New developmental disorder discovered: Variations in the UNC13A gene cause neurological impairments in children

Problems speaking or walking, muscle tremors, and seizures – in a large interdisciplinary collaboration, researchers led by Noa Lipstein and Nils Brose have discovered a new developmental disorder that can be traced back to variations in the UNC13A gene. The findings not only open up treatment options for those affected, but also offer new insights into other neurological diseases, such as amyotrophic lateral sclerosis (ALS).

Researchers have discovered a new developmental disorder: variants of the UNC13A gene cause severe neurological impairments. The team has identified three different forms of the the developmental disorder: Depending on the gene variant, affected individuals exhibit different symptoms of diverse severity and have different underlying molecular mechanisms. In the future, antisense oligonucleotide therapies that exclusively suppress the production of disease-causing UNC13A protein copies could alleviate the symptoms in two forms of the disease.

Whether we are writing an email, rushing for a bus, or humming a tune, every thought, feeling, and action relies on communication between our roughly 100 billion nerve cells. This exchange of information happens at synapses, where messenger substances are passed from one cell to another. One key player in this process is the protein UNC13A (Munc13-1), which enables the release of neurotransmitters – the messenger substances of the brain. Beyond that, UNC13A is also essential for the adaptability of synapses, a property crucial for learning and memory.

New developmental disorder

Variations in the UNC13A gene, which contains the blueprint for the UNC13A protein, can trigger a previously unknown neurological developmental disorder. This was discovered by research led by Nils Brose at the Max Planck Institute for Multidisciplinary Sciences (Göttingen, Germany) and Noa Lipstein, formerly a member of Brose’s department and now group leader at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (Berlin, Germany) and ECN member, together with clinical geneticists Anita Rauch (University of Zurich, Switzerland) and Reza Asadollahi (University of Greenwich, UK). Their findings were recently published in the journal Nature Genetics.

In collaboration with multiple clinics worldwide, they have so far identified 50 patients diagnosed with this syndrome – and many of them have now received an explanation for its cause. The spectrum of impairments caused by the gene alterations ranges from delayed development and intellectual disabilities to impaired speech and motor function, tremors, and epileptic seizures. In some cases, it can even lead to death in early childhood.

Three forms of developmental disorder

Brose’s Department of Molecular Neurobiology has studied the function of the UNC13A protein for many years. This long-term effort allowed the team to decipher the causes of the developmental disorder at the molecular level. Using electrophysiological studies on mice and the nematode C. elegans, the research team investigated how different genetic variations of the UNC13A gene affect the function of nerve cell synapses. So far, the researchers have identified the mechanisms by which genetic variants in 20 patients cause disease.

“The symptoms vary depending on which function of the UNC13A protein is affected,” explains Lipstein. “The disorder can be grouped into three subtypes, each of which is caused by different impairments in nerve cells communication. Each subtype causes its own set of symptoms and therefore requires its own therapeutic approach, even though the cause lies in the same gene,” she emphasizes.

Approaches for new therapies

The researchers’ findings offer hope for new therapies: “For example, antisense oligonucleotide therapies, which suppress the production of disease-causing proteins and thus increase the relative abundance of normal UNC13A protein, could potentially reduce the symptoms of two forms of this developmental disorder,” Brose says. The new findings may also aid in the development of treatments for neurodegenerative diseases, such as ALS, frontotemporal dementia, and Alzheimer’s disease. Recent studies have shown that altered UNC13A protein production is a key factor in the progression of these diseases.

“Our studies highlight the importance of long-term basic research. Identifying the precise molecular basis of this developmental disorder is a crucial step toward developing future treatment methods”, Lipstein notes.

Publication: Asadollahi, R., Ahmad, A., Boonsawat, P. et al. Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function. Nat Genet (2025). doi.org/10.1038/s41588-025-02361-5

Source: Press release FMP

Nerve cells (green) form neural networks in which information is transmitted. Errors in this communication can lead to neurodegenerative, neurological, and neuropsychiatric diseases. © Pia Venneker