Shana E. McCormack

Circulating branched-chain amino acid concentrations are associated with obesity and future insulin resistance in children and adolescents.

What is already known about this subject Circulating concentrations of branched‐chain amino acids (BCAAs) can affect carbohydrate metabolism in skeletal muscle, and therefore may alter insulin sensitivity. BCAAs are elevated in adults with diet‐induced obesity, and are associated with their future risk of type 2 diabetes even after accounting for baseline clinical risk factors.

Metastatic Pheochromocytoma/Paraganglioma Related to Primary Tumor Development in Childhood or Adolescence: Significant Link to SDHB Mutations

PURPOSE To present data on the high rate of SDHB mutations in patients with metastatic pheochromocytoma/paraganglioma whose initial tumor presentation began in childhood or adolescence. PATIENTS AND METHODS From 2000 to 2010, 263 patients with pheochromocytoma/paraganglioma were evaluated through the National Institutes of Health (NIH), Bethesda, MD. Of the 263 patients, 125 patients were found to have metastatic disease; of these 125 patients, 32 patients presented with a tumor before 20 years of age. An additional 17 patients presented with a tumor before 20 years of age but demonstrated no development of metastatic disease. Genetic testing for mutations in the VHL, MEN, and SDHB/C/D genes was performed on patients without previously identified genetic mutations. RESULTS Of the 32 patients who presented with metastatic disease and had their primary tumor in childhood or adolescence, sequence analysis of germline DNA showed SDHB mutations in 23 patients (71.9%), SDHD mutations in three patients (9.4%), VHL mutations in two patients (6.3%), and an absence of a known mutation in four patients (12.5%). The majority of these 32 patients (78.1%) presented with primary tumors in an extra-adrenal location. CONCLUSION The majority of patients with metastatic pheochromocytoma/paraganglioma who presented with a primary tumor in childhood/adolescence had primary extra-adrenal tumors and harbored SDHB mutations. Except for primary tumors located in the head and neck where SDHD genetic testing is advised, we recommend that patients who present with metastatic pheochromocytoma/paraganglioma with primary tumor development in childhood or adolescence undergo SDHB genetic testing before they undergo testing for other gene mutations, unless clinical presentation or family history suggests a different mutation.

Infant BMI or Weight-for-Length and Obesity Risk in Early Childhood.

BACKGROUND: Weight-for-length (WFL) is currently used to assess adiposity under 2 years. We assessed WFL- versus BMI-based estimates of adiposity in healthy infants in determining risk for early obesity. METHODS: Anthropometrics were extracted from electronic medical records for well-child visits for 73 949 full-term infants from a large pediatric network. World Health Organization WFL and BMI z scores (WFL-z and BMI-z, respectively) were calculated up to age 24 months. Correlation analyses assessed the agreement between WFL-z and BMI-z and within-subject tracking over time. Logistic regression determined odds of obesity at 2 years on the basis of adiposity classification at 2 months. RESULTS: Agreement between WFL-z and BMI-z increased from birth to 6 months and remained high thereafter. BMI-z at 2 months was more consistent with measurements at older ages than WFL-z at 2 months. Infants with high BMI (≥85th percentile) and reference WFL (5th–85th percentiles) at 2 months had greater odds of obesity at 2 years than those with high WFL (≥85th percentile) and reference BMI (5th–85th percentiles; odds ratio, 5.49 vs 1.40; P < .001). At 2 months, BMI had a higher positive predictive value than WFL for obesity at 2 years using cut-points of either the 85th percentile (31% vs 23%) or 97.7th percentile (47% vs 29%). CONCLUSIONS: High BMI in early infancy is more strongly associated with early childhood obesity than high WFL. Forty-seven percent of infants with BMI ≥97.7th percentile at 2 months (versus 29% of infants with WFL ≥97.7th percentile at 2 months) were obese at 2 years. Epidemiologic studies focused on assessing childhood obesity risk should consider using BMI in early infancy.

Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5′-UTRs that likely improve translational efficiency, and stabilization of 3′-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD+ redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease.

Effects of exercise and lifestyle modification on fitness, insulin resistance, skeletal muscle oxidative phosphorylation and intramyocellular lipid content in obese children and adolescents

Obesity‐related insulin resistance is highly prevalent in children and adolescents, and contributes to an increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. Intensive exercise training may improve insulin sensitivity.

A trans-ethnic genome-wide association study identifies gender-specific loci influencing pediatric aBMD and BMC at the distal radius

Childhood fractures are common, with the forearm being the most common site. Genome-wide association studies (GWAS) have identified more than 60 loci associated with bone mineral density (BMD) in adults but less is known about genetic influences specific to bone in childhood. To identify novel genetic factors that influence pediatric bone strength at a common site for childhood fractures, we performed a sex-stratified trans-ethnic genome-wide association study of areal BMD (aBMD) and bone mineral content (BMC) Z-scores measured by dual energy X-ray absorptiometry at the one-third distal radius, in a cohort of 1399 children without clinical abnormalities in bone health. We tested signals with P < 5 × 10(-6) for replication in an independent, same-age cohort of 486 Caucasian children. Two loci yielded a genome-wide significant combined P-value: rs7797976 within CPED1 in females [P = 2.4 × 10(-11), β =- 0.30 standard deviations (SD) per T allele; aBMD-Z] and rs7035284 at 9p21.3 in males (P = 1.2 × 10(-8), β = 0.28 SD per G allele; BMC-Z). Signals at the CPED1-WNT16-FAM3C locus have been previously associated with BMD at other skeletal sites in adults and children. Our result at the distal radius underscores the importance of this locus at multiple skeletal sites. The 9p21.3 locus is within a gene desert, with the nearest gene flanking each side being MIR31HG and MTAP, neither of which has been implicated in BMD or BMC previously. These findings suggest that genetic determinants of childhood bone accretion at the radius, a skeletal site that is primarily cortical bone, exist and also differ by sex.

Body mass index (BMI) trajectories in infancy differ by population ancestry and may presage disparities in early childhood obesity.

CONTEXT No consensus definition exists for excess adiposity during infancy. After age 2 years, high body mass index (BMI) is related to adverse cardiometabolic outcomes. Before age 2 years, the utility of BMI as a metric of excess adiposity is unknown. OBJECTIVES The objective of the study was to characterize infant BMI trajectories in a diverse, longitudinal cohort and investigate the relationship between the infancy BMI trajectory and childhood obesity. SUBJECTS Healthy, nonpreterm infants (n = 2114) in the Genetic Causes for Complex Pediatric Disorders study (The Childrens Hospital of Philadelphia) with six or more BMI measurements in the first 13.5 months participated in the study. DESIGN For each infant, the BMI trajectory was modeled using polynomial regression. Independent effects of clinical factors on magnitude and timing of peak BMI were assessed. The relationship between infancy BMI and early childhood BMI (age 4 y) was examined (n = 1075). RESULTS The cohort was 53% male and 61% African-American. Peak BMI was 18.6 ± 1.7 kg/m(2) and occurred at 8.6 ± 1.4 months. In multivariate analysis, boys had a higher (0.50 kg/m(2), P < .001) peak BMI than girls. The peak was higher (0.53 kg/m(2), P ≤ .001) and occurred earlier (by 12 d, P < .001) in African-American vs white children. The odds of obesity at age 4 years increased among children with higher (odds ratio 2.02; P < .001) and later (odds ratio 1.26; P = .02) infancy peak BMI. CONCLUSIONS We demonstrate sex- and ancestry-specific differences in infancy BMI and an association of infancy peak BMI with childhood BMI. These findings support the potential utility of infancy BMI to identify children younger than age 2 years with increased risk for later obesity.

Genetics of Obesity and Type 2 Diabetes in African Americans

Obesity and type 2 diabetes are highly prevalent and lead to significant morbidity and mortality. In the United States, the impact of these conditions may be worse on historically underserved minorities, particularly African Americans. Genetic ancestry and differences in physiology are unlikely to be the sole or primary determinants of these disparities. In addition, research in this area has the ethically problematic possibility of conflating race with biology. Despite these important considerations and the challenges of conducting this work, population-based approaches for investigating the etiology of obesity and T2D may yield useful information about the pathophysiology of disease, and have implications that extend to all affected individuals. The purpose of this paper is to describe what is understood about the genetic variation that underlies obesity and T2D in African Americans and other individuals of more recent African descent and to highlight several examples that illustrate how ensuring adequate minority representation in genetic research improves its quality. For a variety of reasons a number of unique insights have been possible as a result of these efforts.

An integrated mechanism of pediatric pseudotumor cerebri syndrome: evidence of bioenergetic and hormonal regulation of cerebrospinal fluid dynamics

Pseudotumor cerebri syndrome (PTCS) is defined by the presence of elevated intracranial pressure (ICP) in the setting of normal brain parenchyma and cerebrospinal fluid (CSF). Headache, vision changes, and papilledema are common presenting features. Up to 10% of appropriately treated patients may experience permanent visual loss. The mechanism(s) underlying PTCS is unknown. PTCS occurs in association with a variety of conditions, including kidney disease, obesity, and adrenal insufficiency, suggesting endocrine and/or metabolic derangements may occur. Recent studies suggest that fluid and electrolyte balance in renal epithelia is regulated by a complex interaction of metabolic and hormonal factors; these cells share many of the same features as the choroid plexus cells in the central nervous system (CNS) responsible for regulation of CSF dynamics. Thus, we posit that similar factors may influence CSF dynamics in both types of fluid-sensitive tissues. Specifically, we hypothesize that, in patients with PTCS, mitochondrial metabolites (glutamate, succinate) and steroid hormones (cortisol, aldosterone) regulate CSF production and/or absorption. In this integrated mechanism review, we consider the clinical and molecular evidence for each metabolite and hormone in turn. We illustrate how related intracellular signaling cascades may converge in the choroid plexus, drawing on evidence from functionally similar tissues.

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society

The purpose of this statement is to provide consensus-based recommendations for optimal management and care for patients with primary mitochondrial disease. This statement is intended for physicians who are engaged in the diagnosis and management of these patients. Working group members were appointed by the Mitochondrial Medicine Society. The panel included members with several different areas of expertise. The panel members utilized surveys and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve. Consensus-based recommendations are provided for the routine care and management of patients with primary genetic mitochondrial disease.