Brain-Derived Neurotrophic Factor and Obesity in the WAGR Syndrome
BDNF Haploinsufficiency in Patients with WAGR Syndrome Is Associated with Decreased Behavioral
Responses to Pain
Childhood Stature in WAGR Syndrome
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1: N Engl J Med. 2008 Aug 28;359(9):918-27.
http://content.nejm.org/cgi/content/abstract/359/9/918?ct
Brain-Derived Neurotrophic Factor and Obesity in
the WAGR Syndrome
Han JC, Liu QR, Jones M, Levinn RL, Menzie CM, Jefferson-George KS, Adler-Wailes DC, Sanford EL, Lacbawan FL, Uhl GR, Rennert OM, Yanovski JA.
Unit on Growth and Obesity, Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1103, USA.
BACKGROUND:
Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13, approximately 4 Mb centromeric to BDNF (11p14.1), result in the Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome. We hypothesized that the subphenotype of obesity in the WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF.
METHODS: We studied the relationship between genotype and body-mass index (BMI) in 33 patients with the WAGR syndrome who were recruited through the International WAGR Syndrome Association. The extent of each deletion was determined with the use of oligonucleotide comparative genomic hybridization.
RESULTS: Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI z scores throughout childhood than did patients with intact BDNF (mean [+/-SD] z score at 8 to 10 years of age, 2.08+/-0.45 in patients with heterozygous BDNF deletions vs. 0.88+/-1.28 in patients without BDNF deletions; P=0.03). By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval [CI], 77 to 100) were obese (BMI > or = 95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% CI, 3 to 56; P<0.001). The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P=0.001).
CONCLUSIONS: Among persons with the WAGR syndrome, BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity; thus, BDNF may be important for energy homeostasis in humans.
2008 Massachusetts Medical Society
PMID: 18753648 [PubMed - in process]
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BDNF Haploinsufficiency in Patients with WAGR Syndrome
Is Associated with Decreased Behavioral Responses to Pain
Rebecca L. Levinn, Jack W. Tsao, Diane C. Adler-Wailes, Chanelle A. Wijesinghe, Kyra S. Jefferson-George, Owen M. Rennert, Jack A. Yanovski, Joan C. Han. Unit on Growth and Obesity, PDEGEN, NICHD, National Institutes of Health, Bethesda, MD; Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD.
BACKGROUND: WAGR syndrome (Wilms tumor, Aniridia, Genitourinary abnormalities, and mental Retardation) is caused by heterozygous contiguous gene deletions of variable size on Chromosome 11. The gene that encodes brain-derived neurotrophic factor (BDNF) is included in the region of deletion in about half of WAGR patients. In animal studies, BDNF appears to play a role in modulating nociceptive sensory inputs. No quantitative data exist relating pain perception to BDNF haploinsufficiency in humans.
OBJECTIVE: To study patients with WAGR syndrome to determine if parent-reported behavioral responses to pain differ among those with and without BDNF haploinsufficiency.
DESIGN/METHODS: Comparative genomic hybridization was performed for 31 subjects with WAGR syndrome (age 13.9 8.3y) to establish if one copy of the BDNF gene was deleted. Parents completed the Non-Communicating Children s Pain Checklist-Revised (NCCPC-R), which assesses occurrence of behavioral responses (subscales: vocal, social, facial, physical activity, body and limb, physiological, and eating/sleeping) to injuries and illnesses considered painful to most people. Scores for subjects with and without BDNF haploinsufficiency were compared using the Mann-Whitney U test.
RESULTS: 58% of subjects had BDNF haploinsufficiency (BDNF+/-). Compared to those with both BDNF alleles intact (BDNF+/+), BDNF+/- subjects had lower mean NCCPC-R total response scores (BDNF+/- vs. BDNF+/+: 22.815.9 vs. 35.417.0, p=0.031), as well as lower NCCPC-R subscores for vocal (p=0.010), facial (p=0.043), body and limb (p=0.033), and physiological (p=0.044) responses (primarily subscales that reflect perception of pain intensity). No statistically significant differences were observed for social, physical activity, and eating/sleeping responses (subscales previously found not to be correlated with pain intensity).
CONCLUSIONS: Among individuals with WAGR syndrome, BDNF haploinsufficiency is associated with fewer behavioral responses to typically painful stimuli. These data support a role for BDNF in human nociception.
First Author is a Student
E-PAS2008:634504.8
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Childhood Stature in WAGR Syndrome
RL Levinn, JC Han, CA Wijesinghe, JK Gustafson, JM Checchi, DC Adler-Wailes, KS Jefferson-George, OM Rennert, JA Yanovski, Unit on Growth & Obesity, PDEGEN, NICHD, NIH, Bethesda, MD
Background: WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, mental Retardation) is a rare genetic disorder caused by heterozygous contiguous gene deletions of variable size at Chromosome 11p13. Short stature has been observed in case reports, but not longitudinally studied.
Objective: To assess stature during childhood in subjects with WAGR syndrome.
Design/Method: Anthropometric measurements were obtained from medical records of 40 subjects with WAGR syndrome, and Z-scores calculated using CDC 2000 and NHANES II data. Individual height-Z (HtZ) was averaged from all measurements within a specified age range. Growth velocity-Z (GVZ) was computed from the slope of the best-fit line of heights between ages 2.5-9y. HtZ was compared to population mean (one-sample T-test vs. 0) and mid-parental height-Z (MPHZ) (paired-samples T-test). 20 subjects with WAGR syndrome and 20 healthy controls (matched for age, sex, race, BMI) were also compared for differences in IGF-1. Deletion size was determined by oligo microarray comparative genomic hybridization.
Results: All subjects had normal birth length (meanSD: 49.9 2.8cm) and pre-pubertal GVZ (0.080.68), but postnatal HtZ was lower than population mean and MPHZ for ages 2-20y (Figure 1). HtZ at 17-20y was negatively associated with size of deletion (= -0.90, p<0.001). Every 1Mb increase in deletion size predicted a decrease in final HtZ by 0.13. There was no significant difference between IGF-1 in WAGR subjects and controls (232139 vs. 286187, p=0.43). Neither HtZ nor GVZ was significantly associated with IGF-1, or with history of Wilms tumor. Based on parental report, average age of pubarche in males was 11.31.7y, and menarche in females 11.91.6y.
Discussion: Children with WAGR syndrome have postnatal short stature that is modest in early childhood and more pronounced post-pubertally, with lower final HtZ associated with larger deletions. Normal IGF-1 and pre-pubertal GVZ do not suggest growth hormone insufficiency. Inadequate pubertal growth spurt in the setting of non-delayed or slightly advanced puberty may contribute to decreased final height in patients with WAGR syndrome.
DISCLOSURE: Yanovski, JA: Principal Investigator, Roche Pharmaceuticals; Principal Investigator, O.N. Diagnostics, LLC, Obecure; Investigator, Abbott Laboratories.
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