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Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

ABSTRACT: In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.

SUBMITTER: Han JC

PROVIDER: S-EPMC3762943 | biostudies-literature | 2013 Nov-Dec

REPOSITORIES: biostudies-literature

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Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

Han Joan C JC Thurm Audrey A Golden Williams Christine C Joseph Lisa A LA Zein Wadih M WM Brooks Brian P BP Butman John A JA Brady Sheila M SM Fuhr Shannon R SR Hicks Melanie D MD Huey Amanda E AE Hanish Alyson E AE Danley Kristen M KM Raygada Margarita J MJ Rennert Owen M OM Martinowich Keri K Sharp Stephen J SJ Tsao Jack W JW Swedo Susan E SE

Cortex; a journal devoted to the study of the nervous system and behavior 20130219 10

In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twe ...[more]

PMID: 23517654

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Project description:BackgroundBrain-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.MethodsWe 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.ResultsDeletions 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).ConclusionsAmong 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.

Project description:Executive functioning (EF) deficits co-occur frequently with autism spectrum disorder (ASD) and have a long-term detrimental impact on quality of life of children and their families. Timely identification of risk for EF vulnerabilities may hasten access to early intervention and alleviate their long-term consequences. This study examines (1) if EF deficits are elevated in toddlers with ASD compared to nonautistic siblings of children with ASD, typically developing (TYP) toddlers, and toddlers with atypical developmental presentation; and (2) if EF deficits have a detrimental effect on adaptive functioning in ASD. Participants were recruited between September 2014 and October 2019 and included 73 toddlers with ASD, 33 nonautistic siblings of children with ASD, 35 toddlers with atypical development, and 28 TYP toddlers matched on chronological age (M = 39.01 months, SD = 3.11). EF deficits were measured using the BRIEF-P; adaptive skills were measured using the VABS-II. Whenever appropriate, analyses were controlled for MSEL verbal and nonverbal developmental quotient, ADOS-2 autism severity scores, and sex. Analyses revealed that toddlers with ASD exhibited elevated BRIEF-P scores across all domains compared to each of the three comparison groups. Higher BRIEF-P scores were associated with lower adaptive social, communication, and daily living skills while controlling for symptom severity, verbal and nonverbal functioning, and sex. In conclusion, marked vulnerabilities in EF are already present in 3-year-old toddlers with ASD and are predictive of the level of adaptive functioning in ASD. EF vulnerabilities in toddlers should be targeted for intervention to improve long-term outcomes in ASD. LAY SUMMARY: Many children with autism experience vulnerabilities in executive functioning (EF), which may include challenges with inhibition, working memory, cognitive flexibility, and planning. The study shows that these vulnerabilities can already be detected at age three and that their presence is linked with lower social, communication, and daily living skills. Screening children with ASD for EF challenges and helping those who have difficulties may improve their long-term outcomes.

Dataset Information

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

Publications

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

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