Dr. Hilde van Esch published an article recently with her colleagues on research that was funded by the Jerome Lejeune Foundation. Dr. van Esch is studying a rare x-linked chromosomal disorder called MECP2 duplication syndrome that only affect boys. Dr. van Esch has shared some of her findings with us here and points to the possibility of one day providing targeted therapeutic interventions to improve the lives of those boys born with this genetic condition.

If we are not mistaken, you were the first to describe MECP2 duplication syndrome. How did you make this discovery and do you know the incidence of this syndrome in the population?

In the Center for Human Genetics at the University of Leuven, we have a long tradition in genetic research of intellectual disability syndromes that are linked to the X chromosome. Back in 2005, we developed a specific micro-array chip, to look for genomic aberrations on the X chromosome in the many unsolved X-linked families. In four different families we detected an extra copy of a small region on the long arm of the X chromosome (duplication) in all severely affected male individuals. Within this duplicated region, the MECP2 gene is present, and given the important role of this gene during brain development and functioning, we hypothesized that increased protein dosage would be responsible for this syndrome. Our initial hypothesis has been confirmed with the many novel cases reported and diagnosed today.

It is however difficult to know the exact incidence, but we know that the MECP2 duplication is one of the most frequent aberrations on the X chromosome found in male individuals with severe developmental delay.

Can you describe the features of MECP2 duplication syndrome?

The first symptoms are already present at birth. Most children are hypotonic and sometimes have feeding problems. Their motor and cognitive development is severely delayed. Some children learn to walk independently and can use some single words. In half of the children, epilepsy occurs, starting during childhood. These epilepsies are often drug-resistant and can have an important impact on further development and functioning. We also notice an increased susceptibility to infections, mostly of the upper and lower airways. This might results in early demise, unfortunately.

Could MECP2dup be referred to as Rett syndrome for males? Is this an accurate description? If so, why, and why does it not affect females?

I would not refer to this syndrome as Rett syndrome for males. The clinical course in both syndromes is somehow different, e.g. MECP2dup is already present at birth, we do not see that often the stereotypies or loss of purposeful hand use. Also the underlying pathophysiology in both syndromes seems to be different, as we have shown in our recent study.

Female carriers are in general protected because they inactivate the X chromosome that carries the duplication (skewing of X-inactivation). We know, however, of some female carriers that show a milder phenotype or a phenotype as severe as in the males because of additional genetic and/or chromosomal causes that result in the expression of the abnormal X chromosome.

Your recently published research in Nature (Sept 8, 2015) shows the benefit of using induced pluripotent stem cells for research on neurological disorders. What were you able to observe in the development of neurons derived from a patient with MECP2?

The first observation is that we were able to differentiate neurons from the patients’ stem cells, but that these neurons looked different: when looking under the microscope they had more dendrites (increased arborization); however, when zooming in to the spines (contact points between neurons), they looked more immature. Also at the spine contact points, the synapses, there were more proteins present. It looks as if these neurons painstakingly try to transfer information from one to another, but fail to do this. This was also observed when measuring the electro-physical activity of these neurons in their respective network. Compared with control neurons, the disease neurons fired much more (enhanced burst activity), but probably with much less efficiency than normal neurons.

Your research also points to a possible treatment for MECP2. I believe it is a drug also used to inhibit the growth of cancer cells. How does this drug appear to resolve the cellular defects in MECP2dup?

We know that MECP2 plays an important role in the control of other genes (switching them on or off). That is the reason that we used more than 35 different drugs that are known to have an effect on gene regulation. Only one of them was able to rescue the abnormal morphology and the abnormal electrophysiology that we observed in the disease neurons. Indeed, NCH51 has been shown in other experiments (in a dish) to have an effect on cancer growth. One can hypothesize that in the case of cancer, also the gene regulation is disturbed. However, we will need more in depth experiments to unravel the exact mechanism of this drug.

Do you have enough confidence at this point in the identification of NCH 51 as a possible treatment to consider moving the drug into clinical trial? If so, how far in the future?

The fact that this drug could rescue the abnormalities in the disease neurons is of course very promising. But we need to be careful. First it will be important to be sure that this drug is specific and does not harm other cells in our body. We did not really see an effect on the control neurons, but again, all this work was done in a dish and only with a certain cell type. Before going into clinical trial, I would like to see whether this drug also works in an animal model, e.g. the duplication mouse model.

Does your research have any benefit for other genetic intellectual disabilities?

Although we focused on one particular neurodevelopmental disease, I am confident that everything we can learn about normal and abnormal neurodevelopment, will be of benefit for other syndromes. We now know that the common denominator of many intellectual disability syndromes is the dysfunction of the synapse (the billions of places where neurons communicate with each other). It is clear that we need drugs that not only target specific proteins, but rather have an effect on entire pathways, irrespective of the underlying genetic defect.