A Curable Brain Disorder?

It's correctable in mice: will this also work in humans?

Posted Mar 29, 2016

Rett syndrome is rare, but that doesn’t make it uninteresting. It’s the result of a mutation in one of the genes on the X chromosome (it’s called MeCP2). Whilst the MeCP2 protein is found all over the body, there’s much more of it in the brain. It acts by modifying the action of other genes: an epigenetic event.  Although females have two X chromosomes, one is inactivated in each cell, so if they have Rett syndrome about half the cells of their brain are normal.  Boys, with only one X, have all abnormal cells, and usually die before birth.   

Girls with Rett initially develop normally, but at around two years begin to lose speech and motor ability, have seizures and abnormal patterns of breathing together with serious cognitive deficiencies and some autistic features (though Rett is no longer classified as an autism spectrum disorder).  They may survive well into adulthood but require total round-the-clock care.

Mice can be made mutant for MeCP2, and they show some similar features, including typical movement abnormalities, seizures and breathing difficulties. They die relatively young.  Careful examination of their brains has shown that, unlike some other developmental brain disorders, there are no signs of increased rates of death of neurons; they have the normal number.  What does seem to happen is that their neurons fail to develop the normal halo of dendrites, the processes projecting from nerve cells that enable them to connect with other nerve cells and so make the networks that characterize the brain.  Their brain cells remain, they just don’t communicate properly.

So what’s so interesting?  Adrian Bird and his colleagues in Edinburgh have shown that, if they replace the missing mutant gene with a normal one, even after the mice have developed their version of Rett syndrome, there is a remarkable recovery.  They walk normally again, their breathing improves, and they no longer die early.  Examination of their brains shows that their neuronal dendrites have regrown to look much more normal.  It’s a striking example of the plasticity of the brain at both anatomical and functional levels, and an unexpected ability for the brain to be repaired.

Can this be applied to human cases of Rett syndrome?  Modern techniques of gene therapy or gene editing promise much, and there is a strong case for hoping that they might, by replacing or activating the faulty gene, result in the same astonishing recovery in Rett girls as in mice. It might also be possible to develop drugs that mimic the action of MeCP2, now that we know what it does. If Rett is treated effectively in this way, then this opens the door for hope in other genetic disorders; there are those with features similar to Rett syndrome.  It’s an exciting and encouraging prospect[1]. The brain, under some circumstances, shows astonishing powers of recovery, which gives new hope for more effective treatment of a range of neurological conditions.

Andreas Rett (1924-1997) was an Austrian neurologist, noted not only for the description of his eponymous syndrome, but as a pioneering advocate of multileveled constructive and effective care for children with neurodevelopmental disabilities. He opened the first home for these children in Vienna in 1951.  He faced considerable opposition, both professionally and politically, in a culture that had little sympathy at that time for any effort to support the care of these children. He had been a member of  the Hitler's Youth movement, though he was only 9 when the Nazis came to power. His posthumous reputation suffered because, unlike others, he never publicly acknowledged or recanted his involvement, however peripheral, in Austria's horrendous past. Rett died before the genetic mechanism of his syndrome had been discovered.

Despite the very considerable recent advances in molecular and cell biology, the promise of gene therapy has not really been fulfilled so far.  The hope was that, if a single gene defect could be discovered that caused a disorder (cystic fibrosis is one example), then replacing that faulty gene might alleviate the condition.  There are good experimental ways of modifying genes, but there has been less success transferring them to a clinical situation in humans. Rett syndrome may prove to be an achievable target, particularly since new methods of editing genes have recently become available. Single gene disorders are relatively rare, but treating them effectively would not only relieve such people of their very considerable handicap, it would also hold out promise for a wider application to vulnerabilities to other diseases. Reversal of Rett syndrome, if it were to be achieved, would be a real milestone.

[1] For a more detailed, technical account, see D M Katz et al (2016) Trends in Neurosciences, volume 39, pp 100-112.