The suggestion by Rudolph Jaenisch and colleagues that decreased BDNF may in fact explain the brain pathology seen in Rett syndrome is most interesting.

I would like to propose that it is possible that Mecp2 mutations resulting in increased leptin levels may explain this. Melzner and colleagues (1) report that methyl-CpG binding proteins participate in transcriptional repression and regulation of the human leptin gene. Brunetti et al. (2) find that leptin inhibits depolarization-induced norepinephrine and dopamine release. Ivy and colleagues (3) find that noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Is it possible that increased leptin as a consequence of an Mecp2 mutation has resulted in reduced noradrenergic stimulation of BDNF transcription? The study by the Elefteriou group (4) reporting that elevating serum levels reduces bone mass, which is a characteristic of Rett syndrome, would seem to support the above hypothesis.

References:

1. Melzner I, Scott V, Dorsch K, Fischer P, Wabitsch M, Bruderlein S, Hasel C, Moller P. Leptin gene expression in human preadipocytes is switched on by maturation-induced demethylation of distinct CpGs in its proximal promoter. J Biol Chem. 2002 Nov 22;277(47):45420-7. Epub 2002 Sep 3.

2. Brunetti L, Michelotto B, Orlando G, Vacca M. Leptin inhibits norepinephrine and dopamine release from rat hypothalamic neuronal endings. Eur J Pharmacol. 1999 May 21;372(3):237-40.

3. Ivy AS, Rodriguez FG, Garcia C, Chen MJ, Russo-Neustadt AA. Noradrenergic and serotonergic blockade inhibits BDNF mRNA activation following exercise and antidepressant. Pharmacol Biochem Behav. 2003 Apr;75(1):81-8.

4. Elefteriou F, Takeda S, Ebihara K, Magre J, Patano N, Kim CA, Ogawa Y, Liu X, Ware SM, Craigen WJ, Robert JJ, Vinson C, Nakao K, Capeau J, Karsenty G. Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3258-63. Epub 2004 Feb 20.

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I had proposed that mutations in MECP2 may result in increased leptin levels in Rett syndrome. I see that Blardi and colleagues report that patients with classic Rett syndrome and preserved-speech variant had leptin values significantly higher than controls. Ashwood et al. also report elevated leptin levels in those with early-onset autism.

View all comments by Mary Reid