Could Rett Syndrome be reversible?

Adrian Cousins,
Wellcome Images

Rett Syndrome is the only autism spectrum disorder that has a known genetic cause.  Normally when you think of a genetic disorder you get the impression of an irreversible condition that is with a person for their entire life.  But that might not be the case.

Newer research is showing that this might not be the case and that genetic disorders can sometimes be mitigated,  reversed, or even cured.  In the case of Rett Syndrome, a recent paper in Epigenetics is suggesting that it might be possible to compensation for the defects that lead to Rett Syndrome -

MeCP2 deficiency downregulates specific nuclear proteins that could be partially recovered by valproic acid in vitro.

MeCP2, the major causative factor of Rett syndrome and related phenotypes including autism, is a two-face nuclear modulator acting via transcriptional and chromatin remodeling mechanisms. This study investigated the expression of several nuclear proteins and their dependence on MeCP2 dose and presence of the Rett causative R306C mutation. To this end, we developed in vitro models representing MeCP2 deficiency induced by siRNAs, and cells expressing the R306C mutation. Using an extended antibody microarray validated by specific assays, revealed that MeCP2 dose was correlated with specific nuclear proteins profiles including the BRM/SNF2 component of SWI/SNF complex, PRMT1 methyl transferase and HDAC2. Furthermore, while exposing the MeCP2 knock-down system to therapeutic concentrations of valproic acid (VPA), a known HDACs inhibitor, we observed a partial restoration of MeCP2 expression levels. Exposure to VPA also increased the levels of BRM, as well as of BDNF, an important co-factor in MeCP2-mediated pathway. Our findings provide additional evidence of diverse mechanisms of MeCP2 function as transcriptional repressor and activator of specific genes. As it has been recently demonstrated that post-natal restoration of MeCP2 deficiency may reverse neurological defects in a mouse model of Rett syndrome, we suggest to study the restorative effect of HDAC inhibitors in MeCP2-deficient mouse model.

The thing that I find most interesting here is that valproic acid, the substance that might help restore normal functioning, is one of the substances that is known to increase the risk of autism during pregnancy.  Or in other words, if you are on valproic acid while you are pregnant, you stand a good chance of having a child with autism.  Yet the same substance might be able to help correct the problems that lead to Rett Syndrome, go figure.

Obviously it goes without saying that this research is very theoretical in nature and that there has been no case where Rett's was actually reversed in a person.  However, it is encouraging that there may be the possibility of one day being able to "cure" a genetic form of autism.  It gives me hope that someday other forms of autism can be cured.