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 (6–28y), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7–54y), and 20 healthy controls (4–32y) 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 judgment, 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 IQ that was 20 points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.

Rare pain insensitive individuals offer unique insights into how pain circuits function, and have led to the development of new strategies for pain control. We investigated pain sensitivity in humans with WAGR (Wilms tumor, aniridia, genitourinary anomaly, range of intellectual disabilities) syndrome, who have variably-sized heterozygous deletion of the 11p13 region. The deletion region can be inclusive or exclusive of the brain-derived neurotrophic factor (BDNF) gene, a crucial trophic factor for nociceptive afferents. Nociceptive responses assessed by quantitative sensory testing (QST), demonstrated reduced pain sensitivity only in the WAGR subjects whose deletion boundaries included the BDNF gene. Corresponding behavioral assessments were made in heterozygous Bdnf knockout rats to examine the specific role of Bdnf. These analogous experiments revealed impairment of Aδ and C-fiber mediated heat nociception, determined by acute nociceptive thermal stimuli, and in aversive behaviors evoked when the rats were placed on a hot plate. Similar results were obtained for C-fiber mediated cold responses and cold avoidance on a cold plate device. Together, these results suggested a blunted responsiveness to aversive stimuli. Our parallel observations in humans and rats show that heterozygous deletion of the BDNF gene reduces pain sensitivity, and establish BDNF as a determinant of nociceptive sensitivity.

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