were associated with ipsilateral CAKUT (P < .05). In addition, 75% of albuminuria cases (P = .031), 83.3% of hypertension cases (P = .004), and 100% of decreased eGFRcases (P = .031) were significantly associated with CAKUT (renal parenchymal anomaly category), being the strongest predictor of GFR the presence or absence of CAKUT.Neonatal ultrasound screening is useful for the early diagnosis of SFK. The presence of ipsilateral CAKUT should be evaluated in all patients with SFK as congenital anomalies of the renal parenchyma are associated with a poorer prognosis. Because morbidity from CAKUTs may not develop until adulthood, patients should be closely followed throughout life.
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http://dx.doi.org/10.1097/MD.0000000000011819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133615PMC
August 2018

Impact of APOE2allele on lipid profile change after a weight loss program.

Nutr Hosp 2018 03 1;35(2):305-311. Epub 2018 Mar 1.

Department of Physical Activity and Sport Sciences. Faculty of Health Sciences. Camilo José Cela University. Urb. Villafranca del Castillo, Calle Castillo de Alarcón, 49, 28692 Villanueva de la Cañada, Madrid. Spain.

Background: apolipoprotein E (ApoE) polymorphism is a genetic determinant of lipid and lipoprotein levels and the risk for coronary heart disease.

Objective: to evaluate the impact of ApoE2allele in lipid plasma levels and the influence of a healthy hypocaloric diet plus a controlled physical activity on the lipid profile, we performed a study in a cohort of overweight and obese healthy subjects (Body Mass Index (BMI) between 25 and 34.9 kg·m-2).

Methods: one hundred eighty participants (96 women), aged 18-50 years participated in a 22 weeks weight loss intervention based on same dietary treatment and different controlled exercise programs. All subjects followed a hypocaloric diet (25-30% less energy intake than the daily energy expenditure). Blood samples were obtained for lipids measurements at the beginning and end of the study.

Results: after intervention, men of the E2 group showed the greatest decreases in low-density lipoprotein (LDL), triglycerides (TG) and total cholesterol (TC) values (p = 0.039; p = 0.001; p = 0.001; respectively). For high-density lipoprotein (HDL), E2 group had significant differences compared with E4 at pre- (p = 0.020) and post-intervention values (p = 0.024).

Conclusion: our results show great changes in men carrying ApoE2, mainly in TG and TC concentrations after treatment with hypocaloric diet and controlled exercise. Therefore, adding supervised training to nutritional intervention seems to be a good alternative for the reinforcement of the effect of the treatment.
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http://dx.doi.org/10.20960/nh.1278DOI Listing
March 2018

Relapses in patients with Henoch-Schönlein purpura: Analysis of 417 patients from a single center.

Medicine (Baltimore) 2016 Jul;95(28):e4217

Division of Rheumatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria Division of Internal Medicine, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria Division of Pathology, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria Division of Pediatrics, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria Division of Dermatology, Hospital Universitario Marqués de Valdecilla, IDIVAL, University of Cantabria, Santander, Spain.

To further investigate into the relapses of Henoch-Schönlein purpura (HSP), we analyzed the frequency, clinical features, and predictors of relapses in series of 417 unselected patients from a single center. After a median follow-up of 12 (interquartile range [IQR]: 2-38) years, almost one-third of the 417 patients (n = 133; 32%; 85 men/48 women) had experienced at least 1 relapse. At the time of disease diagnosis, patients who later experienced relapses had less commonly infections than those who never suffered flares (30.8% vs 41.9%; P = 0.03). In contrast, patients who experienced relapses had a longer duration of the first episode of palpable purpura than those without relapses (palpable purpura lasting >7 days; 80.0% vs 68.1%; P = 0.04). Abdominal pain (72.3% vs 62.3%; P = 0.03) and joint manifestations (27.8% vs 15.5%; P = 0.005) were also more common in patients who later developed relapses. In contrast, patients who never suffered relapses had a slightly higher frequency of fever at the time of disease diagnosis (9.3% vs 3.8%; P = 0.06). At the time of disease diagnosis, corticosteroids were more frequently given to patients who later had relapses of the disease (44% vs 32% in nonrelapsing patients; P = 0.03). Relapses generally occurred soon after the first episode of vasculitis. The median time from the diagnosis of HSP to the first relapse was 1 (IQR: 1-2) month. The median number of relapses was 1 (IQR 1-3). The main clinical features at the time of the relapse were cutaneous (88.7%), gastrointestinal (27.1%), renal (24.8%), and joint (16.5%) manifestations. After a mean ± standard deviation follow-up of 18.9 ± 9.8 years, complete recovery was observed in 110 (82.7%) of the 133 patients who had relapses. Renal sequelae (persistent renal involvement) was found in 11 (8.3%) of the patients with relapses. The best predictive factors for relapse were joint and gastrointestinal manifestations at HSP diagnosis (odds ratio [OR]: 2.22; 95% confidence interval [CI]: 1.34-3.69, and OR: 1.60; 95% CI: 1.01-2.53, respectively). In contrast, a history of previous infection was a protective factor for relapses (OR: 0.60; 95% CI: 0.38-0.94). In conclusion, joint and gastrointestinal manifestations at the time of diagnosis of HSP are predictors of relapses.
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http://dx.doi.org/10.1097/MD.0000000000004217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4956820PMC
July 2016

Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria.

J Hum Genet 2016 Aug 28;61(8):731-44. Epub 2016 Apr 28.

Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Department of Pediatrics, Hospital Clínico Universitario de Santiago de Compostela, CIBERER, Health Research Institute of Santiago de Compostela (IDIS), A Choupana, s/n, Santiago de Compostela, A Coruña, Spain.

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase (PAH) gene. This study aimed to assess the genotype-phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH4 responsiveness was evaluated using a 6R-BH4 loading test. We assessed genotype-phenotype associations and genotype-BH4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype-phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH4 loading test: 102 were responders (87, carried either one or two BH4-responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH4 responsiveness, which is relevant for patient management, treatment and follow-up.
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http://dx.doi.org/10.1038/jhg.2016.38DOI Listing
August 2016

Role of the monocarboxylate transporter MCT1 in the uptake of lactate during active recovery.

Eur J Appl Physiol 2016 May 29;116(5):1005-10. Epub 2016 Mar 29.

Laboratory of Pediatrics, Facultad de Medicina, Universidad de Cantabria, Avda. Cardenal Herrera Oria s/n, 39011, Santander, Cantabria, Spain.

Purpose: We assessed the role of monocarboxylate transporter 1 (MCT1) on lactate clearance during an active recovery after high-intensity exercise, by comparing genetic groups based on the T1470A (rs1049434) MCT1 polymorphism, whose influence on lactate transport has been proven.

Methods: Sixteen young male elite field hockey players participated in this study. All of them completed two 400 m maximal run tests performed on different days, followed by 40 min of active or passive recovery. Lactate samples were measured immediately after the tests, and at min 10, 20, 30 and 40 of the recoveries. Blood lactate decreases were calculated for each 10-min period. Participants were distributed into three groups according to the T1470A polymorphism (TT, TA and AA).

Results: TT group had a lower blood lactate decrease than AA group during the 10-20 min period of the active recovery (p = 0.018). This period had the highest blood lactate for the whole sample, significantly differing from the other periods (p ≤ 0.003). During the passive recovery, lactate declines were constant except for the 0-10-min period (p ≤ 0.003), suggesting that liver uptake is similar in all the genetic groups, and that the difference seen during the active recovery is mainly due to muscle lactate uptake.

Conclusions: These differences according to the polymorphic variant T1470A suggest that MCT1 affects the plasma lactate decrease during a crucial period of active recovery, where the maximal lactate amount is cleared (i.e. 10-20 min period).
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http://dx.doi.org/10.1007/s00421-016-3365-3DOI Listing
May 2016

Influence of ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms on body weight and body composition changes after a controlled weight-loss intervention.

Appl Physiol Nutr Metab 2016 Mar 25;41(3):307-14. Epub 2015 Nov 25.

a Laboratory of Exercise Physiology Research Group, Department of Health and Human Performance, Faculty of Physical Activity and Sport Sciences, Technical University of Madrid, Ciudad Universitaria de Madrid, Calle Martín Fierro 7. 28040 Madrid, Spain.

The β-2 and β-3 adrenergic receptors (ADRB2 and ADRB3) are thought to play a role in energy expenditure and lipolysis. However, the effects of the ADRB2 glutamine (Gln) 27 glutamic acid (glutamate) (Glu) and ADRB3 tryptophan (Trp) 64 arginine (Arg) polymorphisms on weight loss remain controversial. The aim of this study was to investigate the effect of these polymorphisms on changes in weight and body composition during a controlled weight-loss program. One hundred seventy-three healthy overweight and obese participants (91 women, 82 men) aged 18-50 years participated in a 22-week-long intervention based on a hypocaloric diet and exercise. They were randomly assigned to 1 of 4 groups: strength, endurance, strength and endurance combined, and physical activity recommendations only. Body weight, body mass index (BMI), and body composition variables were assessed before and after the intervention. Genetic analysis was carried out according to standard protocols. No effect of the ADRB2 gene was shown on final weight, BMI, or body composition, although in the supervised male group, Glu27 carriers tended to have greater weight (p = 0.019, 2.5 kg) and BMI (p = 0.019, 0.88 kg/m(2)) reductions than did noncarriers. There seems to be an individual effect of the ADRB3 polymorphism on fat mass (p = 0.004) and fat percentage (p = 0.036), in addition to an interaction with exercise for fat mass (p = 0.038). After the intervention, carriers of the Arg64 allele had a greater fat mass and fat percentage than did noncarriers (p = 0.004, 2.8 kg). In conclusion, the ADRB2 Gln27Glu and ADRB3 Trp64Arg polymorphisms may influence weight loss and body composition, although the current evidence is weak; however, further studies are necessary to clarify their roles.
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http://dx.doi.org/10.1139/apnm-2015-0425DOI Listing
March 2016

6R-tetrahydrobiopterin treated PKU patients below 4 years of age: Physical outcomes, nutrition and genotype.

Mol Genet Metab 2015 May 1;115(1):10-6. Epub 2015 Apr 1.

Gastroenterology and Paediatric Nutrition Unit, Virgen del Camino Hospital, C/ De Irunlarrea 4, 31008, Pamplona, Spain. Electronic address:

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] mgkg(-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.
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http://dx.doi.org/10.1016/j.ymgme.2015.03.007DOI Listing
May 2015
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