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People with hyperekplexia react profoundly to sudden noises, movements and touch.

“Loud noises such as clapping your hands can cause an excessive startle in newborns,” explained Ghada Aboheimed, an assistant professor at King Saud University in Saudi Arabia and the lead author of of the condition in the Journal of Biological Chemistry.

In addition to excessive startle response, hyperekplexia is characterized by nonepileptic seizures and extreme muscle stiffness that even can prevent voluntary movement. This rare condition often is diagnosed at birth and is known to be caused by genetic mutations in GLRA1, SLC6A5, GLRB and several other genes that play roles in glycine-mediated signaling in the nervous system.

In , Aboheimed and co-authors discovered in a newborn girl a novel mutation in GLRB that caused a recessive form of hyperekplexia. “We collected samples from hyperekplexia patients and their families from different hospitals in Saudi Arabia and analyzed the genetic cause of their disease using advanced sequencing and analysis technologies,” Aboheimed said.

The mutation that the team identified led to decreased expression of the beta-subunit of the glycine receptor ion channel. Using coimmunoprecipitation and confocal microscopy, the researchers found altered cellular localization of the α/β receptor dimer. Using patch clamp electrophysiology, they demonstrated reduced glycine sensitivity of the mutant receptor. The mutated residue, found on an outer transmembrane helix, introduced steric clashes that destabilized the protein and led to decreased activation of the ion channel upon glycine binding.

Aboheimed said that she hopes the identification of this and similar mutations can help doctors accurately diagnose hyperekplexia in newborns.

“When added to the epilepsy gene screening panels, (the genes) will help to avoid misdiagnosing hyperekplexia with epilepsy, resulting in early genetic diagnosis of the disease and preventing the use of multiple antiepileptic treatments administered to newborns, and potentially death due to apnea,” she said.

People with hyperekplexia usually are treated with the drug clonazepam, which is an anti-anxiety and anti-spastic medication. The girl in Aboheimed’s study found to have the novel mutation in GLRB responded well to clonazepam and is in school, she said. As they get older, most patients experience sudden falls, which can cause serious injuries, and excessive startle to sudden loud noises, which can prevent them from doing normal activities such as driving a car.

“Studying rare diseases such as hyperekplexia can help patients’ families understand the genetic cause of the disease and the inheritance mode … But working on such cases sometimes leads to identifying novel genes and thus further understanding the pathogenesis of the disease,” Aboheimed said. “Our next step is to identify other possible genes related to this disease to help us broaden our understanding of its pathology, and eventually to develop personalized treatment using gene therapy.”