Given the unusual and distinctive combination of impaired cognitive function, hyperactivity, and severe obesity and the similarities in phenotype to a previously reported patient with a mutant TrkB and the strong evidence for loss of expression of one allele of BDNF, it would seem highly plausible that the clinical phenotype in this patient has resulted from a reduction in BDNF. However, the patient does harbor a chromosomal inversion and not a simple loss of function mutation, and it is possible that some aspects of her phenotype could relate to positional effects at other genes in the region. However, none of the rodent models or human mutations disrupting other genes in this region have been associated with a comparable neurobehavioral and obesity phenotype. Nonetheless, we cannot exclude the possibility of disruption of other genes of unknown function. As yet, we have not fully characterized the distal breakpoint and thus cannot exclude the possibility that a centrally expressed gene is disrupted either directly or indirectly. However, inspection of the human transcript map revealed no other obvious candidate genes near either inversion breakpoint.
There is evidence from other chromosomal rearrangements involving 11p to suggest that the 11p12–14 region harbors an important gene for the regulation of body weight. Chromosomal deletions spanning 11p11.2–p14.1 have been reported in WAGR syndrome associated with obesity (20
). Borg et al. (21
) recently reported a patient with mild mental retardation, dysmorphic features, and obesity who had a complex chromosomal translocation, t(3;12), and an additional balanced translocation, t(11;21)(p14;q22.1), with a chromosome breakpoint mapping to within 100 kb downstream of BDNF
The cognitive findings reported here are consistent with the role of BDNF in learning and memory. Both the proband and the patient with a mutation in TrkB showed general impairments of intelligence, language, numeracy, attention, and memory. BDNF has been implicated in hippocampal function throughout the lifespan (22
); therefore, everyday memory deficits were expected in these two patients. BDNF is known to play a role in the development and maturation of neurons in brain regions other than the hippocampus; thus, BDNF haploinsufficiency would be expected to be associated with the more general profile of cognitive dysfunction that we observed.
Interestingly, despite the similarities in their impaired cognitive function, the two patients showed different profiles on the Sunderland Memory Questionnaire and the Social Communication Questionnaire, with the BDNF-haploinsufficient patient performing in the normal range on both, while the TrkB patient was rated to be impaired on both. Although performance on the Sunderland Memory Questionnaire has been reported to be consistent with performance on standardized memory assessments (23
), it is possible to obtain inconsistent results, as in the pro-band, as the tests tap different aspects of memory. Furthermore, poor performance on formal testing might also reflect difficulties in focusing attention and/or comprehending task instructions.
It is possible that a child with a TrkB mutation may be impaired on all tests including social communication (i.e., frontal lobe damage and more general brain damage) and, thus, be more severely affected than a child with BDNF haploinsufficiency, as TrkB is also the receptor for the neurotrophin NT4/5. However, as there is considerable overlap between BDNF and NT4 in terms of brain expression and in terms of effects on long-term potentiation and memory (24
), it is impossible to reliably attribute these subtle differences between two patients to loss of one ligand versus loss of the receptor with any degree of confidence. Whereas the involvement of BDNF in the development of the forebrain and in functions of learning and memory has long been established, a possible role in energy homeostasis has emerged much more recently. In the hypothalamus, BDNF is expressed predominantly in the ventromedial hypothalamus (8
) but also in the dorso-medial hypothalamus (25
) and possibly other hypothalamic areas. Expression is nutritionally regulated (8
) and, at least in the dorsomedial hypothalamus, appears to be regulated by leptin (25
). There is some evidence to suggest that BDNF-expressing neurons may lie downstream of MC4R neuronal pathways, as ventromedial hypothalamus mRNA levels are reduced in mc4r-null mice and restored by administration of the melanocortin agonist MT-II (8
). It is notable that both the patient with the TrkB missense mutation and this patient are markedly hyperphagic and obese (18
). This is consistent with the increased food intake and obesity seen in the bdnf
heterozygous–null mice (11
) and the trkB
hypomorphic mouse (8
Neural growth factors such as BDNF may influence energy balance either through their effects on the development of the hypothalamus or by being dynamically regulated neurotransmitters involved in hypothalamic feeding circuits. In rodents, there are no gross morphological changes in the brains of bdnf
heterozygous–null mice, and they remain responsive to the administration of BDNF with a reduction in food intake comparable with wild-type mice, suggesting that BDNF-responsive pathways are intact (11
). Also, the postnatal conditional BDNF knockout exhibits increased food intake and is obese (12
). Thus, the rodent data suggest that the effects of BDNF on energy homeostasis cannot be explained simply by a lack of development of BDNF-responsive circuits in the hypothalamus.
An alternative mechanism is that BDNF modulates synaptic plasticity. It is impossible to directly test whether synaptic plasticity is relevant in the human brain. However, it is worth noting that the most studied plasticity phenomenon, long-term potentiation in relation to learning and memory, is mediated by BDNF; thus, it is very plausible that BDNF may exert similar effects on hypothalamic feeding circuits.
Modulation of synaptic plasticity may offer a novel therapeutic approach for the treatment of human obesity. Flier and colleagues (26
) recently demonstrated that another neuronal growth factor, ciliary neurotrophic factor, could promote neurogenesis in the adult mouse hypothalamus, and this mechanism may explain the long-term resetting of body weight “set points” seen in obese patients treated with the ciliary neurotrophic factor analog, axokine.
In summary, by describing the clinical and phenotypic features of a child with loss of one functional copy of BDNF, we have provided some of the first direct evidence for the functions of this important neurotrophin in the human brain. Understanding the mechanisms whereby BDNF regulates hypothalamic neuronal circuits may have potential therapeutic benefits for the treatment of human obesity.