Scientists have identified a new genetic neurodevelopmental disease that can cause growth delays, seizures and learning problems in humans. Their findings are published in the journal eLife.
The disorder is caused by a recessive mutation in the gene CAMK2A, known for its role in regulating learning and memory in animals. The researchers believe that dysfunctional CAMK2 genes could be contributing to other neurological disorders as well, such as epilepsy and autism. The findings could open up potential new paths for treating these conditions.
“A significant number of children are born with growth delays, neurological defects and intellectual disabilities every year across the world,” said senior author Dr. Bruno Reversade, research director at the Institute of Medical Biology and Institute of Molecular and Cell Biology, A*STAR, Singapore, who supervised the study.
“While specific genetic mutations have been identified for some patients, the cause remains unknown in many cases. Identifying novel mutations would not only advance our understanding of neurological diseases in general, but would also help clinicians diagnose children with similar symptoms and/or carry out genetic testing for expecting parents.”
The research began when the scientists were made aware of a pair of young siblings who exhibited neurodevelopmental delay with frequent, unexplained seizures and convulsions. Although their bodies had developed normally, they had not gained the ability to walk or speak.
“We believed that the children had novel mutations in CAMK2A, and we wanted to see if this were true,” said Reversade.
A healthy, functioning CAMK2A protein consists of several subunits. Using a genomic method known as exome sequencing, the researchers discovered a single coding error influencing a key residue in the CAMK2A gene that prevents its subunits from assembling correctly.
Next, the scientists moved their research to the roundworm Caenorhabditis elegans, and noticed how this particular mutation disrupts the ability of CAMK2A to ensure proper neuronal communication and normal motor function. This suggests that this mutation is indeed the cause of the neurodevelopmental defects seen in the siblings.
According to the researchers, this new disorder may represent the first human disease caused by inherited mutations on both copies of the CAMK2A gene. In addition, another study published recently identified single-copy mutations on both CAMK2A and CAMK2B that led to intellectual disabilities as soon as the mutations occurred.
“We would like to bring these findings to the attention of those working in the area of pediatric genetics, such as clinicians and genetic counselors, as there are likely more undiagnosed children with similar symptoms who have mutations in their CAMK2A gene,” explains co-first author Dr. Franklin Zhong, research scientist in Reversade’s lab at A*STAR.
“Neuroscientists working to understand childhood brain development, neuronal function and memory formation also need to consider this new disease, since CAMK2A is associated with these processes. In future, it would be interesting to test whether restoring CAMK2A activity can bring therapeutic benefit to patients with this condition, as well as those with related neurological disorders.”