Background: Rett syndrome (RTT) is caused by mutations in the transcriptional repressor methyl CpG-binding protein 2 (MECP2). Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis, and plasticity, and it has been shown that BDNF expression is regulated by MeCP2 through a complex interaction. A common polymorphism of BDNF (Val66Met [p.V66M]) has been found to correlate with severity and course of several neuropsychiatric disorders.
Methods: We examined the association between disease severity score, assessed by the modified Percy score, and BDNF polymorphism, using regression methods, in 125 mutation-positive patients with RTT from the Australian Rett Syndrome Database and an Israeli cohort.
Results: Those who were heterozygous (Val/Met) had slightly more severe disease than those who were homozygous for the wild-type (Val/Val) BDNF polymorphism (increased severity score 2.1, p = 0.09). In those with p.R168X, a commonly occurring MECP2 mutation in RTT, there was a 6-point increase in severity score for those who were heterozygous for the BDNF polymorphism, both unadjusted (p = 0.02) and adjusted for age (p = 0.03). Individuals with the p.R168X mutation and heterozygous for the BDNF polymorphism were also at an increased risk of seizure onset (hazard ratio 5.3, 95% confidence interval 1.6-17.7) compared with those homozygous for the wild-type BDNF allele.
Conclusions: In addition to mutation type and degree of X-chromosome skewing, the common brain-derived neurotrophic factor (BDNF) polymorphism appears to be another genetic modifier of Rett syndrome (RTT) severity. This suggests that BDNF function may play a significant role in the pathogenesis of RTT.