Publications by authors named "Gabriel A Martos-Moreno"

43 Publications

The pubertal growth spurt is diminished in children with severe obesity.

Pediatr Res 2020 Nov 10. Epub 2020 Nov 10.

Department of Physiology/Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

Background: At the population level, there is a negative linear correlation between childhood body mass index (BMI) and pubertal height gain. However, in children with obesity, there are no studies showing whether the severity of obesity affects pubertal height gain. Moreover, how obesity in childhood affects pubertal timing is controversial, especially in boys. We aimed to investigate the impact of severe obesity in childhood on the pubertal growth spurt in both sexes.

Methods: The study group consisted of 68 patients (32 boys) with childhood onset obesity followed in a Spanish university hospital. The QEPS growth model was used to calculate pubertal growth function estimates for each individual. The highest individual prepubertal BMI SDS value was related to the age at onset of pubertal growth and pubertal height gain. Results were compared to analyses from individuals in a community-based setting (n = 1901) with different weight status.

Results: A higher peak BMI in childhood was associated with less specific pubertal height gain in children with moderate-to-extreme obesity. For boys, the higher the BMI, the earlier the onset of pubertal growth. For girls with obesity, this correlation was not linear.

Conclusions: Obesity in childhood impairs the pubertal growth spurt in a severity-related fashion.

Impact: The higher the BMI in childhood, the lower the pubertal height gain in children with moderate-to-extreme obesity. For boys with obesity, the higher the BMI, the earlier the onset of pubertal growth. The results contribute to the research field of how weight status in childhood is related to pubertal timing and pubertal growth. The results have implications for understanding how childhood obesity is related to further growth.
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http://dx.doi.org/10.1038/s41390-020-01234-3DOI Listing
November 2020

Ethnicity Strongly Influences Body Fat Distribution Determining Serum Adipokine Profile and Metabolic Derangement in Childhood Obesity.

Front Pediatr 2020 9;8:551103. Epub 2020 Oct 9.

Departments of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

Body fat content and distribution in childhood is influenced by sex and puberty, but interethnic differences in the percentage and distribution of body fat also exist. The abdominal visceral/subcutaneous fat ratio has been the main feature of body fat distribution found to associate with the serum adipokine profile and metabolic derangement in adulthood obesity. This has also been assumed for childhood obesity despite the known singularities of this disease in the pediatric age in comparison to adults. We aimed to investigate the effect of ethnicity, together with sex and pubertal status, on body fat content and distribution, serum adipokine profile, metabolic impairment and liver steatosis in children and adolescents with obesity. One hundred and fifty children with obesity (50% Caucasians/50% Latinos; 50% males/50% females) were studied. Body fat content and distribution were studied by whole body DXA-scan and abdominal magnetic resonance, and their relationships with liver steatosis (as determined by ultrasonography), glycemia, insulinemia, lipid metabolism, uric acid, total and HMW-adiponectin, leptin, leptin-receptor, and sex steroid levels were explored. Latino patients had more severe truncal obesity (higher trunk/lower limb fat ratio, odds ratio 10.00; < 0.05) and higher prevalence of liver steatosis than Caucasians regardless of sex or pubertal status, but there were no difference in the visceral/subcutaneous abdominal fat ratio, except for pubertal females. A higher trunk/lower limb fat ratio, but not the visceral/subcutaneous abdominal fat ratio, was associated with adipokine profile impairment (higher free leptin index and lower adiponectin levels), insulin resistance and dyslipidemia, and was further enhanced when liver steatosis was present ( < 0.05). A higher abdominal visceral/subcutaneous fat ratio was observed in prepubertal children ( < 0.01), except for Latino females, whereas predominant subcutaneous fat deposition was observed in adolescents. Ethnicity is one of the main determinants of increased trunk body fat accumulation in Latino children with obesity, which is best estimated by the trunk/lower limb fat ratio and related to the development of metabolic derangement and liver steatosis.
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http://dx.doi.org/10.3389/fped.2020.551103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581788PMC
October 2020

Insulin Resistance in Obese Children: What Can Metabolomics and Adipokine Modelling Contribute?

Nutrients 2020 Oct 29;12(11). Epub 2020 Oct 29.

Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, 28009 Madrid, Spain.

The evolution of obesity and its resulting comorbidities differs depending upon the age of the subject. The dramatic rise in childhood obesity has resulted in specific needs in defining obesity-associated entities with this disease. Indeed, even the definition of obesity differs for pediatric patients from that employed in adults. Regardless of age, one of the earliest metabolic complications observed in obesity involves perturbations in glucose metabolism that can eventually lead to type 2 diabetes. In children, the incidence of type 2 diabetes is infrequent compared to that observed in adults, even with the same degree of obesity. In contrast, insulin resistance is reported to be frequently observed in children and adolescents with obesity. As this condition can be prerequisite to further metabolic complications, identification of biological markers as predictive risk factors would be of tremendous clinical utility. Analysis of obesity-induced modifications of the adipokine profile has been one classic approach in the identification of biomarkers. Recent studies emphasize the utility of metabolomics in the analysis of metabolic characteristics in children with obesity with or without insulin resistance. These studies have been performed with targeted or untargeted approaches, employing different methodologies. This review summarizes some of the advances in this field while emphasizing the importance of the different techniques employed.
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http://dx.doi.org/10.3390/nu12113310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692749PMC
October 2020

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

Authors:
Félixe Pelletier Stefanie Perrier Ferdy K Cayami Amytice Mirchi Stephan Saikali Luan T Tran Nicole Ulrick Kether Guerrero Emmanouil Rampakakis Rosalina M L van Spaendonk Sakkubai Naidu Daniela Pohl William T Gibson Michelle Demos Cyril Goizet Ingrid Tejera-Martin Ana Potic Brent L Fogel Bernard Brais Michel Sylvain Guillaume Sébire Charles Marques Lourenço Joshua L Bonkowsky Coriene Catsman-Berrevoets Pedro S Pinto Sandya Tirupathi Petter Strømme Ton de Grauw Dorota Gieruszczak-Bialek Ingeborg Krägeloh-Mann Hanna Mierzewska Heike Philippi Julia Rankin Tahir Atik Brenda Banwell William S Benko Astrid Blaschek Annette Bley Eugen Boltshauser Drago Bratkovic Klara Brozova Icíar Cimas Christopher Clough Bernard Corenblum Argirios Dinopoulos Gail Dolan Flavio Faletra Raymond Fernandez Janice Fletcher Maria Eugenia Garcia Garcia Paolo Gasparini Janina Gburek-Augustat Dolores Gonzalez Moron Aline Hamati Inga Harting Christoph Hertzberg Alan Hill Grace M Hobson A Micheil Innes Marcelo Kauffman Susan M Kirwin Gerhard Kluger Petra Kolditz Urania Kotzaeridou Roberta La Piana Eriskay Liston William McClintock Meriel McEntagart Fiona McKenzie Serge Melançon Anjum Misbahuddin Mohnish Suri Fernando I Monton Sebastien Moutton Raymond P J Murphy Miriam Nickel Hüseyin Onay Simona Orcesi Ferda Özkınay Steffi Patzer Helio Pedro Sandra Pekic Mercedes Pineda Marfa Amy Pizzino Barbara Plecko Bwee Tien Poll-The Vera Popovic Dietz Rating Marie-France Rioux Norberto Rodriguez Espinosa Anne Ronan John R Ostergaard Elsa Rossignol Rocio Sanchez-Carpintero Anna Schossig Nesrin Senbil Laura K Sønderberg Roos Cathy A Stevens Matthis Synofzik László Sztriha Daniel Tibussek Dagmar Timmann Davide Tonduti Bart P van de Warrenburg Maria Vázquez-López Sunita Venkateswaran Pontus Wasling Evangeline Wassmer Richard I Webster Gert Wiegand Grace Yoon Joost Rotteveel Raphael Schiffmann Marjo S van der Knaap Adeline Vanderver Gabriel Á Martos-Moreno Constantin Polychronakos Nicole I Wolf Geneviève Bernard

J Clin Endocrinol Metab 2021 Jan;106(2):e660-e674

Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.

Context: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date.

Objective: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy.

Design: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated.

Setting: This was a multicenter retrospective study using information collected from 3 predominant centers.

Patients: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included.

Main Outcome Measures: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts.

Results: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients.

Conclusions: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.
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http://dx.doi.org/10.1210/clinem/dgaa700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823228PMC
January 2021

A combination of circulating chemokines as biomarkers of obesity-induced insulin resistance at puberty.

Pediatr Obes 2021 Feb 27;16(2):e12711. Epub 2020 Aug 27.

Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.

Background: In obesity adipose tissue undergoes structural re-modelling leading to a chronic low-grade inflammatory state linked to insulin resistance (IR).

Objective: We aimed to develop a clinically relevant biomarker model for stratifying IR in adolescents with obesity.

Methods: Cytokines [tumour cell derived factor 1α, monocyte chemoattract protein (MCP) 1, eotaxin and fractalkine], growth factors [brain-derived neurotrophic factor, pro-fibrotic platelet-derived growth factor (PDGF-BB) and insulin-like growth factor 1] and biochemical/metabolic factors were analysed in serum of 143 pubertal patients with obesity (50% IR; 50% non-IR) and 33 controls. Factor analysis, correlation, binary logistic regression and receiver operating characteristic analysis were used to evaluate combinations of these biomarkers as possible diagnostic tools for IR.

Results: Two biomarker IR models combining levels of triglycerides (TG)/HDL, eotaxin, MCP-1 and PDGF-BB in pubertal patients with obesity of both sexes were defined. Altered levels of MCP-1, eotaxin, and PDGF-BB constitute a main component that determines 27.7% of the variance explaining IR. Growth and inflammatory factors comprise two other components linked to the first, together accounting for 59.2% of the variance determining IR.

Conclusions: PDGF-BB, MCP-1, eotaxin, TG and cholesterol concentrations constitute a solid panel of biomarkers associated with IR in pubertal children with obesity that could be useful in their stratification in a clinical setting for stratification.
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http://dx.doi.org/10.1111/ijpo.12711DOI Listing
February 2021

Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data.

Bone 2020 08 14;137:115413. Epub 2020 May 14.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, IIS La Princesa, Av. de Menéndez Pelayo, 65, 28009 Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Calle Arzobispo Morcillo, 4, 28029 Madrid, Spain; CIBERobn, Instituto de Salud Carlos III, C/ Sinesio Delgado, 4, 28029 Madrid, Spain. Electronic address:

Asfotase alfa is an enzyme replacement therapy approved for treatment of patients with pediatric-onset hypophosphatasia (HPP), a rare, inherited, systemic disease causing impaired skeletal mineralization, short stature, and reduced physical function in children. The role of dual X-ray absorptiometry (DXA) in the assessment of children with HPP has been insufficiently explored. This post hoc analysis included pooled DXA data from 2 open-label, multicenter studies in 19 children with HPP. The study population was aged ≥5 to <18 years and had received asfotase alfa for ≤6.6 years at enrollment (male: 79%; median age at enrollment: 10.4 y [range: 5.9-16.7]; treatment duration: 6.3 y [range: 0.1-6.6]. Baseline height Z-scores indicated short stature (median [min, max]: -1.26 [-6.6, 0]); mean [SD]: -2.30 [1.97]), thus requiring height adjustment of DXA Z-scores. At Baseline, few patients had height-adjusted bone mineral density (BMD) Z-scores of -2 or less for whole body (n = 3) or lumbar spine (n = 5). In treated patients, mean whole body and lumbar spine BMDZ-scores did not change over time, but whole body and lumbar spine height- adjusted bone mineral content (BMC) Z-scores increased significantly from Baseline to Last Assessment (P ≤ 0.0056). Improvements in Radiographic Global Impression of Change (RGI-C) scale scores correlated significantly with increases in whole body and lumbar spine BMCZ-scores (P < 0.05) but not BMDZ-Scores. Improvements in Rickets Severity Score (RSS) correlated significantly with increases in lumbar spine BMDZ-scores and whole body BMC Z-scores (P < 0.05). No significant correlations were observed between any DXA and bone histomorphometry measure. These findings suggest that DXA BMD Z-scores, which are commonly used in clinical practice, have limited utility in assessing deficient bone mineralization in patients with HPP. Although BMCZ-scores increased significantly over time with asfotase alfa therapy, the lack of significant changes in more than one DXA parameter suggests that this tool may not be useful in everyday clinical practice. Furthermore, the use of BMC as an independent metric is not typical or recommended by guidelines. Complementary measures, such as skeletal radiographs supplemented with age-appropriate functional assessments, should be considered.
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http://dx.doi.org/10.1016/j.bone.2020.115413DOI Listing
August 2020

Clinical and Molecular Description of 16 Families With Heterozygous IHH Variants.

J Clin Endocrinol Metab 2020 08;105(8)

Institute of Medical and Molecular Genetics (INGEMM); IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.

Context: Heterozygous variants in the Indian hedgehog gene (IHH) have been reported to cause brachydactyly type A1 and mild hand and feet skeletal anomalies with short stature. Genetic screening in individuals with short stature and mild skeletal anomalies has been increasing over recent years, allowing us to broaden the clinical spectrum of skeletal dysplasias.

Objective: The objective of this article is to describe the genotype and phenotype of 16 probands with heterozygous variants in IHH.

Patients And Methods: Targeted next-generation sequencing or Sanger sequencing was performed in patients with short stature and/or brachydactyly for which the genetic cause was unknown.

Results: Fifteen different heterozygous IHH variants were detected, one of which is the first reported complete deletion of IHH. None of the patients showed the classical phenotype of brachydactyly type A1. The most frequently observed clinical characteristics were mild to moderate short stature as well as shortening of the middle phalanx on the fifth finger. The identified IHH variants were demonstrated to cosegregate with the short stature and/or brachydactyly in the 13 probands whose family members were available. However, clinical heterogeneity was observed: Two short-statured probands showed no hand radiological anomalies, whereas another 5 were of normal height but had brachydactyly.

Conclusions: Short stature and/or mild skeletal hand defects can be caused by IHH variants. Defects in this gene should be considered in individuals with these findings, especially when there is an autosomal dominant pattern of inheritance. Although no genotype-phenotype correlation was observed, cosegregation studies should be performed and where possible functional characterization before concluding that a variant is causative.
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http://dx.doi.org/10.1210/clinem/dgaa218DOI Listing
August 2020

Sex, puberty, and ethnicity have a strong influence on growth and metabolic comorbidities in children and adolescents with obesity: Report on 1300 patients (the Madrid Cohort).

Pediatr Obes 2019 12 2;14(12):e12565. Epub 2019 Aug 2.

Department of Endocrinology, Research Institute "La Princesa", Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, 65E-28009, Madrid, Spain.

Background: The capacity to correctly assess insulin resistance and its role in further obesity-associated metabolic derangement in children is under debate, and its determinants remain largely unknown.

Objective: We investigated the association of the insulin secretion profile with other metabolic derangements and anthropometric features in children and adolescents with obesity, exploring the role of ethnicity.

Patients And Methods: Growth and metabolic features, including fasting insulin levels and insulin secretory profile in an oral glucose tolerance test (OGTT), were analyzed according to ethnicity in 1300 patients with obesity (75.8% Caucasians/19.0% Latinos).

Results: Height and bone age were influenced by sex, ethnicity, and insulinemia. Latino patients had higher insulin (P < .001), but similar glycemia both prepubertally and postpubertally, compared with Caucasians. Type 2 diabetes was uncommon (0.1%). Impaired glucose tolerance was associated to higher age, BMI, uric acid, and triglyceride levels (all P < .05), as was fasting hyperinsulinism. Impaired fasting glucose or HbA1c 5.7% to 6.4% showed no association with further metabolic derangement. A delayed insulin peak in the OGTT was associated to more severe metabolic disturbances.

Conclusions: Obesity-associated hyperglycemia is unusual in our environment whereas fasting and late postprandial hyperinsulinemia are highly prevalent, with this being influenced by race and closely related with lipid metabolism impairment.
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http://dx.doi.org/10.1111/ijpo.12565DOI Listing
December 2019

Natural History of Perinatal and Infantile Hypophosphatasia: A Retrospective Study.

J Pediatr 2019 06 9;209:116-124.e4. Epub 2019 Apr 9.

University Children's Hospital, University of Würzburg, Würzburg, Germany.

Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia.

Study Design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6-dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator-free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life.

Results: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6-dependent seizures and respiratory distress and failure were associated significantly (P < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4] U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator-free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years.

Conclusions: Patients with perinatal or infantile hypophosphatasia and vitamin B6-dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life.

Trial Registration: ClinicalTrials.gov: NCT01419028.
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http://dx.doi.org/10.1016/j.jpeds.2019.01.049DOI Listing
June 2019

Heterozygous rare genetic variants in non-syndromic early-onset obesity.

Int J Obes (Lond) 2020 04 29;44(4):830-841. Epub 2019 Mar 29.

Hospital Infantil Universitario Niño Jesús, Department of Endocrinology, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Department of Pediatrics, Avenida Menéndez Pelayo, 65, 28009, Madrid, Spain.

Background: Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions.

Objective: We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to non-syndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years).

Methods: Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset.

Results: Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets.

Conclusions: Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in ~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.
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http://dx.doi.org/10.1038/s41366-019-0357-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101277PMC
April 2020

Efficacy and Safety of Asfotase Alfa in Infants and Young Children With Hypophosphatasia: A Phase 2 Open-Label Study.

J Clin Endocrinol Metab 2019 07;104(7):2735-2747

Children's Hospital Research Institute of Manitoba, Winnipeg, Manitoba, Canada.

Context: Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.

Objective: To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP followed for up to 6 years.

Design: Phase 2 open-label study (July 2010 to September 2016).

Setting: Twenty-two sites; 12 countries.

Participants: Sixty-nine patients [median (range) age: 16.0 (0.02 to 72) months] with severe HPP and sign/symptom onset before age 6 months.

Intervention: Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.

Main Outcome Measures: Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score [-3 (severe worsening) to +3 (complete/near-complete healing)]. Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).

Results: During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 [+2.0 (-1.7, +3.0)], Year 1 [+2.0 (-2.3, +3.0)], and Last Assessment [+2.3 (-2.7, +3.0); P < 0.0001 all]. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders [n = 50 (72%)], nonresponders [n = 19 (28%)] had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.

Conclusions: Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
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http://dx.doi.org/10.1210/jc.2018-02335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6530655PMC
July 2019

Metabolomics changes in patients with PAPP-A2 deficiency in response to rhIGF1 treatment.

Growth Horm IGF Res 2018 Oct - Dec;42-43:28-31. Epub 2018 Aug 12.

Departments of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain; La Princesa Research Institute, Madrid, Spain; Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutriciόn (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain; IMDEA Food Institute, CEI UAM & CSIC, Madrid, Spain. Electronic address:

Objective: Mutations in the pregnancy-associated plasma protein A2 (PAPP-A2) gene have recently been shown to cause postnatal growth failure in two prepubertal patients from a non-consanguineous Spanish family due to the resulting decrease in IGF1 bioavailability. Although a specific pharmacological treatment of this entity is yet to be established, both children received progressive subcutaneous doses (40 to 120 μg/kg) of rhIGF1 twice daily for 2 years. The improvements in growth, hyperinsulinemia and bone mineral density have been previously reported. The objective of this study was to analyze the changes in metabolism associated with these responses to rhIGF1 treatment.

Design: Herein we present a detailed characterization of the acute and long-term changes in the metabolic profiles of these two siblings with PAPP-A2 deficiency after the initial injections of rhIGF1 and after two years of treatment.

Results: By using a GC-MS-based untargeted metabolomics approach, metabolic fingerprinting yielded the identification of 70 serum metabolites including amino acids (46%), organic acids (21%) carbohydrates (16%), fatty acids (14%), and purine bases (3%). Free fatty acids (FFAs) and amino acids showed the largest changes in the compared metabolic profiles, suggesting that rhIGF1 treatment has the greatest effects on lipid and protein metabolic pathways in the PAPP-A2 deficient subjects.

Conclusions: The administration of rhIGF1 resulted in changes related to crucial metabolic pathways, including lipid and protein metabolism, and this could be associated with the previously reported treatment-induced improvement in the mild basal hyperinsulinemia.
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http://dx.doi.org/10.1016/j.ghir.2018.08.002DOI Listing
March 2019

Response to growth hormone in patients with mutations.

EMBO Mol Med 2018 07;10(7)

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain.

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http://dx.doi.org/10.15252/emmm.201809143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034130PMC
July 2018

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature.

Clin Endocrinol (Oxf) 2018 06 24;88(6):820-829. Epub 2018 Mar 24.

Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, Universidad Autonóma de Madrid, IdiPAZ, Madrid, Spain.

Objective: Mutations in the aggrecan gene (ACAN) have been identified in two autosomal dominant skeletal dysplasias, spondyloepiphyseal dysplasia, Kimberley type (SEDK), and osteochondritis dissecans, as well as in a severe recessive dysplasia, spondyloepimetaphyseal dysplasia, aggrecan type. Next-generation sequencing (NGS) has aided the identification of heterozygous ACAN mutations in individuals with short stature, minor skeletal defects and mild facial dysmorphisms, some of whom have advanced bone age (BA), poor pubertal spurt and early growth cessation as well as precocious osteoarthritis.

Design And Methods: This study involves clinical and genetic characterization of 16 probands with heterozygous ACAN variants, 14 with short stature and mild skeletal defects (group 1) and two with SEDK (group 2). Subsequently, we reviewed the literature to determine the frequency of the different clinical characteristics in ACAN-positive individuals.

Results: A total of 16 ACAN variants were located throughout the gene, six pathogenic mutations and 10 variants of unknown significance (VUS). Interestingly, brachydactyly was observed in all probands. Probands from group 1 with a pathogenic mutation tended to be shorter, and 60% had an advanced BA compared to 0% in those with a VUS. A higher incidence of coxa valga was observed in individuals with a VUS (37% vs 0%). Nevertheless, other features were present at similar frequencies.

Conclusions: ACAN should be considered as a candidate gene in patients with short stature and minor skeletal defects, particularly those with brachydactyly, and in patients with spondyloepiphyseal dysplasia. It is also important to note that advanced BA and osteoarticular complications are not obligatory conditions for aggrecanopathies/aggrecan-associated dysplasias.
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http://dx.doi.org/10.1111/cen.13581DOI Listing
June 2018

rhIGF-1 Treatment Increases Bone Mineral Density and Trabecular Bone Structure in Children with PAPP-A2 Deficiency.

Horm Res Paediatr 2018 16;89(3):200-204. Epub 2018 Feb 16.

Department of Pediatrics and Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain.

Aim: Our objective was to determine changes in bone mineral density (BMD), trabecular bone score (TBS), and body composition after 2 years of therapy with recombinant human insulin-like growth factor-1 (rhIGF-1) in 2 prepubertal children with a complete lack of circulating PAPP-A2 due to a homozygous mutation in PAPP-A2 (p.D643fs25*) resulting in a premature stop codon.

Methods: Body composition, BMD, and bone structure were determined by dual-energy X-ray absorptiometry at baseline and after 1 and 2 years of rhIGF-1 treatment.

Results: Height increased from 132 to 145.5 cm (patient 1) and from 111.5 to 124.5 cm (patient 2). Bone mineral content increased from 933.40 to 1,057.97 and 1,152.77 g in patient 1, and from 696.12 to 773.26 and 911.51 g in patient 2, after 1 and 2 years, respectively. Whole-body BMD also increased after 2 years of rhIGF-1 from baseline 0.788 to 0.869 g/cm2 in patient 1 and from 0.763 to 0.829 g/cm2 in patient 2. After 2 years of treatment, both children had an improvement in TBS. During therapy, a slight increase in body fat mass was seen, with a concomitant increase in lean mass. No adverse effects were reported.

Conclusion: Two years of rhIGF-1 improved growth, with a tendency to improve bone mass and bone microstructure and to modulate body composition.
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http://dx.doi.org/10.1159/000486336DOI Listing
September 2018

[Hypophosphatasia: Clinical manifestations, diagnostic recommendations and therapeutic options].

An Pediatr (Barc) 2018 Jun 16;88(6):356.e1-356.e11. Epub 2017 Jul 16.

Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Sanitaria La Princesa, Departamento de Pediatría, Universidad Autónoma de Madrid, CIBERobn, Instituto de Salud Carlos III, Madrid, España; Instituto de Alimentación IMDEA, CEI UAM+CSIC, Madrid, España.

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.
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http://dx.doi.org/10.1016/j.anpedi.2017.06.004DOI Listing
June 2018

The impact of intrauterine and extrauterine weight gain in premature infants on later body composition.

Pediatr Res 2017 Oct 5;82(4):658-664. Epub 2017 Jul 5.

Department of Neonatology, Hospital Universitario La Paz, Red de Salud Materno Infantil y Desarrollo - SAMID, Universidad Autónoma de Madrid, Madrid, Spain.

BackgroundThe impact of intrauterine and extrauterine growth on later insulin resistance and fat mass (FM) in very low birth weight (VLBW) infants is not well established. The aim of our study was to evaluate the effects of intrauterine and early/late extrauterine growth on later insulin resistance and body composition in VLBW infants from 6 months' corrected age (CA) to 36 months.MethodsProspective measurements of body composition by dual-energy X-ray absorptiometry and insulin resistance by homeostasis model assessment insulin resistance (HOMA-IR) along with other fasting plasma biochemistries were made in 95 VLBW infants at 6, 12, 18, and 24 months' CA and 36 months' postnatal age. Mixed-effect models were used to evaluate the effects of age, sex, maturation status, and Δweight SD score on percentage FM (PFM), FM index (FMI), fat-free mass index (FFMI), and HOMA-IR.ResultsPFM and FMI were negatively associated with a decrease in weight-SD scores from birth to 36 weeks' postmenstrual age (PMA; P=0.001) and from 36 weeks' PMA to 6 months' CA (P=0.003). PFM and FMI were higher in AGA than in small for gestational age (SGA) infants. HOMA-IR was not associated with the Δweight-SD scores in either period.ConclusionsCatch-down growth in terms of weight is associated with persistently lower adiposity but not insulin resistance up to 36 months of age.
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http://dx.doi.org/10.1038/pr.2017.123DOI Listing
October 2017

Novel genes involved in severe early-onset obesity revealed by rare copy number and sequence variants.

PLoS Genet 2017 May 10;13(5):e1006657. Epub 2017 May 10.

Genetics Unit, Universitat Pompeu Fabra, Barcelona, Spain.

Obesity is a multifactorial disorder with high heritability (50-75%), which is probably higher in early-onset and severe cases. Although rare monogenic forms and several genes and regions of susceptibility, including copy number variants (CNVs), have been described, the genetic causes underlying the disease still remain largely unknown. We searched for rare CNVs (>100kb in size, altering genes and present in <1/2000 population controls) in 157 Spanish children with non-syndromic early-onset obesity (EOO: body mass index >3 standard deviations above the mean at <3 years of age) using SNP array molecular karyotypes. We then performed case control studies (480 EOO cases/480 non-obese controls) with the validated CNVs and rare sequence variants (RSVs) detected by targeted resequencing of selected CNV genes (n = 14), and also studied the inheritance patterns in available first-degree relatives. A higher burden of gain-type CNVs was detected in EOO cases versus controls (OR = 1.71, p-value = 0.0358). In addition to a gain of the NPY gene in a familial case with EOO and attention deficit hyperactivity disorder, likely pathogenic CNVs included gains of glutamate receptors (GRIK1, GRM7) and the X-linked gastrin-peptide receptor (GRPR), all inherited from obese parents. Putatively functional RSVs absent in controls were also identified in EOO cases at NPY, GRIK1 and GRPR. A patient with a heterozygous deletion disrupting two contiguous and related genes, SLCO4C1 and SLCO6A1, also had a missense RSV at SLCO4C1 on the other allele, suggestive of a recessive model. The genes identified showed a clear enrichment of shared co-expression partners with known genes strongly related to obesity, reinforcing their role in the pathophysiology of the disease. Our data reveal a higher burden of rare CNVs and RSVs in several related genes in patients with EOO compared to controls, and implicate NPY, GRPR, two glutamate receptors and SLCO4C1 in highly penetrant forms of familial obesity.
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http://dx.doi.org/10.1371/journal.pgen.1006657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443539PMC
May 2017

Molecular and clinical analysis of ALPL in a cohort of patients with suspicion of Hypophosphatasia.

Am J Med Genet A 2017 Mar 27;173(3):601-610. Epub 2017 Jan 27.

Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz, IdiPAZ, Universidad Autónoma de Madrid, Madrid, Spain.

Hypophosphatasia (HPP) is a rare autosomal dominant or recessive metabolic disorder caused by mutations in the tissue nonspecific alkaline phosphatase gene (ALPL). To date, over 300 different mutations in ALPL have been identified. Disease severity is widely variable with severe forms usually manifesting during perinatal and/or infantile periods while mild forms are sometimes only diagnosed in adulthood or remain undiagnosed. Common clinical features of HPP are defects in bone and tooth mineralization along with the biochemical hallmark of decreased serum alkaline phosphatase activity. The incidence of severe HPP is approximately 1 in 300,000 in Europe and 1 in 100,000 in Canada. We present the clinical and molecular findings of 83 probands and 28 family members, referred for genetic analysis due to a clinical and biochemical suspicion of HPP. Patient referrals included those with isolated low alkaline phosphatase levels and without any additional clinical features, to those with a severe skeletal dysplasia. Thirty-six (43.3%) probands were found to have pathogenic ALPL mutations. Eleven previously unreported mutations were identified, thus adding to the ever increasing list of ALPL mutations. Seven of these eleven were inherited in an autosomal dominant manner while the remaining four were observed in the homozygous state. Thus, this study includes a large number of well-characterized patients with hypophosphatasemia which has permitted us to study the genotype:phenotype correlation. Accurate diagnosis of patients with a clinical suspicion of HPP is crucial as not only is the disease life-threatening but the patients may be offered bone targeted enzymatic replacement therapy. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37991DOI Listing
March 2017

Treatment With Recombinant Human Insulin-Like Growth Factor-1 Improves Growth in Patients With PAPP-A2 Deficiency.

J Clin Endocrinol Metab 2016 Nov 20;101(11):3879-3883. Epub 2016 Sep 20.

Department of Pediatrics and Pediatric Endocrinology (M.T.M.-C., V.B., J.P., J.A.C., G.A.M.-M., J.A.) Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Universidad Autónoma de Madrid, Department of Pediatrics, Centro de Investigación Biomédica en Red (CIBEROBN), Instituto de Salud Carlos III, 28009 Madrid, Spain; Department of Endocrinology (F.H.), Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, 28040 Madrid, Spain; Cincinnati Center for Growth Disorders (A.D.), Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229; Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE) (H.M.D.), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), FEI, División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, Argentina; Department of Basic Science and Craniofacial Biology (S.Y.), New York University College of Dentistry, New York, New York 10010; Oregon Health and Science University (R.G.R.), Portland, Oregon 97239; Stat5 LLC (R.G.R.), Los Altos, California 94022; Genetics Unit (L.A.P.-J.), Universitat Pompeu Fabra, Hospital del Mar Research Institute (IMIM), and CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 08003 Barcelona, Spain; Department of Molecular Biology and Genetics (C.O.), Aarhus University, 8000 Aarhus, Denmark; and Medical Research Laboratory (J.F.), Department of Clinical Medicine, Faculty of Health, Aarhus University and Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8000 Aarhus, Denmark.

Context: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that specifically cleaves IGFBP-3 and IGFBP-5. Mutations in the PAPP-A2 gene have recently been shown to cause postnatal growth failure in humans, with specific skeletal features, due to the resulting decrease in IGF-1 bioavailability. However, a pharmacological treatment of this entity is yet to be established.

Case Description: A 10.5-year-old girl and a 6-year-old boy, siblings from a Spanish family, with short stature due to a homozygous loss-of-function mutation in the PAPP-A2 gene (p.D643fs25*) and undetectable PAPP-A2 activity, were treated with progressive doses (40, 80, 100, and 120 μg/kg) of recombinant human IGF-1 (rhIGF-1) twice daily for 1 year. There was a clear increase in growth velocity and height in both siblings. Bioactive IGF-1 was increased, and spontaneous GH secretion was diminished after acute administration of rhIGF-1, whereas serum total IGF-1 and IGFBP-3 levels remained elevated. No episodes of hypoglycemia or any other secondary effects were observed during treatment.

Conclusion: Short-term treatment with rhIGF-1 improves growth in patients with PAPP-A2 deficiency.
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http://dx.doi.org/10.1210/jc.2016-2751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393598PMC
November 2016

[X-linked hypophosphatemic rickets due to mutations in PHEX: Clinical and evolutionary variability].

An Pediatr (Barc) 2016 Jul 21;85(1):41-3. Epub 2016 May 21.

Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, España; Departamento de Pediatría, Universidad Autónoma de Madrid, Madrid, España; CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, España. Electronic address:

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http://dx.doi.org/10.1016/j.anpedi.2016.04.012DOI Listing
July 2016

[Skeletal dysplasias: New medical treatments].

An Pediatr (Barc) 2016 Jul 23;85(1):1-3. Epub 2016 Apr 23.

Servicio de Pediatría, Hospital Infantil Universitario Niño Jesús, Madrid, España; Servicio de Endocrinología, Hospital Infantil Universitario Niño Jesús, Madrid, España; Departamento de Pediatría, Universidad Autónoma de Madrid, Madrid, España; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, España.

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http://dx.doi.org/10.1016/j.anpedi.2016.03.015DOI Listing
July 2016

Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability.

EMBO Mol Med 2016 04;8(4):363-74

Department of Pediatrics & Pediatric Endocrinology, Hospital Infantil Universitario Niño Jesús Instituto de Investigación La Princesa Universidad Autónoma de Madrid, Madrid, Spain Program of Pediatric Obesity, CIBEROBN Instituto de Salud Carlos III, Madrid, Spain

Mutations in multiple genes of the growth hormone/IGF-I axis have been identified in syndromes marked by growth failure. However, no pathogenic human mutations have been reported in the six high-affinity IGF-binding proteins (IGFBPs) or their regulators, such as the metalloproteinase pregnancy-associated plasma protein A2 (PAPP-A2) that is hypothesized to increase IGF-I bioactivity by specific proteolytic cleavage of IGFBP-3 and -5. Multiple members of two unrelated families presented with progressive growth failure, moderate microcephaly, thin long bones, mildly decreased bone density and elevated circulating total IGF-I, IGFBP-3, and -5, acid labile subunit, and IGF-II concentrations. Two different homozygous mutations in PAPPA2, p.D643fs25* and p.Ala1033Val, were associated with this novel syndrome of growth failure. In vitro analysis of IGFBP cleavage demonstrated that both mutations cause a complete absence of PAPP-A2 proteolytic activity. Size-exclusion chromatography showed a significant increase in IGF-I bound in its ternary complex. Free IGF-I concentrations were decreased. These patients provide important insights into the regulation of longitudinal growth in humans, documenting the critical role of PAPP-A2 in releasing IGF-I from its BPs.
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http://dx.doi.org/10.15252/emmm.201506106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4818753PMC
April 2016

Large exonic deletions in POLR3B gene cause POLR3-related leukodystrophy.

Orphanet J Rare Dis 2015 Jun 5;10:69. Epub 2015 Jun 5.

Departments of Pediatrics, Neurology and Neurosurgery, Montreal Children's Hospital, McGill University Health Center, 1001 Boulevard Décarie, Montréal, QC, H4A 3J1, Canada.

POLR3-related (or 4H) leukodystrophy is an autosomal recessive disorder caused by mutations in POLR3A or POLR3B and is characterized by neurological and non-neurological features. In a small proportion of patients, no mutation in either gene or only one mutation is found. Analysis of the POLR3B cDNA revealed a large deletion of exons 21-22 in one case and of exons 26-27 in another case. These are the first reports of long deletions causing POLR3-related leukodystrophy, suggesting that deletions and duplications in POLR3A or POLR3B should be investigated in patients with a compatible phenotype, especially if one pathogenic variant has been identified.
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http://dx.doi.org/10.1186/s13023-015-0279-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520020PMC
June 2015

A proteomic approach to obesity and type 2 diabetes.

J Cell Mol Med 2015 Jul 9;19(7):1455-70. Epub 2015 May 9.

Departments of Endocrinology and Pediatrics, Hospital Infantil Universitario Niño Jesús, Universidad Autónoma de Madrid, Madrid, Spain.

The incidence of obesity and type diabetes 2 has increased dramatically resulting in an increased interest in its biomedical relevance. However, the mechanisms that trigger the development of diabetes type 2 in obese patients remain largely unknown. Scientific, clinical and pharmaceutical communities are dedicating vast resources to unravel this issue by applying different omics tools. During the last decade, the advances in proteomic approaches and the Human Proteome Organization have opened and are opening a new door that may be helpful in the identification of patients at risk and to improve current therapies. Here, we briefly review some of the advances in our understanding of type 2 diabetes that have occurred through the application of proteomics. We also review, in detail, the current improvements in proteomic methodologies and new strategies that could be employed to further advance our understanding of this pathology. By applying these new proteomic advances, novel therapeutic and/or diagnostic protein targets will be discovered in the obesity/Type 2 diabetes area.
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http://dx.doi.org/10.1111/jcmm.12600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511345PMC
July 2015

[Obesity associated metabolic impairment is evident at early ages: Spanish collaborative study].

Nutr Hosp 2014 Oct 1;30(4):787-93. Epub 2014 Oct 1.

Unidad de Endocrinología Infantil. Hospital Universitario de Cruces de Barakaldo España..

Unlabelled: The objectives of this study are to provide a description of the demographic, anthropometric characteristics and metabolic abnormalities in children with early-onset (< 10 years) and of very-early-onset obesity (< 5 years). We also evaluate the diagnostic ability using the definition of metabolic syndrome (MS) according to different criteria.

Methods: It is a retrospective, case-control, cross-sectional, multicenter study. A total of 10 Pediatric Endocrinology Units in different Spanish hospitals were involved. A group of 469 children with early-onset obesity and another group of 30 children with very early-onset obesity were studied. The control group consisted of 224 healthy children younger than 10 years. Anthropometric and analytical determination of carbohydrates metabolism parameters and the lipid profile were performed.

Results: The presence of metabolic alterations associated with obesity in children and adolescents in Spain is remarkable, either on their own, or encompassed within the definition of MS. This prevalence increases substantially when considering the peripheral resistance to insulin action as a diagnostic criterion. It also shows how children who could not be diagnosed with MS according to the definition provided by the International Diabetes Federation (IDF) due to age below 10 years, these alterations are already present in a remarkable percentage. In fact, metabolic abnormalities are already present in the very-early-onset obese children ( <5 years).

Conclusion: In Spanish children there are metabolic alterations associated with obesity in the infant-juvenile stages alone or encompassed within the definition of MS,and are already present at earlier ages.
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http://dx.doi.org/10.3305/nh.2014.30.4.7661DOI Listing
October 2014

Underdiagnosed Beckwith-Wiedemann syndrome among early onset obese children.

Arch Dis Child 2014 Oct 1;99(10):965-7. Epub 2014 Aug 1.

Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Instituto de Investigación La Princesa, Madrid, Spain Department of Pediatrics, Universidad Autónoma de Madrid, Madrid, Spain CIBER Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain.

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http://dx.doi.org/10.1136/archdischild-2014-307097DOI Listing
October 2014

Proteomic analysis allows for early detection of potential markers of metabolic impairment in very young obese children.

Int J Pediatr Endocrinol 2014 10;2014(1). Epub 2014 Jun 10.

Edison Biotechnology Institute, Ohio University, Konneker Research Laboratories, 1 Water Tower Drive, The Ridges, 45701 Athens, Ohio, USA ; Molecular and Cellular Biology Program, Ohio University, Athens, Ohio, USA ; Department of Biomedical Sciences, College of Osteopathic Medicine, Ohio University, Athens, Ohio, USA.

Background: Early diagnosis of initial metabolic derangements in young obese children could influence their management; however, this impairment is frequently not overt, but subtle and undetectable by routinely used clinical assays. Our aim was to evaluate the ability of serum proteomic analysis to detect these incipient metabolic alterations in comparison to standard clinical methods and to identify new candidate biomarkers.

Methods: A cross-sectional study of fasting serum samples from twenty-two prepubertal, Caucasian obese (OB; 9.22 ± 1.93 years; 3.43 ± 1.08 BMI-SDS) and twenty-one lean controls (C; 8.50 ± 1.98 years; -0.48 ± 0.81 BMI-SDS) and a prospective study of fasting serum samples from twenty prepubertal, Caucasian obese children (11 insulin resistant [IR]) before (4.77 ± 1.30 BMI-SDS) and after weight reduction (2.57 ± 1.29 BMI-SDS) by conservative treatment in a reference hospital (Pros-OB) was performed. Proteomic analysis (two-dimension-eletrophoresis + mass spectrometry analysis) of serum and comparative evaluation of the sensitivity of routinely used assays in the clinics to detect the observed differences in protein expression level, as well as their relationship with anthropometric features, insulin resistance indexes, lipid profile and adipokine levels were carried out.

Results: Study of the intensity data from proteomic analysis showed a decrease of several isoforms of apolipoprotein-A1, apo-J/clusterin, vitamin D binding protein, transthyretin in OB vs. C, with some changes in these proteins being enhanced by IR and partially reversed after weight loss. Expression of low molecular weight isoforms of haptoglobin was increased in OB, enhanced in IR and again decreased after weight loss, being positively correlated with serum interleukin-6 and NAMPT/visfatin levels. After statistical correction for multiple comparisons, significance remained for a single isoform of low MW haptoglobin (OB vs. C and IR vs. non-IR) and Apo A1 (IR vs. non-IR). Assays routinely used in the clinical setting (ELISA/kinetic nephelometry), only partially confirmed the changes observed by proteomic analysis (ApoA1 and haptoglobin).

Conclusion: Proteomic analysis can allow for the identification of potential new candidate biomarkers as a complement to routinely used assays to detect initial changes in serum markers of inflammation and lipid metabolism impairment in young obese children.
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http://dx.doi.org/10.1186/1687-9856-2014-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4063220PMC
June 2014