Broadening the picture of GNAO1 encephalopathies
Mutations in the GNAO1 gene are a well-known cause of severe neurodevelopmental disorders, most often associated with early-onset epilepsy, movement problems, and developmental delay. However, the full clinical spectrum of GNAO1-related disorders is not yet fully understood.
A new subcategory of the disease with milder symptoms
The GNAO1 gene encodes Gαo, a key signaling protein in the brain. In a recent study published in the Molecular Autism journal, researchers from the laboratory of Prof. Vladimir Katanev describe two children with severe speech disorders and intellectual disability, one from UK and one from Germany, who carry new GNAO1 mutations. They also analyzed a third, previously reported patient from Australia with similar symptoms.
The three patients with severe speech disorders and intellectual disability, but no movement disorders are localized in UK, Germany and Australia.
The research team uncovered profound alterations in the signaling activity of the Gαo protein and in its interactions with key regulatory partners. Despite these disruptions, the mutant proteins were correctly localized at the cell membrane, pointing to a disease mechanism distinct from that seen in more typical GNAO1-related encephalopathies
Our findings show that GNAO1 mutations can affect speech development, even without the movement disorders usually associated with this gene.
Potential implications
Despite presenting unusual features and no movement disorders, all three variants responded to zinc treatment. Previously reported only in more severe cases, this suggests that zinc may represent a potential therapeutic option for these patients.
Together, these findings expand both the clinical and mechanistic understanding of GNAO1-related disorders and reinforce the importance of including GNAO1 in genetic testing for children with severe speech disorders and intellectual disability, even without seizures or movement problems. Studying more patients will be crucial to better link specific genetic changes to symptoms and guide personalized treatment.