Scientists discover novel mutation associated with alternating hemiplegia of childhood

Posted on: 12 July 2022

Scientists at Trinity and the Institute Imagine at Necker Hospital, Paris, today announced a significant advance in our understanding of a very rare condition called alternating hemiplegia of childhood (AHC).

This devastating condition, which can lead to repeated paralysis of one side of the body – and sometimes both sides at once – usually begins to affect children before 18 months of age. To date, only one causative gene has been identified.

The scientists in Dublin and Paris have now identified a second gene (CLDN5) as being responsible for the condition in two unrelated cases of AHC in France. The protein product of this gene, claudin-5, is critical for maintaining the integrity of the blood-brain barrier (BBB). Intriguingly, the mutated form of the protein turns the barrier into a channel that is selective for negatively charged ions. In this regard, the ionic compositions of the brain are likely shifted in these children and this is a key driver of the condition.

“This finding was based on an amazing collaboration with Prof Arnold Munnich’s group at the Institute Imagine in Paris. The identity of these de novo mutations in unrelated children suggests that the barrier is turning into a channel. This is exciting on numerous levels as it is the first report of the BBB turning into a channel, but it also sheds light on the devastating pathology of AHC, which may assist in clinical management of patients with this mutation,” said Dr Matthew Campbell, Professor in Genetics in Trinity’s School of Genetics and Microbiology.

Importantly, the work has implications for our basic understanding of the junctional protein that forms the BBB.  As this is the first report of the human BBB becoming a channel, there may be avenues for drug delivery that have never been explored. This will now form the basis of the next steps of the project.

An MRI-based image obtained through a technique called arterial spin labelling, which allows scientists to image blood flow rates in the brain. The image shows a huge increase in blood flow (red) during an acute stage of hemiplegia (one-sided paralysis) in a child diagnosed with alternating hemiplegia of childhood (AHC), caused by a mutation in the CLDN5 gene. Credit: Prof Matthew Campbell, Trinity.

Dr Yosuke Hashimoto, visiting researcher from the Japanese Society for the Promotion of Science (JSPS), and his equally contributing colleague Dr Karine Poirier from the Institute Imagine, added:

“This exciting project has shed light on a very rare condition affecting children. We are delighted that our work was able to quickly identify the causative mutation for the disease as well as progressing our understanding of the pathology of the disease.” 

Commenting on the study, Prof Arnold Munnich from the Institute Imagine in Paris, said:

“We are delighted this work has progressed so quickly and our groups have been able to work very closely to identify the cause of this condition. Studies like this will benefit families and clinicians immensely in the years to come.”

A multidisciplinary team of geneticists, neurologists and radiologists from Ireland and France undertook the study. The research, published this week in the international journal Brain was supported by Science Foundation Ireland (SFI), FutureNeuro, Japanese Society for the Promotion of Science (JSPS) and the European Research Council (ERC).

The article can be read on the publisher’s website.

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