The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome.
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.
Zeev
B Ben
BB
Pediatric Neurology Unit, Safra Pediatric Hospital, Sheba Medical Center, Ramat-Gan, Israel.
Bebbington
A
A
Ho
G
G
Leonard
H
H
de Klerk
N
N
Gak
E
E
Vecsler
M
M
Vecksler
M
M
Christodoulou
J
J
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000375:Aging / Q000502:physiology; D001315:Australia / Q000453:epidemiology; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D016208:Databases, Factual; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007557:Israel / Q000453:epidemiology; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics*; D015518:Rett Syndrome / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D055815:Young Adult
D019208:Brain-Derived Neurotrophic Factor; D004247:DNA