Joan C. Han

Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.

The FTO gene rs9939609 obesity-risk allele and loss of control over eating

BACKGROUND Children with rs9939609 FTO variant alleles (homozygous = AA and heterozygous = AT) are predisposed to greater adiposity than are those with 2 wild-type alleles (TT). OBJECTIVE Because FTO is highly expressed in hypothalamic regions that are important for appetite, FTO genotype may affect energy balance by influencing eating behavior. Loss of control (LOC) eating, a behavior commonly reported by overweight youth, predicts excessive weight gain in children. However, the relation between FTO genotype and LOC eating has not been previously examined. DESIGN Two-hundred eighty-nine youth aged 6-19 y were genotyped for rs9939609, underwent body-composition measurements, and were interviewed to determine the presence or absence of LOC eating. A subset (n = 190) participated in a lunch buffet test meal designed to model an LOC eating episode. Subjects with AA and AT genotypes were grouped together for comparison with wild-type TT subjects. RESULTS Subjects with at least one A allele (67.7%) had significantly greater body mass indexes, body mass index z scores (P < 0.01), and fat mass (P < 0.05). Of the AA/AT subjects, 34.7% reported LOC compared with 18.2% of the TT subjects (P = 0.002). Although total energy intake at the test meal did not differ significantly by genotype (P = 0.61), AA/AT subjects consumed a greater percentage of energy from fat than did the TT subjects (P < 0.01). CONCLUSIONS Children and adolescents with 1 or 2 FTO rs9939609 obesity-risk alleles report more frequent LOC eating episodes and select foods higher in fat at a buffet meal. Both LOC eating and more frequent selection of energy-dense, palatable foods may be mechanisms through which variant FTO alleles lead to excess body weight.

Compound Heterozygosity for Mutations in PAX6 in a Patient With Complex Brain Anomaly, Neonatal Diabetes Mellitus, and Microophthalmia

We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals. Published 2009 Wiley‐Liss, Inc.

The Stability of Metabolic Syndrome in Children and Adolescents

CONTEXT Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome. OBJECTIVE To examine the short- and long-term stability of pediatric metabolic syndrome. DESIGN Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6-17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6-12 yr at baseline. PATIENTS AND SETTING Convenience samples of obese and nonobese youth ages 6-17 yr participating in research studies were collected at a clinical research hospital. RESULTS Short-term metabolic syndrome stability (repeat measurements performed 19.7 +/- 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 +/- 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases. CONCLUSIONS Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.

Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome is a rare genomic disorder caused by deletion of the 11p14-p12 chromosome region. The majority of WAGR patients have mental retardation and behavioral problems, and more than 20% of the patients also have features of autism. While the Wilms tumor/genitourinary anomalies and aniridia are caused by deletion of WT1 and PAX6 respectively, the genomic cause of mental retardation and autism in WAGR syndrome remains unknown. Using oligonucleotide arrays, we have characterized the 11p14-p12 deletions in 31 patients and identified all the genes involved in each deletion. The deletions had sizes ranging from 4.9 to 23 Mb that encompass 18–62 genes (40 on average). In addition to WT1 and PAX6, all the patients had deletion of PRRG4 (transmembrane gamma-carboxyglutamic acid protein 4). The majority of them had deletion of BDNF (brain-derived neurotrophic factor) and SLC1A2 [solute carrier family 1 (glial high affinity glutamate transporter) member 2]. Deletion of BDNF and SLC1A2 occurred in patients with autism more frequently than in those without autism. Literature review on the functions of the genes suggests that haploinsufficiency of SLC1A2, PRRG4, and BDNF may contribute to mental retardation and behavioral problems. In particular, BDNF may modulate the risk of autism in WAGR patients as suggested by its link with Rett syndrome as a target of MECP2. We observed that all the de novo deletions occurred in the chromosome 11 inherited from the father in the families genotyped, implying a predisposition for de novo mutations occurring in spermatogenesis and possible involvement of imprinting in cognitive impairment in WAGR patients.

Patients with Bardet-Biedl Syndrome Have Hyperleptinemia Suggestive of Leptin Resistance

OBJECTIVE Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls. DESIGN AND METHODS Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype. RESULTS Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations. CONCLUSIONS Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

Lower Brain-Derived Neurotrophic Factor in Patients with Prader-Willi Syndrome Compared to Obese and Lean Control Subjects

CONTEXT Brain-derived neurotrophic factor (BDNF) haploinsufficiency is associated with hyperphagia and obesity in both animals and humans. BDNF appears to function downstream of the leptin-melanocortin signaling pathway to control energy balance. The potential role of BDNF in the etiology of the severe hyperphagia associated with PWS has not been previously explored. OBJECTIVE The aim was to compare BDNF concentrations in subjects with PWS and obese controls (OC) and lean controls (LC). DESIGN AND SETTING We conducted a cross-sectional study at an outpatient clinical research center. PARTICIPANTS We studied 13 subjects with PWS [five females and eight males; mean + or - sd: age, 11.0 + or - 4.1 yr; body mass index (BMI)-Z, 2.05 + or - 0.78], 13 OC (eight females, five males; age, 12.3 + or - 2.7 yr; BMI-Z, 2.18 + or - 0.61), and 13 LC (six females, seven males; age, 12.4 + or - 2.6 yr; BMI-Z, -0.57 + or - 0.73). MAIN OUTCOME MEASURE BDNF was measured in serum and plasma by ELISA. Analysis of covariance adjusted for age, sex, and BMI-Z. RESULTS All groups were comparable for age (P = 0.50) and sex distribution (P = 0.49). BMI-Z was comparable between PWS and OC (P = 0.89) and lower in LC (P < 0.001). Adjusted serum BDNF was comparable (P = 0.35) in OC (mean + or - sem: 13.5 + or - 1.2 ng/ml) and LC (19.2 + or - 1.3 ng/ml), but lower in PWS (8.3 + or - 1.2 ng/ml; P = 0.01 vs. OC; P = 0.03 vs. LC). Adjusted plasma BDNF in PWS (217 + or - 130 pg/ml) was lower than OC (422 + or - 126 pg/ml; P = 0.02), but statistically comparable with LC (540 + or - 143 pg/ml; P = 0.10). CONCLUSIONS Lower BDNF in PWS suggests insufficient central BDNF production because BDNF in peripheral circulation is believed to reflect cerebral BDNF output. Decreased BDNF may be a potential cause for the disordered satiety and morbid obesity associated with PWS. Further studies are needed to confirm this preliminary pilot study in a larger cohort of patients with PWS.

Psychological Symptoms and Insulin Sensitivity in Adolescents

Shomaker LB, Tanofsky‐Kraff M, Young‐Hyman D, Han JC, Yanoff LB, Brady SM, Yanovski SZ, Yanovski JA. Psychological symptoms and insulin sensitivity in adolescents.

Whole-Exome sequencing identifies novel LEPR mutations in individuals with severe early onset obesity

Obesity is a major public health problem that increases the risk for a broad spectrum of co‐morbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance.

Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children

C‐type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate and plays a key role in endochondral growth. Its amino‐terminal propeptide (NTproCNP) is an equimolar product of CNP biosynthesis and is easily measured in plasma. Preliminary studies suggest that NTproCNP levels correlate with height velocity in sheep and children. The objectives of the study were to correlate NTproCNP levels with height velocity and to define the reference range for plasma CNP and NTproCNP across childhood.