Study shows promise for treating developmental and epileptic brain disease

Studies show that a pair of mutations detected in people with developmental and epileptic brain disease can be traced back to the same ion channel.

Image Credit: Monika Wisniewska / Shutterstock.com

Now, scientists have demonstrated how the function of the ion channel is impacted by both these independent mutations: by rendering it excessively active and highly responsive to stimulation. This discovery is a significant step towards solving the mechanisms responsible for causing the symptoms in patients.

Developmental and epileptic encephalopathies are essentially a heterogeneous class of disorders defined by intellectual disability and epilepsy. Genetic analysis underscored the involvement of an ion channel known as TRPM3. This ion channel is triggered by heat and various chemical ligands. It helps individuals detect toxic heat and plays a significant role in inflammatory pain.

Two different mutations in the gene encoding TRPM3 were identified in nine individuals with a diagnosed developmental and epileptic encephalopathy. Since the functional consequences of the mutations remained elusive, we set out to understand how disturbances of this particular ion channel can cause intellectual disability and epileptic seizures.”

Thomas Voets, Flanders Institute for Biotechnology

At VIB-KU Leuven, Voets focuses on ion channels and their contribution to pain and heat sensation.

An overly active channel

Voets, in collaboration with Joris Vriens (KU Leuven) and the research team at the Laboratory for Ion Channel Research, could demonstrate that both mutations impact TRPM3 channel gating.

Clinical reports pointed out that next to the seizures and intellectual disability, several of the affected patients showed altered sensitivity to heat and pain, which hinted at a modified function of TRPM3.”

Joris Vriens, Flanders Institute for Biotechnology

The scientists can definitely show that both mutations promote a considerable gain in the activity of ion channels. In addition to increased basal activity, the scientists also noticed a higher susceptibility to stimulation by heat and an endogenous neurosteroid.

Most remarkably, one of the two mutations led to much more pronounced functional modifications, such as reduced sensitivity to an anticonvulsant medication and anomalous activation.

The two mutations identified in the TRPM3 gene give rise to channels with substantially altered functional properties. Whereas the individual effects of both mutations differ, both can be considered as strong gain-of-function mutants, with increased activity, both under basal conditions and when stimulated.”

Thomas Voets, Flanders Institute for Biotechnology

“These two mutations also provide the first genetic evidence that link TRPM3 to a pain phenotype in humans,” Vriens concluded.

The scientists have proposed that this enhanced activity of ion channels may lie at the basis of seizure development and neurodevelopmental symptoms in individuals.