Norrie Disease and Epilepsy – Is there a link?

In my very first blog post, I had put forward a hypothesis that the epilepsy seen in some cases of Norrie Disease (ND) could be linked to the Blood Brain Barrier (BBB) dysfunction which occurs in ND. I had also mentioned a research article (van EA Vliet et al., 2014) which links BBB dysfunction with epilepsy.

Since epilepsy happens to a great many people, not just to patients of ND, I set out in search of an answer to the question - is there really a link between ND and epilepsy?

I thought I would start by educating myself a bit more on the link between the BBB and epilepsy, by reaching out to Dr. Vliet, one of the authors of the above mentioned study. Dr. Vliet is a member of the Faculty of Science, University of Amsterdam.

Dr. Vliet has very kindly answered my questions with respect to epilepsy and the BBB, and has also been kind enough to allow me to share my learnings with the readers of this blog.

He would, however, like readers to note that he is not a clinician, but a basic scientist, that he is not an expert on Norrie Disease, and that his answers are from the perspective of preclinical work done by him.

Qs1: Would a leaky blood brain barrier always lead to epilepsy? If not, then do we know which aspect of BBB dysfunction gives rise to epilepsy?
The reason why I ask is because only a small percentage (perhaps 5-10%) of ND cases have seizures. On the other hand, 30-50% of cases are reported to have mental problems ranging from mild to severe (cognitive impairment, autistic behavior, psychosis), and it is my assumption (which could of course be wrong) that these problems are caused by BBB dysfunction.

Ans.: A leaky BBB does not always lead to epilepsy. Most likely the amount/extent of leakage, the brain region in which in occurs, and other pathological factors that may occur (e.g. gliosis, neuronal loss etc.) are also important. From preclinical epilepsy models we see that the larger the extent of leakage, particularly in the hippocampus/parahippocampus (temporal lobe), the more likely the chance to develop epilepsy. Lastly, BBB leakage does not immediately lead to seizures, it takes time (in animals a few weeks).

Qs2: Conversely, is epilepsy always caused by BBB dysfunction? Apparently epilepsy is the 4th most common neurological disorder, so I wonder if it is wrong on my part to try and link the BBB dysfunction of ND to the epilepsy seen in ND.

Ans.: There are many factors that can lead to epilepsy (e.g. tumors, inflammation, infection, injury etc.), BBB leakage is one of them. So epilepsy is not always caused by BBB leakage.

Qs3: If we were to conclude that a person’s epilepsy was caused by BBB dysfunction, then would restoring the BBB integrity cure the problem of epilepsy?

Ans.: That's a very good point. Therefore, we aim to restore BBB function and thereby hope to inhibit or prevent epilepsy. In preclinical models this seems to be the case but it has not been tested in people with epilepsy.

I thank Dr. Vliet for his valuable time.

Dear reader, I must now apply what I have learnt, to the case of Norrie disease.

Past research (Hartzer et al., 1999) has established that the Norrie disease gene (NDP) is expressed in the hippocampus: …… In order to further determine the role of the Norrie disease gene, we studied the distribution pattern of its mRNA in the retina and in brain by in situ hybridization. …….. High expression levels were also observed in the cerebellar granular layer, hippocampus, olfactory bulb, cortex, and epithelium of the rabbit brain. …….

However, later research done by Prof. Jeremy Nathans and colleagues (Nathans et al., 2014) suggests that the protein (Norrin) which is encoded by the gene does not play a role in BBB maintenance in the hippocampus: …… mutation of Ndp produces only a relatively mild loss of BBB integrity that is confined to the cerebellum and olfactory bulb. ……

This study does talk of BBB dysfunction in other parts of the brain in the case of a mutation of the NDP gene, but that is under very special circumstances (other genes being mutated in combination with the NDP gene), but even then there is no mention of the hippocampus.

So if the NDP gene is expressed in the hippocampus, then it must be doing something there. What is that something? Also, we know nothing about the extent of damage in the brain caused by various mutations of the Norrie gene. What if the BBB dysfunction in those cases of ND where epilepsy has happened is more severe than in other cases? Would that have a bearing on the question in focus?

There is more work to be done here.

Till next time then,

Meenu.