In a recent study, researchers have linked a debilitating neurological disease in children to mutations in a gene that regulates neuronal development through control of protein movement within neuronal cells.

In this study, authors show that the recessive loss-of- function mutations in the gene DENND5A leads to a severe form of epileptic encephalopathy.

Epileptic encephalopathy is a rare but devastating sub-form of epilepsy that results in severe mental and physical disabilities in children from birth. It is often caused by improper development of the brain. Individuals with epileptic encephalopathy caused by mutations in DENND5A present with serious anomalies in brain structure along with calcifications in the brain and altered facial features.

Researchers performed whole exome sequencing on three children with epileptic encephalopathy from two families, one from Saudi Arabia and another from Jordan. Both families were related to each other (consanguineous). This greatly increases the chance that rare mutations that are recessive and that cause no harm to the parents are expressed in the children.

The whole exome sequencing, along with extensive and complex genetic analysis, revealed that recessive mutations in DENND5A were responsible for the disease, with the Saudi family and the Jordanian family having different mutations but in the same DENND5A gene. They found that mutations in DENND5A lead to a lack of the DENND5A protein, resulting in underdevelopment of the central nervous system. The protein expressed from the DENND5A gene is present at highest levels in the nervous system especially while the brain is developing, corroborating the evidence that mutations in the gene cause epileptic encephalopathy.

The researchers discovered that the DENND5A protein controls the movement of receptors for key developmental factors called neurotrophins. Disruption of DENND5A function leads to altered levels of these receptors that lead to the severe neurological developmental defects in the patients.

This finding also improves our understanding of neuronal development. The observation that loss-of-function mutations in DENND5A causes epileptic encephalopathy suggests that DENND5A protein controls membrane trafficking pathways critical for normal neuronal development and strengthens the argument that protein trafficking processes in cells are critical for normal neuronal development and function.

"Our study demonstrates the importance of membrane trafficking in neuronal development and it provides a new pathophysiological mechanism for this disease type. This will allow physicians around the world to test if mutations in DENND5A are causing the disease in their patients, and also to provide genetic counselling for affected families," says the lead author on the study.